This question is typical and quite easy. The antihypertensive drugs that have been shown to slow the progression of diabetic nephropathy are the ACE inhibitors and ARAIIs. Specifically, angiotensin II receptor blockers have demonstrated their efficacy in this field for type 2 DM, which together with the side effects that IECAS produce in the patient makes an ARAII the drug of choice. This does not seem to me to be an open question (without going into pharmacoeconomic issues, of course...).

This question is typical and quite easy. The antihypertensive drugs that have been shown to slow the progression of diabetic nephropathy are the ACE inhibitors and ARAIIs. Specifically, angiotensin II receptor blockers have demonstrated their efficacy in this field for type 2 DM, which together with the side effects that IECAS produce in the patient makes an ARAII [HIDDEN]. This does not seem to me to be an open question (without going into pharmacoeconomic issues, of course...).

A 58-year-old woman comes for a follow-up visit for diabetes mellitus and hypertension. She feels well but states that she has stopped taking verapamil because of constipation. She presents with intolerance to ACE inhibitors due to coughing. On examination, blood pressure is 156/92 mm Hg. CBC includes a creatinine of 1.6 mg/dL, 24-hour urine protein excretion of 1.5 g/day, and a creatinine clearance of 45 ml/min. On this basis, what is the most effective treatment to slow the progression of the patient's type 2 diabetic nephropathy?

Angiotensin converting enzyme inhibitor.

Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies.

Blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or with angiotensin II type 1 (AT1) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies. Additionally, this beneficial effect is not dependent on blood pressure control. To assess and compare the effects of lisinopril (up to 40 mg/day), candesartan (up to 32 mg/day) and combination therapy (lisinopril up to 20 mg/day plus candesartan up to 16 mg/day) on urinary protein excretion, 45 patients with primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8+/-2.4 g/g) and normal or slightly reduced renal function (CCr 95+/-33 mL/min) were enrolled in a six month multicenter, prospective, open, randomized, active-controlled and parallel-group trial with 1:1:1 allocation. Blood pressure goal was set at or below 125/75 mm Hg for all patients, with additional antihypertensive medication prescribed if required. Renal function, estimated by creatinine clearance, remained stable throughout the study. Hyperkalemia (K>5.5 mmol/L) was detected in 3.1% of all measurements in follow-up, and was more frequent in patients treated with lisinopril alone or lisinopril plus candesartan (P<0.001) than in those on candesartan alone. No other relevant adverse event was recorded. The blood pressure goal (<125/75 mm Hg) was achieved by week 4 in all treatment groups (P<0.005 when compared to baseline), and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically significant differences between groups. Urinary protein/creatinine ratio (percentage reduction 95% confidence intervals CI) decreased in patients treated with lisinopril alone to -33% (CI -12-56) to -31% (CI 0-68) and to -50% (CI -9-90), in patients treated with candesartan to -28% (CI -12-45), to -41% (CI -30-52) and to -48% (CI -32-63), in patients treated with the combination of both to -60% (CI -44-77) to -54% (CI -38-69) and to -70% (CI -57-83) at two, three, and six months, respectively. All comparisons with baseline achieved statistical significance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with candesartan alone at two and six months (P=0.004 and P=0.023, respectively) and than treatment with lisinopril only at two months (P=0.03). Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated.

Pharmacologic management of diabetic nephropathy.

Diabetes mellitus and hypertension are leading causes of end stage renal disease in the United States. Drug therapy that focuses on tight glycemic control and blood pressure control reduces the progression of nephropathy and cardiovascular complications. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the progression of renal disease in patients with diabetes. The angiotensin II receptor blockers (ARBs) losartan and irbesartan have also been shown to reduce microalbuminuria compared with placebo. The nondihydropyridine calcium channel blockers (CCBs) verapamil and diltiazem have been shown to be as effective as an ACE inhibitor in reducing urinary albumin excretion. This paper reviews the pathophysiology and diagnosis of diabetic nephropathy and recent clinical trials assessing the most appropriate therapeutic options for delaying the progression of nephropathy in patients with diabetes. Primary and review articles that addressed the pathophysiology, diagnosis, and therapeutic options for attenuating the progression of diabetic nephropathy were retrieved through a MEDLINE search (January 1990 to August 2002) and the bibliographies of identified articles were reviewed. English-language sources were searched using the following search terms: diabetes mellitus, nephropathy, proteinuria, ACE inhibitors, and ARBs. Studies published in peer-reviewed journals that were determined to be methodologically sound, with appropriate statistical analysis of the results, were selected for inclusion in this review. Patients with type 1 diabetes mellitus and evidence of nephropathy should be started on an ACE inhibitor unless contraindicated. The ARBs and ACE inhibitors are viable choices for patients with type 2 diabetes mellitus and evidence of proteinuria. Patients who experience adverse events such as dry cough with ACE inhibitors can be switched to ARBs. Clinical literature suggests that if monotherapy with an ACE inhibitor or ARB does not provide an adequate response, a nondihydropyridine CCB should be added to the regimen. Nondihydropyridine CCBs should also be considered when ACE inhibitors and ARBs are contraindicated. ACE inhibitors and ARBs should be considered first-line therapy for patients with type 2 diabetes mellitus and nephropathy. The ACE inhibitors are still the drug of choice for patients with type 1 diabetes mellitus and evidence of incipient or overt nephropathy. If therapeutic goals are not achieved with an ACE inhibitor or ARB, then the addition of a nondihydropyridine CCB should be considered.

Current recommendations for the treatment of hypertension: are they still valid?

Recent trials have helped to clarify indications for the initial pharmacological therapy of hypertension. Both the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) and World Health Organization-international Society of Hypertension (WHO-ISH) recommendations should be revised. The more recent trials indicate that: (1) diuretics and beta-blockers appear to be as effective in reducing overall morbidity/ mortality as other agents (Swedish Trial in Old Patients with Hypertension [STOP-2], United Kingdom Prospective Diabetes Study [UKPDS], Intervention as a Goal in Hypertension Treatment [INSIGHT], Nordic diltiazem [NORDIL]); (2) the use of an a-blocker results in more cardiovascular events, especially congestive heart failure, when compared with a diuretic (Antihypertensive Therapy and Lipid Lowering Heart Attack Trial [ALLHAT]); (3)the use of an angiotensin-converting enzyme (ACE) inhibitor results in fewer myocardial infarctions and episodes of heart failure than calcium channel blockers in the elderly and in diabetic patients (Fosinopril vs. Amlodipine Cardiovascular Events Randomized Trial [FACET], Appropriate Blood Pressure Control in Diabetes [ABCD], STOP-2) - other data (Captopril Prevention Project [CAPPP]) suggest that the use of an ACE inhibitor is preferred in diabetic patients; (4) overall cardiovascular events are similar with calcium channel blockers compared with a diuretic - however, there are fewer strokes with non-dihydropyridine calcium channel blockers (NORDIL) and a trend towards an increase in heart failure and myocardial infarctions with either a dihydropyridine or non-dihydropyridine calcium channel blockers compared with a diuretic (INSIGHT, NORDIL); (5) angiotensin receptor blockers (ARBs) will decrease proteinuria and slow progression of renal disease in type 2 diabetic patients when compared with regimens that do not include an ARB or an ACE inhibitor (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL], Irbesartan Type II Diabetic Nephropathy Trial [IDNT], Irbesartan Type II Diabetes with Microalbuminuria [IRMA Il]). The debate over initial therapy may be moot. High-risk hypertensive patients should probably be treated initially with combination therapy, one of which should be a diuretic. The use of diuretics and beta-blockers as well as ACE-inhibitors alone or with a diuretic should be considered as initial therapy (a change from JNCVI). Alpha-blockers should be reserved for special situations, i.e. prostatic hypertrophy (in contrast to WHO-ISH recommendations). An ACE-inhibitor or ARB, usually along with a diuretic, can be considered as preferred therapy in hypertensive diabetic patients. Some data suggest equal or greater reduction in strokes with a calcium channel blocker than other medications.

[Renoprotective effect of triple therapy with low-dose angiotensin receptor blocker, low-dose diuretic and Ca-antagonist in hypertensive type 2 diabetic patients with overt nephropathy].

Combination therapy with angiotensin receptor antagonist(ARB) plus angiotensin converting enzyme inhibitor(ACE-I) (ARB/ACE-I) was efficacious in reducing proteinuria in patients with progressive renal disease. However, this therapy may be associated with the worsening of anemia and hyperkalemia. The present study addressed whether or not triple therapy with low-dose ARB, low-dose diuretic (D) and calcium channel blocker(CCB) (ARB/D/CCB) is as effective as therapy with low-dose ARB/ACE-I in retarding the progression of overt diabetic nephropathy. In the triple therapy, the patients were initially subjected to monotherapy with CCB for 24 weeks. Low-dose ARB and low-dose D were added to the treatment for an additional 24-week period. In parallel, patients undergoing double therapy were initially treated with low-dose ACE-I alone for 24 weeks, and then low-dose ARB was added for an additional 24-week period. The results were as follows: 1) In the triple therapy, blood pressure was reduced by 9 mmHg in systole and 5 mmHg in diastole (not significant) compared to monotherapy with CCB. There was a significant decline in proteinuria (3.3 +/- 1.2 g/day in the CCB-treated period vs. 2.1 +/- 1.0 g/day in the ARB/D/CCB-treated period, n = 12, p = 0.0143). Furthermore, a significant improvement in the slope of reciprocal serum creatinine concentration(1/Cr) was found in response to triple therapy(1/Cr: -0.0118 +/- 0.0009 in the CCB-treated vs. -0.0035 +/- 0.0028(I/mg/dl/month) in the ARB/D/CCB-treated period, n = 12, p < 0.001). There was neither a worsening of anemia nor an increase in the serum potassium(K) concentration. 2) In the double therapy, blood pressure was reduced by 12 mmHg in systole(p = 0.0079, n = 11) and 6 mmHg in diastole(n = 11, p = 0.0037) compared to the monotherapy with ACE-I. A significant improvement in the slope of 1/Cr was found in the double therapy(1/Cr: -0.0095 +/- 0.0052 in the ACE-I treated period vs. -0.0029 +/- 0.0028(I/mg/dl/month) in the ARB/ACE-I, n = 11, p < 0.001). In addition, there was a substantial reduction in hematocrit and increase in serum K concentration. The present result suggests that triple therapy consisting of ARB/D/CCB is as efficacious as double therapy with ARB/ACE-I in protecting the kidney from the progression in patients with diabetic overt nephropathy. The former may be expected to have less adverse effects.

Diabetic nephropathy

Blood pressure control: Multiple randomized clinical trials have demonstrated a benefit of decreasing systolic blood pressure to <140 mmHg in patients with diabetic nephropathy. High blood pressure is associated with accelerated development of microalbuminuria, over proteinuria and declining kidney function. Angiotensin-converting-enzyme inhibitors, as well as angiotensin II receptor blockers, are particularly helpful in patients with diabetes to lower blood pressure and slow the progression of nephropathy. More intensive blood pressure lower (125-130/<80) in patients with diabetic mellitus has been shown to decrease the risk of progression of diabetic nephropathy as well as other diabetic complications. Some patients might require dual therapy to adequately control pressure, in which case calcium channel blockers or diuretics are a good second-line option.

Angiotensin II receptor blocker

Medical uses Angiotensin II receptor blockers are used primarily for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy primarily because of persistent and/or dry cough. They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, in particular candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type 2 diabetes, and may delay the progression of diabetic nephropathy. A 1998 double-blind study found "that lisinopril improved insulin sensitivity whereas losartan did not affect it." Candesartan is used experimentally in preventive treatment of migraine. Lisinopril has been found less often effective than candesartan at preventing migraine.

Antihypertensive drug

The ratio of CCBs' anti-proteinuria effect, non-dihydropyridine to dihydropyridine was 30 to -2. ACE inhibitors ACE inhibitors inhibit the activity of angiotensin-converting enzyme (ACE), an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor. captopril enalapril fosinopril lisinopril moexipril perindopril quinapril ramipril trandolapril benazepril A systematic review of 63 trials with over 35,000 participants indicated ACE inhibitors significantly reduced doubling of serum creatinine levels compared to other drugs (ARBs, α blockers, β blockers, etc.), and the authors suggested this as a first line of defense. The AASK trial showed that ACE inhibitors are more effective at slowing down the decline of kidney function compared to calcium channel blockers and beta blockers. As such, ACE inhibitors should be the drug treatment of choice for patients with chronic kidney disease regardless of race or diabetic status.

Effects of ACE inhibition supplementary to beta blockers and diuretics in early diabetic nephropathy.

Angiotensin converting enzyme (ACE) inhibition has shown promising results in diabetic nephropathy, but long-term results on survival are not available. In a cohort of patients receiving antihypertensive treatment predominantly consisting of beta blockers in combination with diuretics, support for an improved survival has been presented. Addition of ACE inhibition to such a combination treatment may be favorable both due to the suggested renoprotective effects of ACE inhibitors and because diuretics activate the renin-angiotensin system. In 10 insulin-dependent diabetic patients with early diabetic nephropathy [urinary albumin excretion rate (UAE) less than 100o micrograms/min], who were receiving continuous therapy with metoprolol and bendroflumethiazide, a double-blind crossover study with four months addition of ramipril 5 mg (Ramace) and placebo was conducted. UAE (radioimmunoassay) and fractional albumin excretion were significantly reduced after the four months of ramipril administration [UAE: 114.1 x/divided by 1.3 (geometric mean x/divided by confidence factor] versus 174.6 x/divided by 1.2 micrograms/min, 2P less than 0.005). Renal plasma flow (clearance of 131I-hippuran) tended to increase [497 +/- 25 (mean +/- SE) vs. 464 +/- 28 ml/min/1.73 m2, 2P = 0.08], while GFR (125I-iothalamate) stayed unchanged (121 +/- 8 vs. 120 +/- 9 ml/min/1.73 m2). Mean arterial pressure during clearance studies fell moderately (95 +/- 3 vs. 101 +/- 1 mm Hg, 2P less than 0.05) and renal resistance was decreased (2P less than 0.03). ACE activity was suppressed in all patients. Twenty-four-hour ambulatory blood pressure measurements were not significantly different after the two periods (daytime averages: 91 +/- 2 vs. 93 +/- 2, nighttime 80 +/- 2 vs. 84 +/- 3 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy.

Treatment of hypertension with ACE inhibitors in diabetic patients reduces proteinuria and slows progression of nephropathy compared with agents that do not maintain declines in proteinuria. Calcium channel blockers (CCBs) have variable effects on proteinuria; their long-term effects on progression of diabetic nephropathy are not known. The current study examines the hypothesis that CCBs that maintain reductions in proteinuria slow progression of nephropathy associated with non-insulin dependent diabetes mellitus (NIDDM) by a degree comparable to ACE inhibitors, given similar levels of blood pressure control. To test this hypothesis we randomized 52 patients with NIDDM associated nephropathy and hypertension, mean age of 63 +/- 8 years, to either the ACE inhibitor, lisinopril (N = 18), nondihydropyridine CCBs (NDCCBs), verapamil SR (N = 8) or diltiazem SR (N = 10), or the beta blocker, atenolol (N = 16). Goal blood pressure was < or = 140/90 mm Hg. Patients were followed for a mean period of 63 +/- 7 months. The primary end point was change in creatinine clearance (CCr) slope in each group. There was no significant difference in mean arterial pressure reduction among the groups over the study period (P = 0.14). The mean rate of decline in CCr was greatest in the atenolol group (-3.48 ml/min/year/1.73 m2; P < 0.0001). There was no difference in the CCr slopes between lisinopril and NDCCBs groups (P = 0.36). Proteinuria was reduced to a similar extent in the lisinopril and NDCCBs groups (P > 0.99). Therefore, in persons with renal insufficiency secondary to NIDDM, similar levels of blood pressure control with either lisinopril or NDCCBs slowed progression of renal disease to a greater extent than atenolol. Moreover, this enhanced slowing of renal disease progression correlated with sustained and significant reductions in proteinuria, findings not observed in the atenolol group.

Diabetics with hypertension not controlled with ACE inhibitors: alternate therapies.

If hypertension in patients with diabetes mellitus type II is not adequately controlled by angiotensin-converting enzyme inhibitors (ACE-i), a beta-blocker is frequently added as second-line therapy. Recently, large randomized trials demonstrated the beneficial effect of second-generation dihydropyridine calcium-channel blockers in these patients. These compounds are increasingly being used to replace beta-blockers. Withdrawal of beta-blockers may influence diabetic control and may cause rebound hypertension. Any rebound hypertension from beta-blocker withdrawal may not occur if the beta-blocker is replaced with a calcium-channel blocker. A calcium-channel blocker will influence vascular resistance (VR) and blood pressure differently than a beta-blocker. Thirty-four patients with diabetes mellitus type II and a resting diastolic blood pressure above 90 mm Hg despite enalapril 10 mg daily (or equipotent dosages of other ACE-i) for at least 3 months were treated in an open label sequential comparison with the same ACE-i in combination with the beta-blocker metoprolol 100 mg for 3 months, and, subsequently for 3 more months with the same ACE-i in combination with the dihydropyridine calcium-channel blocker lercanidipine 10 mg once daily. After 6 weeks, patients with a diastolic blood pressure above 90 mm Hg were titrated up to 200 mg metoprolol or 20 mg lercanidipine once daily. Patients were examined every 6 weeks during the trial, and after 2 weeks while receiving lercanidipine. In addition to blood pressure measurements, VR was measured by iridium strain gauge plethysmography and expressed in units (1 unit = 1 mm Hg/mL blood/100 mL tissue per minute). Two of 34 patients did not complete the protocol because of non-compliance with the lercanidipine treatment in the first 2 weeks of treatment. Their data are included in the analysis. No rebound hypertension 14 days after the change-over of therapies was observed. (Mean arterial pressures [MAPs] were not significantly different from the point of withdrawal of the beta-blockers.) However, heart rate rose from 69+/-7 to 94+/-10 beats/min (p < 0.001). After 3 months on lercanidipine, MAP fell by 6+/-10 mm Hg (p = 0.002) compared to the point of withdrawal of the beta-blocker. Vascular resistance fell by 6.28+/-11.91 units (p<0.01), while glucosylated hemoglobin (HbA1c) rose by 0.4+/-0.5% (p<0.001) and body weight rose by 0.6+/-0.6 kg (p < 0.01). Multiple regression analysis revealed significant associations between decrease in VR, increase in HbAlc, and decrease in MAP, and partial dependence of these variables on one another. In hypertensive patients with diabetes type II, replacement of ACE-i and metoprolol with ACE-i and lercanidipine does not appreciably influence metabolic control and does not cause rebound hypertension. Lercanidipine was more effective than metoprolol as a second-line antihypertensive drug in these patients. At least two mechanisms may be involved: withdrawal of a pressor effect from the beta-blocker, and calcium-channel-mediated vasodilation.

[Can angiotensin-converting enzyme inhibitor be used in chronic kidney disease patients with serum creatinine level greater than 266 micromol/L?].

Angiotensin-converting enzyme inhibitor (ACEI) has been demonstrated to have protective effect for patients with mild to moderate chronic kidney disease (CKD). However, little evidence is available for the benefit or side-effects of ACEI in treating patients with more severe CKD. A prospective, randomized controlled trial was performed to evaluate the renal protective effect and safety of ACEI in patients whose serum creatinine (Scr) levels were higher than 265 micromol/L. 168 CKD patients took benazepril for two months. 21 patients quitted the trial because of cough. The remaining 147 CKD patients were divided into two groups according to their Scr levels. Patients with Scr 133 - 265 micromol/L were included in group A (n = 55), and those with Scr 266-442 micromol/L were included in group B (n = 92). Furthermore, group B were divided randomly into two subgroups, B1 (n = 47) and B2 (n = 45). Benazepril was given (10 - 20 mg/d) as an intervention for group A and group B1. Additional calcium-channel antagonist and/or beta-blocker and/or vasodilator were used for blood pressure control in those two groups. Patients in group B2 served as controls who take calcium-channel antagonist and/or beta-blocker and/or vasodilator but not Benazepril. The target blood pressure is 125/75 mm Hg or less in all groups. All patients were followed for two years. Doubling of the baseline Scr level or end-stage renal disease with the need for dialysis was regarded as the major end point of the trial. (1) The magnitude of mean arterial pressure reduction was comparable in group A [(12.90 +/- 3.21) mm Hg], group B1 [(13.36 +/- 4.27) mm Hg] and group B2 [(10.38 +/- 3.85) mm Hg]. There was no significant change among them (P > 0.05 in all). (2) The magnitude of urinary protein reduction (Delta) in group A [(0.52 +/- 0.29) g/24 h], group B1 [(0.50 +/- 0.26) g/24 h] were much higher than that in group B2 [(0.19 +/- 0.13) g/24 h] (P < 0.05), but there was no significant difference between group A and B1 (P = 0.94). (3) By the end of two years, the percentages of cases reaching the major end point in group A, group B1 and group B2 were 19.23%, 40.90% and 51.35% respectively. There was significant difference among the three groups (chi(2) = 12.14, upsilon = 2, P = 0.002). (4) After two years of treatment, the left ventricular mass indexes and the percentages of left ventricular hypertrophy in group A, group B1 and group B2 were all decreased significantly. There were no statistical differences among the three groups. (5) The incidence of ACEI related adverse reactions, such as rapid increase of Scr more than 30%, dry cough or hyperkalemia were not different among the three groups. Benazepril slows the progression of CKD in patients with Scr higher than 266 micromol/L, it is safe in these patients.

Antihypertensive drug

However, ACE inhibitors (and angiotensin II receptor antagonists) should not be a first-line treatment for black hypertensives without chronic kidney disease. Results from the ALLHAT trial showed that thiazide-type diuretics and calcium channel blockers were both more effective as monotherapy in improving cardiovascular outcomes compared to ACE inhibitors for this subgroup. Furthermore, ACE inhibitors were less effective in reducing blood pressure and had a 51% higher risk of stroke in black hypertensives when used as initial therapy compared to a calcium channel blocker. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. Notable side effects of ACE inhibitors include dry cough, high blood levels of potassium, fatigue, dizziness, headaches, loss of taste and a risk for angioedema. Angiotensin II receptor antagonists

Angiotensin II receptor blocker

Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system. Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. They selectively block the activation of the AT1 receptor, preventing the binding of angiotensin II compared to ACE inhibitors. ARBs and the similar-attributed ACE inhibitors are both indicated as the first-line antihypertensives in patients developing hypertension along with left-sided heart failure. However, ARBs appear to produce less adverse effects compared to ACE inhibitors.

Angiotensin converting enzyme inhibitors versus calcium antagonists in the treatment of diabetic hypertensive patients.

Angiotensin converting enzyme inhibitors and calcium antagonists are effective agents for controlling high blood pressure in diabetic patients. We selected 30 type II diabetic patients with proteinuria and evaluated the effect of these drugs on renal function and proteinuria. In a double-blind trial, patients received either 40 mg/day enalapril or 40 mg/day nifedipine during 12 months. They also received a hypoproteic diet with 0.8 g/kg wt/day of protein. In the enalapril group (10 men and eight women), mean arterial blood pressure was 112.0 +/- 12 mm Hg, creatinine clearance was 58.6 +/- 12.4 ml/min, and 24-hour proteinuria was 4.36 +/- 3.23 g/24 hr before treatment. After treatment, mean arterial blood pressure was 82.0 +/- 8.30 mm Hg (p less than 0.001), creatinine clearance was 66.6 +/- 13.8 ml/min (NS), and 24-hour proteinuria was 0.56 +/- 0.78 g/24 hr (p less than 0.001). In the nifedipine group (six men and six women), mean arterial blood pressure was 114.0 +/- 8.0 mm Hg, creatinine clearance was 67.8 +/- 19.6 ml/min, and 24-hour proteinuria was 2.84 +/- 1.31 g/24 hr before treatment. After treatment, mean arterial blood pressure was 86.0 +/- 7.0 mm Hg (p less than 0.001), creatinine clearance was 51.4 +/- 7.9 ml/min (p less than 0.001), and 24-hour proteinuria was 2.66 +/- 0.89 g/24 hr (NS). These results show a similar hypotensive action and different renal effects between these two drugs after 12 months of treatment.

Beta blocker

A 2007 study revealed diuretics and beta blockers used for hypertension increase a patient's risk of developing diabetes mellitus, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes. Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta blockers as first-line treatment of hypertension due to the risk of diabetes.

Diabetic nephropathy

The status of diabetic nephropathy may be monitored by measuring two values: the amount of protein in the urine - proteinuria; and a blood test called the serum creatinine. The amount of the proteinuria reflects the degree of damage to any still-functioning glomeruli. The value of the serum creatinine can be used to calculate the estimated glomerular filtration rate (eGFR), which reflects the percentage of glomeruli which are no longer filtering the blood. Treatment with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, which dilates the arteriole exiting the glomerulus, thus reducing the blood pressure within the glomerular capillaries, which may slow (but not stop) progression of the disease. Three classes of diabetes medications – GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors– are also thought to slow the progression of diabetic nephropathy.

[Are all antihypertensive drugs renoprotective?].

Blood pressure, together with proteinuria, represents one of the most important factors in the progression of chronic renal failure (CRF). Antihypertensive therapy is beneficial to slow down the progression of a variety of chronic renal diseases, no matter what the cause. Intraglomerular hypertension, increased glomerular permeability and proteinuria should be identified, since they can be treated to prevent or minimize further glomerular injury. But not all antihypertensive drugs are equally effective to prevent the progression of CRF. Recent large trials indicate that blood pressure lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an additive renoprotective effect in diabetic and nondiabetic renal diseases. In nondiabetic patients, the AIPRI and REIN studies support that angiotensin-converting enzyme (ACE) inhibitors have a long-term renoprotective effect. The benefits of ACE inhibitors can be demonstrated even in patients who are not hypertensive. Angiotensin II receptor antagonists are shown to be renoprotective in type 2 diabetics (RENAAL and IDNT). However, whether these renoprotective effects are due to blood pressure reduction or due to the specific pharmacologic RAAS blockade is still a matter of debate. This discussion is still open, because the reduction in blood pressure levels was lower in patients treated with a drug that interferes with the RAAS compared with other antihypertensive regimens. It is concluded that both ACE inhibitors and AT II receptor antagonists are lowering the intraglomerular pressure independent of any change in systemic blood pressure by dilatation of the efferent arteriole of the glomerulus. These additional nonpressure-related effects may protect renal function by their antiproteinuric effect. In addition, beneficial effect of ACE inhibitors are related to reduction of AT II, which has potent proinflammatory effects independent of its hemodynamic influences. Other drugs, such as diuretics, beta blockers, and hydralazine, do not induce efferent dilatation and, therefore, may be less likely to reverse intraglomerular hypertension. For example, hydralazine and nifedipine appear to produce prominent afferent or preglomerular arteriolar dilatation. This will allow more of the systemic pressure to be transmitted to the glomerulus. Therefore, short-acting dihydropyridine calcium channel blockers (CCB) are not recommended. By comparison, long-acting dihydropyridines such as diltiazem and verapamil are less potent vasodilators and may primarily decrease the resistance of the efferent arteriole, similar to the ACE inhibitors. They may have an antiproteinuric activity. Yet, there is lack of large prospective randomized trials.A beta blocker as antihypertensive agent is indicated as second- or third-line drug especially in patients with additional cardiovascular disease. Other antihypertensive drugs can be added as necessary to achieve the treatment goals for arterial hypertension. The use of a diuretic will often be helpful in patients who already have renal insufficiency, since fluid overload is an important cause of hypertension and may also enhance the effectiveness of drugs that interfere with the RAAS. alpha(1)-receptor or sympathetic blockers are further possible drugs for combination antihypertensive therapy.

Management of hypertension

Unacceptable combinations are non-dihydropyridine calcium blockers (such as verapamil or diltiazem) and beta-blockers, dual renin–angiotensin system blockade (e.g., angiotensin converting enzyme inhibitor + angiotensin receptor blocker), renin–angiotensin system blockers and beta-blockers, and beta-blockers and centrally acting medications. Combinations of an ACE-inhibitor or angiotensin II–receptor antagonist, a diuretic, and an NSAID (including selective COX-2 inhibitors and non-prescribed medications such as ibuprofen) should be avoided whenever possible due to a high documented risk of acute kidney failure. The combination is known colloquially as a "triple whammy" in the Australian health industry. Tablets containing fixed combinations of two classes of medications are available and, while convenient, may be best reserved for those who have been established on the individual components. Additionally, the use of treatments with vasoactive agents for people with pulmonary

[Antihypertensive therapy in diabetes mellitus].

Approximately 150 million people worldwide have diabetes mellitus, of whom 90% are type II diabetics. It is therefore of no surprise that diabetic nephropathy has become the leading cause of end-stage renal disease. Opposite to what has been known previously, kidney disease is at least as common in type II as in type I diabetes. However, because the majority of type II diabetics has hypertension for many years before diabetes mellitus becomes clinically relevant, renal lesions are often heterogeneous with frequent exclusive presence of ischemic changes. For the treatment of hypertension in diabetics without nephropathy (no microalbuminuria), drugs that exert beneficial effects or are at least neutral with respect to lipid and glucose metabolism, such as ACE inhibitors, angiotensin II-receptor antagonists, non-dihydropyridine-calcium channel blockers and the thiazide-like indapamide, are to be preferred. Although metabolically neutral, dihydropyridine calcium channel blockers should be used with caution, since an increase in cardiovascular morbidity and mortality in type II diabetics treated with these compounds has most recently been described. Once that diabetic nephropathy is established, blood pressure should be lowered to 120/80 mmHg (measured in seated position). Antihypertensive treatment should primarily be based on ACE inhibitors; angiotensin II-receptor antagonists are a valuable alternative if ACE inhibitors are not tolerated. Both ACE inhibitors and angiotensin II-receptor antagonists should be used with high caution in elderly patients with severe atherosclerosis in whom acute renal failure could occur due to the presence of bilateral renal artery stenosis. Newer studies indicate that non-dihydropyridine calcium channel blockers such as verapamil and diltiazem may be as effective as ACE inhibitors in preserving renal function in diabetic nephropathy. A fix-dose combination of the ACE inhibitor trandolapril with verapamil is now available; it should be reserved for patients whose blood pressure and/or proteinuria can not be adequately controlled with ACE inhibitors. Finally, indapamide is the only antihypertensive diuretic with nephroprotective properties.

Antihypertensive drug

Chronic kidney disease. ACE inhibitors or ARBs should be included in the treatment plan to improve kidney outcomes regardless of race or diabetic status. Late-stage Dementia should consider Deprescribing antihypertensives, according to the Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) Diabetes mellitus. The ACE inhibitors and angiotensin receptor blockers have been shown to prevent the kidney and retinal complications of diabetes mellitus. Gout may be worsened by thiazide diuretics, while losartan reduces serum urate. Kidney stones may be improved with the use of thiazide-type diuretics Heart block. β-blockers and nondihydropyridine calcium channel blockers should not be used in patients with heart block greater than first degree. JNC8 does not recommend β-blockers as initial therapy for hypertension

Proteinuria

Analysis It is possible to analyze urine samples in determining albumin, hemoglobin and myoglobin with an optimized MEKC method. Treatment Treating proteinuria mainly needs proper diagnosis of the cause. The most common cause is diabetic nephropathy; in this case, proper glycemic control may slow the progression. Medical management consists of angiotensin converting enzyme (ACE) inhibitors, which are typically first-line therapy for proteinuria. In patients whose proteinuria is not controlled with ACE inhibitors, the addition of an aldosterone antagonist (i.e., spironolactone) or angiotensin receptor blocker (ARB) may further reduce protein loss. Caution must be used if these agents are added to ACE inhibitor therapy due to the risk of hyperkalemia. Proteinuria secondary to autoimmune disease should be treated with steroids or steroid-sparing agent plus the use of ACE inhibitors.

Amiloride

minimal efficacy. For people with resistant hypertension, already taking a thiazide diuretic, an angiotensin converting enzyme inhibitor (ACE-i) or an angiotensin II receptor blocker (ARB), and a calcium channel blocker, the addition of amiloride (or spironolactone) was better at reducing blood pressure than adding a beta-blocker (bisoprolol) or an alpha-1 blocker (doxazosin). When combined with hydrochlorothiazide, the addition of amiloride had positive effects on blood pressure and blood sugar tolerance. Amiloride may therefore be useful for preventing the metabolic side effects of thiazide diuretics, allowing for the use of higher thiazide doses (in line with how they were originally studied).

Antihypertensive drug

In the United States, the JNC8 (Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) recommends thiazide-type diuretics to be one of the first-line drug treatments for hypertension, either as monotherapy or in combination with calcium channel blockers, ACE inhibitors, or angiotensin II receptor antagonists. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. Despite thiazides being cheap and effective, they are not prescribed as often as some newer drugs. This is because they have been associated with increased risk of new-onset diabetes and as such are recommended for use in patients over 65 where the risk of new-onset diabetes is outweighed by the benefits of controlling systolic blood pressure. Another theory is that they are off-patent and thus rarely promoted by the drug industry.

Outcome survey in unselected hypertensive patients with type 2 diabetes mellitus: effects of ACE inhibition.

Although the benefit of angiotensin converting enzyme (ACE) inhibitors in diabetic nephropathy is well documented in double-blind randomized, controlled clinical trials, it is uncertain whether the benefit extends to unselected patients with diabetes mellitus and arterial hypertension in general practice. In 2504 unselected patients with type 2 diabetes mellitus (mean age 63+/-10 years) blood pressure, cardiovascular, renal, and metabolic parameters were assessed at baseline and during a treatment period of 1 year with the ACE inhibitor cilazapril by primary care physicians. The average dose of cilazapril was 2.5 mg/day. Outcome measures were blood pressure, serum creatinine, proteinuria (dip stick), HbA1c levels, evaluation of edema, and exertional dyspnea. In the study cohort, systolic blood pressure decreased by 24+/-17 mm Hg and diastolic blood pressure by 12+/-11 mm Hg. An increase in serum creatinine (> 0.2 mg/dL) occurred more frequently in patients with than in those without renal involvement (19% v 7%; P < .05). Serum creatinine decreased more frequently in patients with renal involvement than in those without (26%+/-4% v 12%+/-3.8%; P < .05). Overall renal function in patients with diabetic nephropathy (n = 318) improved (2.1+/-1.6 mg/dL v 1.7+/-1.4 mg/dL; P < .05). The frequency of proteinuria was lower after 1 year than at baseline (62%+/-9% v 82%+/-8%; P < .05). Metabolic control of diabetes mellitus improved in parallel (median HbA1c 8.0% v 7.0%; P < .01). Scores for edema formation and exertional dyspnea improved as well (P < .01). In this outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively lowered blood pressure, which was associated with an improvement in glucose metabolism, cardiac function, and renal function.

Diabetic nephropathy

RAAS inhibition: Inhibition can be achieved with multiple therapies, mainly ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid antagonists. RAAS inhibition has been proven to be the most effective therapy to slow the progression of diabetic nephropathy in all stages. Although RAAS blockade using more than one agent may further reduce proteinuria, the risk of adverse events (such as hyperkalemia, acute kidney injury) outweigh the potential benefits. Therefore, it is recommended that only one agent is used in patients with DM who have hypertension or any signs of microalbuminuria or diabetic nephropathy.

Lisinopril

Lisinopril is a medication of the angiotensin-converting enzyme (ACE) inhibitor and is considered to be a gold standard drug in the treatment of high blood pressure, and is also used to treat heart failure and after heart attacks. For high blood pressure it is usually a first line treatment. It is also used to prevent kidney problems in people with diabetes mellitus. Lisinopril is taken by mouth. Full effect may take up to four weeks to occur. Within the ACE Inhibitor class, Lisinopril has shown to have less interindividual variability within the drugs, making it a preferable choice for patients with angina and hypertension. Common side effects include headache, dizziness, feeling tired, cough, nausea, and rash. Serious side effects may include low blood pressure, liver problems, high blood potassium, and angioedema. Use is not recommended during the entire duration of pregnancy as it may harm the baby. Lisinopril works by inhibiting the renin–angiotensin–aldosterone system.

[Prolonged treatment of hypertension in diabetic patients with enalapril. 1-year follow-up].

In view of the pharmacological and chemical reasons for using ACE-inhibitors to treat diabetic hypertension, a group of 40 outpatients were treated with Enalapril. The sample consisted of 20 outpatients, 6 males, 14 females aged 48-76 (mean age 63.75), 18 of whom had type II and 2 type I diabetes and 11 under treatment by diet and hypoglycaemic drugs or insulin. All these patients presented slight or moderate essential arterial hypertension (diastolic pressure less than 115 mmHg). For about one year 17 of the patients were given 20 mg/die Enalapril and the remaining three 10 mg/die in a single morning dose. In 16 cases no other treatment was given. In 4 a non-potassium conserving diuretic was also given. Check-ups before six months into and at the end of treatment showed: a statistically significant reduction in systolic (p less than 0.05) and diastolic (p less than 0.01) pressure. In contrast no significant change was noted in heart beat, glycaemia before or after meals, body weight, glycosylated haemoglobin or any other blood chemical parameter considered. In one case only there was a slight increase in proteinuria that was however present at the start of treatment. As far as side effects are concerned there was one case of cardiac palmus during treatment and one case of coughing that regressed totally when treatment was suspended but nothing else of significance. It should be noted that the antidiabetic treatment remained unchanged throughout the period considered in most cases and at most was subjected to minimal qualitative and quantitative adjustments.

Is antihypertensive treatment the same for NIDDM and IDDM patients?

The prevalence of abnormally elevated albumin excretion rate (> 30 mg/24 h) is approximately 40% in insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients. Diabetes has become the leading cause of end-stage renal failure in the US, Japan and Europe. Approximately 90% of the direct and indirect cost of caring for diabetic patients are spent on the complications of diabetes. Identification of patients at high risk of developing diabetic nephropathy is possible by screening for microalbuminuria (30-300 mg/24 h). Elevated urinary albumin excretion rate indicates a substantially increased mortality risk in diabetic patients. Randomised controlled trials in normotensive IDDM and NIDDM patients with persistent microalbuminuria indicate that ACE inhibitors diminish urinary albumin excretion rate, postpone it and may even prevent progression to clinical overt nephropathy. These findings indicate that screening and intervention programs are likely to have life saving effects and lead to considerable economic savings. Systemic blood pressure elevation to a hypertensive level is an early and frequent phenomenon in diabetic nephropathy. Furthermore, nocturnal blood pressure elevation (non-dippers) occurs more frequently in patients with nephropathy. Systemic blood pressure elevation and to a lesser degree albuminuria accelerate the progression of diabetic nephropathy. Effective blood pressure reduction with non-ACE-inhibitors and/or ACE-inhibitors frequently in combination with diuretics: (a) reduces albuminuria; (b) delays the progression of nephropathy; (c) postpones renal insufficiency; and (d) improves survival in IDDM and NIDDM patients with diabetic nephropathy. A specific renal protective effect of ACE-inhibitors in diabetic nephropathy has been demonstrated in IDDM patients with moderately reduced kidney function (s-creatinine > 133 mumol/l) while the data conflict with NIDDM patients. Antihypertensive treatment for diabetic nephropathy simultaneously extends life and saves money. Finally, reduced risk of fatal and non-fatal cardiovascular events have been demonstrated when diabetic patients with isolated systolic hypertension are treated with blood pressure lowering agents. Absolute risk reduction with active treatment compared to placebo was twice as great for the diabetic versus non-diabetic patients (101/1000 versus 51/1000 randomised participants at the 5-year follow-up), reflecting the higher risk of diabetic patients. In conclusion, early detection and aggressive treatment of arterial hypertension with ACE-inhibitors, long acting calcium antagonist and low dose diuretics as first line drugs are highly warranted in diabetic patients with or without diabetic renal disease.

2 year followup of patients with diabetes mellitus nephropathy showing albuminuria reversal following angiotensin converting enzyme inhibitors.

Two-year follow-up of patients with diabetes mellitus (DM) nephropathy shows albuminuria reversal following angiotensin converting enzyme (ACE) inhibitors. To study about a clinical profile of 2-year follow-up of patients with DM nephropathy showing albuminuria reversal following ACE inhibitors. Twenty patients were taken up for study with duly informed consent and suggested for glycemic profile with HbA1C. Baseline renal function, urine microscopy, albuminuria, and other microvascular complications such as neuropathy and retinopathy. These patients were followed up for a period of 2 years with every month follow-up and monthly dose titration of ACE inhibitors, enalapril (Quote: Dr. M. K. Mani), to a maximum tolerable dose and checked after 1 week for raise in creatinine and potassium. Twenty patients, who have attended a secondary level diabetic clinic with diabetic nephropathy and are on regular follow-up for 2 years, were selected. Sick patients requiring parenteral feeds, IV antibiotics, co-morbid conditions such as autonomic gastroparesis and diabetic foot infections, type 1 diabetes and other known kidney disease, chronic kidney disease on dialysis are excluded from the study. EXPECTED RESULT: Reversal of albuminuria. Enalapril is a safe, cheaper ACE inhibitors and the good dose titration coupled with early screening for DM nephropathy really help in halting the progression of chronic kidney disease from DM nephropathy.

Antihypertensive treatment inhibiting the progression of diabetic nephropathy.

In 6 male insulin-dependent proteinuric long-term diabetics aged 26-35 years the rate of progression of nephropathy was followed for an initial control period of 2.0 years and subsequently for 4.1 years during antihypertensive therapy with a beta-receptor blocker combined with Hydralazine and Furosemide. GFR and urinary albumin excretion was measured 3-4 times before and 9-14 times during treatment. Systolic blood pressure was reduced significantly from 162 +/- 14 (SD) mm Hg before treatment to 146 +/- 9 (SD) as a mean during the whole treatment period (2p = 0.002). Diastolic pressure was also reduced significantly, from 103 +/- 9 (SD) mm Hg to 95 +/- 8 (SD), (2p = 0.025). After 49 days of treatment there was a significant fall in albumin clearance as a per cent of GFR from 0.243 +/- 0.28 (SD) to 0.170 +/- 0.20 (SD), (2p < 0.001 for percentage change) with no change in GFR. In five patients the fall rate of GFR was in the initial control period 1.24 ml/min/month +/- 0.8 (SD). In the period when antihypertensive therapy was given it was reduced to 0.45 ml/min/month +/- 0.5 (SD) (2p = 0.037). In the 6th patient there was no decline in GFR neither before, nor during treatment. Before treatment there was a mean yearly percentage increase in albumin excretion of 107 per cent. During treatment this yearly increase was reduced to--7 per cent (2p = 0.002 for differences in slope). The results indicate that the state of renal insufficiency in diabetic patients with nephropathy and moderately increased blood pressure can be postponed by antihypertensive treatment. Other trials should be carried out to define the optimal scheme of treatment.

[Lercanidipine in diabetic patients with renal failure].

To evaluate the safe use of a new calcium channel blocker, lercanidipine, in diabetic chronic renal failure (CRF) patients. The study recruited 42 diabetic CRF patients (creatinine > 1.4 mg/dl for males, creatinine > 1.2 mg/dl for females, or creatinine clearance < 70 ml/min). Mean age was 68.2 +/- 9.1 years. 53.8% were males and 46.2% females. Three patients were type 1 diabetics and 39 ones were type II. All patients were receiving ACE inhibitors (67.4%) or angiotensin II antagonist (32.6%) therapy but they had higher blood pressure than recommended for CRF patients (130/85 mmHg). No patients were under diuretic treatment. Patients were clinically evaluated 1, 3 and 6 months after starting treatment with lercanidipine. Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment, excluding diuretics. Creatinine clearance was measured using 24 h urine collection. BP significantly decrease from 163 +/- 18/90 +/- 8 mmHg to 134 +/- 12/77 +/- 9 mmHg. One half of patients showed significant reduction of blood pressure, 26.7% reached the target blood pressure (< 130/85 mmHg) and 20.0% gets optimal BP control (< 130/85 mmHg). No one patient showed untoward effects. No edema was detected nor adverse effects related to vasodilatation were found. Plasmatic creatinine did not change (1.9 +/- 0.5 baseline vs 1.8 +/- 0.5 mg/dl) and creatinine clearance increased at the end visit (40.1 +/- 14.5 baseline vs 45.4 +/- 18.2 ml/min) but the difference was not significant. Proteinuria was unchanged. Lercanidipine showed a good antihypertensive effect in diabetics CRF patients. It has a good tolerability profile and showed neutral effect on plasmatic lipids. Neither impairment of renal function nor increment in proteinuria were detected.

A clinical trial in type 2 diabetic nephropathy.

A prospective, randomized, three-armed, double-blind, placebo-controlled clinical trial has been completed in 210 sites worldwide to determine whether the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine has a renoprotective effect in patients with overt type 2 diabetic nephropathy. A total of 1,715 subjects randomized during a 3-year period were followed a minimum of 2 years. The goal for all treatment groups was to achieve equivalent blood pressure control, with the blinded study drug (irbesartan, amlodipine, or placebo) as primary therapy with additional antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, calcium antagonists, and angiotensin II receptor antagonists, to achieve seated systolic blood pressure less than 135 mm Hg and diastolic blood pressure less than 85 mm Hg. The primary outcome was the combined endpoint of time to doubling of entry serum creatinine, end-stage renal disease, or death. Secondary outcomes included fatal and nonfatal cardiovascular events. A Clinical Management Committee monitored the conduct of the study. An Outcome Confirmation Committee classified all study outcome events in blinded fashion. An external Data Safety Monitoring Committee monitored unblinded data for interim safety and efficacy analyses of the study. Eligibility criteria included informed consent, age 30 to 70 years, adult-onset diabetes, hypertension, urine protein excretion greater than 900 mg/24 hours, and serum creatinine values of 90 to 265 micromol/L in women and 110 to 265 micromol/L in men. Baseline characteristics were age, 59 +/- 8 years; body mass index, 31 +/- 7 kg/m(2); 67% male; 73% white, 14% black, and 13% other; duration of diabetes, 15 +/- 9 years; retinopathy, 66%; neuropathy, 48%; congestive heart failure, 7.5%; screening seated systolic blood pressure, 156 +/- 18 mm Hg, and diastolic blood pressure, 85 +/- 11 mm Hg; urine protein excretion, 4.0 +/- 3.5 g/24 hours; serum creatinine, 150 +/- 53 micromol/L; serum potassium, 4.6 +/- 0.5 mEq/L; total cholesterol, 229 +/- 58 mg/dL; and hemoglobin A(1c), 8.1 +/- 1.7%. This large-scale international trial should help define the clinical course and standards of care for hypertensive adults with type 2 diabetes mellitus and nephropathy. Results available on May 19, 2001, will help in defining the current controversy of the risks and benefits of blockade of the renin-angiotensin system versus calcium channel blockade versus standard antihypertensive therapy in this large patient population.


Teratoma is the most frequent germinal tumor. It presents differentiation in elements of the three embryonic layers: endoderm, mesoderm and ectoderm. Macroscopically they can be cystic or solid, and histologically the tissues composing the tumor can be mature (well differentiated, like adult tissues) or immature (like embryonic tissues).Mature cystic teratoma is the most frequent: they represent on average 10% of ovarian tumors (5-25% depending on the casuistry). They occur at any age. They predominate in ectodermal tissues, such as skin, lining a cavity of keratinous content. In the cavity a spur is recognized from which hair or tooth structures often arise. Frequent tissues include: nervous tissue, usually glial and ependymal epithelium, respiratory and digestive epithelia and various mesodermal structures. They are bilateral in about 10% of cases. The mature cystic teratoma is benign, but in 2% of them a malignant tumor may develop from one of the tissue components (spinocellular carcinoma, carcinoid, adenocarcinoma, thyroid tissue carcinoma, sarcoma). In this case at first we thought that the option was mature cystic teratoma but thanks to Ramón, when we read it more carefully, we found that it had neuroectodermal and embryonal elements in several of the histological preparations, so we consider that the correct answer is 2.

Teratoma is the most frequent germinal tumor. It presents differentiation in elements of the three embryonic layers: endoderm, mesoderm and ectoderm. Macroscopically they can be cystic or solid, and histologically the tissues composing the tumor can be mature (well differentiated, like adult tissues) or immature (like embryonic tissues).Mature cystic teratoma is the most frequent: they represent on average 10% of ovarian tumors (5-25% depending on the casuistry). They occur at any age. They predominate in ectodermal tissues, such as skin, lining a cavity of keratinous content. In the cavity a spur is recognized from which hair or tooth structures often arise. Frequent tissues include: nervous tissue, usually glial and ependymal epithelium, respiratory and digestive epithelia and various mesodermal structures. They are bilateral in about 10% of cases. The mature cystic teratoma is benign, but in 2% of them a malignant tumor may develop from one of the tissue components (spinocellular carcinoma, carcinoid, adenocarcinoma, thyroid tissue carcinoma, sarcoma). In this case at first we thought that the option was mature cystic teratoma but thanks to Ramón, when we read it more carefully, we found that it had neuroectodermal and embryonal elements in several of the histological preparations, so we consider that [HIDDEN].

A 20-year-old woman with a 15-cm solid-cystic ovarian tumor detected by ultrasound after presenting with nonspecific abdominal symptoms. In the histopathological study of the corresponding specimen, teeth, hairs, areas of intestinal epithelium, areas of squamous epithelium (15%) and bronchial epithelium, as well as neuroectodermal and embryonic elements are found in several of the histological preparations. In reference to this case, point out the correct diagnosis:

Adenocarcinoma arising from the respiratory ciliated epithelium in a benign cystic teratoma of the ovary.

Benign cystic teratoma of the ovary (BCTO) is the most common benign ovarian tumor, accounting for 15-20% of all ovarian tumors. It is usually diagnosed in the third and fourth decades of life. Malignant transformation is rare, occurring in approximately 1-2% of reported cases, with squamous cell carcinoma being the most common form. Adenocarcinoma arising from mature cystic teratoma is extremely rare. We present the patient with a BCTO, where a malignant transformation of respiratory ciliated epithelium resulted in well differentiated adenocarcinoma. Although respiratory epithelium is often found in BCTOs, adenocarcinoma arising from this cell type is uncommon. To our knowledge, this is the fourth reported case of adenocarcinoma arising from the respiratory epithelium of a BCTO.

Malignant transformation of ovarian mature cystic teratoma with a predominant pulmonary type small cell carcinoma component.

A 68-year-old woman was diagnosed with mature cystic teratoma of the left ovary when she was 44 years old. The tumor recently enlarged rapidly, and abdominal magnetic resonance imaging revealed an intrapelvic cystic lesion, which measured 123 × 120 × 107 mm and contained a mural nodule. Under a clinical diagnosis of malignant transformation of mature cystic teratoma, bilateral salpingo-oophorectomy with total hysterectomy and omentectomy were performed. The resected specimen showed a unilocular cystic lesion containing a well-demarcated mural nodule measuring 35 × 30 × 25 mm in the left ovary. A microscopic examination revealed various types of carcinoma in the mural nodule: pulmonary type small cell carcinoma (65%), adenocarcinoma (25%), squamous cell carcinoma (5%), and transitional cell carcinoma (5%). Small cell carcinoma was positive for CD56, synaptophysin, and chromogranin A. The adenocarcinoma component showed intestinal phenotypes; i.e. cytokeratin (CK) 7(-), CK20(+), CDX2(+), estrogen receptor(-), and progesterone receptor (-). Interestingly, CDX2 positivity was retained in all of the carcinomas. It was assumed that the adenocarcinoma had arisen from an intestinal epithelium in the mature cystic teratoma and then differentiated into the diverse histological types mentioned above.

Ovarian Teratoma in Routine Biopsy Material During a Five-Year Period.

Teratomas are tumors derived from germ cells, most frequently arising in the gonads. The aim of this study was to determine the number of ovarian teratomas diagnosed in the routine biopsy material at Ljudevit Jurak Clinical Department of Pathology, Sestre milosrdnice University Hospital Center during a 5-year period, as well as their clinical, gross and microscopic characteristics. Teratomas accounted for 48.6% (n=166) of primary ovarian tumors. The patient mean age was 34.74±12.37 years. Difference in the incidence of teratoma between the left and right ovary was not significant; bilateral teratoma was found in 13 patients. Teratomas were detected by ultrasonography in 115 (69.27%) cases and the rest were found during surgery performed for other indications. Most teratomas (n=161; 96.9%) were mature and cystic (dermoid cysts). Mature and solid teratomas were diagnosed in 5 (3.01%), ovarian struma in 2 (1.8%) cases and strumal carcinoid in 1 (1.2%) case. Mature cystic teratomas contained sebaceous material in 123 (76.8%) cases, and a total of 16 teeth were found; 157 (94.5%) teratomas measured <10 cm in largest diameter. Microscopically, mature cystic teratomas most frequently contained ectodermal (skin with appendages, mature glia and nerve ganglia) and mesodermal (fi brous, fat tissue, cartilage and bone) tissues. Frequently found tissues of endodermal origin were respiratory and intestinal epithelia. Small foci of thyroid tissue were found in 20 (12%) teratomas. Chronic granulomatous foreign body reaction in the wall of mature cystic teratomas was found in 11 (6.8%) tumors.

A case of ovarian mature cystic teratoma presenting as a pedunculated ileal tumor.

We report on a 34-year-old Japanese woman who presented with a pedunculated ileal tumor and who was finally diagnosed as having a right ovarian mature cystic teratoma penetrating and protruding into the ileum. She had undergone laparoscopic left ovarian cystectomy, whose specimen was diagnosed as dermoid cyst when she was 27 years old. The colon fiberscope revealed an ileal polyp, diagnosed as mature teratoma. Because of adhesion to the necrotic nodule between the tumor and the right ovary, ileocecal resection and right ovarian cystectomy were performed. The ileal tumor contained tissues of skin, neuroglia, ganglion, choroid, retina, smooth muscle, as well as fibrous and adipose tissues, cartilage, bone, mucous epithelium, and bronchial structures with bronchial glands. The necrotic nodule showed abscess, granulation tissue, foreign body reaction, hairs, normal ileal epithelium, and the ovary with ovums.

A case of concomitant occurrence of struma ovarii and malignant transformation of cystic teratoma.

A 77-year-old woman received a total abdominal hysterectomy and bilateral salpingo-oophorectomy because of a tumor in the left ovary. The surgical specimen measured 8.5x4.5x4.0 cm, and the solid lesion measured 4.0x3.5x3.5 cm. The solid lesion was diagnosed as struma ovarii. The cyst wall partially comprised squamous epithelium-like and ciliated columnar epithelium-like cells. The tumorous lesion of the cyst wall revealed a poorly differentiated adenocarcinoma. Immunohistochemically, the tumor cells were positive for cytokeratin7, and were negative for cytokeratin20 and thyroid transcription factor-1. The authors diagnosed that struma ovarii and other parats coexisted as a poorly differentiated adenocarcinoma that had arisen from a mature ovarian cystic teratoma. As for the identification of the origin of adenocarcinomas arising from mature ovarian cystic teratomas, more cases need to be identified and investigated.

Well-differentiated cerebellum in an ovarian mature cystic teratoma: a case report and review of the literature.

Mature teratoma is the most common germ cell tumor as it represents 95% of germ cell tumors. Although common in children and young adults, ovarian teratoma can occur at any age. Mature teratomas are composed of mature tissues representing elements derived from more than one embryonic germ layer (ectoderm, mesoderm, and endoderm), with ectodermal derivatives being the usual predominant component; however, the finding of a well-differentiated cerebellum is extremely rare. A 20-year-old Saudi female presented to the emergency department with severe abdominal pain of 1-day duration. Pelvic ultrasound showed a large ovoid- to bilobed-shaped cystic pelvic structure extending to the lower abdomen. The patient underwent left ovarian cystectomy. Microscopic examination showed a cyst wall with skin tissue, including adnexal structures (sebaceous glands), a well-differentiated cerebellum, and mature glial tissue. After extensive sampling, no immature component was identified. Thus, the final diagnosis of a mature cystic teratoma with well-differentiated cerebellum was established. The patient was well postoperatively and was discharged in a stable condition. We report this case of well-differentiated cerebellum within ovarian teratoma to expand the pool of cases reported in literature of this extremely rare entity, as only 22 cases with such findings have been reported in literature to the best of our knowledge. This finding poses a diagnostic challenge to the pathologist due to its rarity and its similarity to immature teratoma. We thus emphasize that thorough sampling of ovarian teratoma is of paramount importance and to keep the aforementioned diagnosis in mind and not confuse it with immature elements, especially in intraoperative consultation and frozen sections.

Teratoma

Malignant transformation A "benign" grade 0 (mature) teratoma nonetheless has a risk of malignancy. Recurrence with malignant endodermal sinus tumor has been reported in cases of formerly benign mature teratoma, even in fetiform teratoma and fetus in fetu. Squamous cell carcinoma has been found in a mature cystic teratoma at the time of initial surgery. A grade 1 immature teratoma that appears to be benign (e.g., because AFP is not elevated) has a much higher risk of malignancy, and requires adequate follow-up. This grade of teratoma also may be difficult to diagnose correctly. It can be confused with other small round cell neoplasms such as neuroblastoma, small cell carcinoma of hypercalcemic type, primitive neuroectodermal tumor, Wilm's tumor, desmoplastic small round cell tumor, and non-Hodgkin lymphoma.

[Malignant transformation of thyroid tissue in an ovarian dermoid cyst: case report].

Mature cystic teratoma is the most common type of ovarian teratomas and also the most frequent tumor originating from germ cells. Usually unilateral, it is, by definition, composed of well-differentiated derivates which originate from all three layers. It is most frequently diagnosed in the female reproductive period; in its pure form, it is generally benign, but occasionally it may undergo malignant transformation in one of its elements. The authors report a case of a 43-year-old woman who underwent a thyroid regulation substitutive therapy 12 years after thyroidectomy which had been performed because of Basedow's disease. On the occasion of her fourth delivery by cesarean section, bilateral cystical formations in both ovaries were found. Upon ending the delivery, the right ovary with the cyst was surgically removed, as well as part of the cystically changed left ovary. The pathohistological analysis of the samples taken from the left ovary cyst pointed to the following diagnosis: dermoid cyst of the ovary a mature cystic teratoma, whereas the samples from the cystic tumor of the right ovary were diagnosed as: ovarian teratoma malignant a papillary carcinoma of the thyroid tissue and cystadenoma papillare serosum ovarii. The histological type of the malignant thyroid tissue neoplasm in the teratoma was a papillary carcinoma consisting of papillary proliferations lined by cuboidal, cylindrical and pseudostratified epithelium with charasteristic "ground glass" nuclei, but without invasion into the blood vessels. Malignant transformation of the ectopic thyroid tissue, which is one of the elements of the ovarian cystic teratoma, is extremely rare: it is diagnosed on basis of the histological picture and criteria which are the same as for the tumor of the thyroid gland. One should not exclude a pssibility that the identical or different pathological alterations characteristic of the thyroid gland may also be detected in the ectopic thyroid tissue of a dermoid cyst. The reported case was chosen due to its complex and rich clinical and pathohistological picture characterized by the occurrence of a bilateral dermoid cyst with the malignant transformation of the thyroid tissue. The malignant neoplasm in the mature ovarian cystic teratoma was papillary carcinoma of the thyroid tissue with all histological properties typical for the thyroid gland carcinoma. The possibility of the malignant transformation of the endodermal thyroid tissue in the mature ovarian cystic teratoma and changes in the thyroid gland of the Basedow's disease type diagnosed before are without clear causation.

Adenocarcinoma arising from respiratory ciliated epithelium in benign cystic teratoma of the ovary: a case report with analyzes of the CT, MRI, and pathological findings.

The malignant transformation of mature cystic teratoma is rare, thus occurring in only 1-2% of all cases. The most common malignancy arising in mature cystic teratoma is squamous cell carcinoma. Adenocarcinoma occurs with less frequency. We herein present a patient with an ovarian mature cystic teratoma who demonstrated a malignant transformation to well-differentiated adenocarcinoma. Malignant transformation was diagnosed preoperatively by contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Microscopically and immunohistochemically, the adenocarcinoma was considered to have arisen from the ciliated respiratory epithelium. After a 28-month of follow-up period, she remains free of the disease. This is the third reported case of adenocarcinoma arising in the respiratory epithelium of an ovarian mature cystic teratoma. Contrast enhanced CT and MRI are useful for making a preoperative diagnosis and an immunohistochemical study is helpful for defining its origin.

Ovarian cancer

Immature, or solid, teratomas are the most common type of ovarian germ cell tumor, making up 40–50% of cases. Teratomas are characterized by the presence of disorganized tissues arising from all three embryonic germ layers: ectoderm, mesoderm, and endoderm; immature teratomas also have undifferentiated stem cells that make them more malignant than mature teratomas (dermoid cysts). The different tissues are visible on gross pathology and often include bone, cartilage, hair, mucus, or sebum, but these tissues are not visible from the outside, which appears to be a solid mass with lobes and cysts. Histologically, they have large amounts of neuroectoderm organized into sheets and tubules along with glia; the amount of neural tissue determines the histologic grade. Immature teratomas usually only affect one ovary (10% co-occur with dermoid cysts) and usually metastasize throughout the peritoneum. They can also cause mature teratoma implants to grow throughout the abdomen in a disease

Immature teratoma

An immature teratoma is a teratoma that contains anaplastic immature elements, and is often synonymous with malignant teratoma. A teratoma is a tumor of germ cell origin, containing tissues from more than one germ cell line, It can be ovarian or testicular in its origin. and are almost always benign. An immature teratoma is thus a very rare tumor, representing 1% of all teratomas, 1% of all ovarian cancers, and 35.6% of malignant ovarian germ cell tumors. It displays a specific age of incidence, occurring most frequently in the first two decades of life and almost never after menopause. Unlike a mature cystic teratoma, an immature teratoma contains immature or embryonic structures. It can coexist with mature cystic teratomas and can constitute of a combination of both adult and embryonic tissue. The most common symptoms noted are abdominal distension and masses. Prognosis and treatment options vary and largely depend on grade, stage and karyotype of the tumor itself.

[Pelvic retroperitoneal teratoma. A case report].

Teratomas are congenital tumors comprising of tissues arising from pluripotent embryonic cells. Their common sites of occurrences are ovary, testis, mediastinum and retroperitoneum. Retroperitoneal teratomas are extremely rare in adults but occur in 3% of children. The presence of a cystic or complex adnexal mass during pregnancy is common with mature teratoma reported in approximately 30-50% of pregnancies. The ultrasound is the number one method of detection. The use of tumor markers is limited because it alters its value during pregnancy. We report a case of a 18 year old female patient who came to the General Hospital Dr. Miguel Silva in Morelia, Michoacán with a gestation age of 10.2 weeks and a recent diagnosis of an asymptomatic adnexal mass. Using the transvaginal approach, the ultrasound reported an irregular gestational sac with the absence of cardiac activity in the embryo. A diffusely echogenic adnexal mass with oval appearance, wall regularity and homogeneous internal echos of 12.96 x 8.99 cm. Exploratory laparotomy was performed finding normal uterus and ovaries, with the posterior retroperitoneal resection of the 15 cm multi-lobed tumor. The surgical specimen measured 13 x 12 x 8 cm, had a brownish color, wall irregularity, soft consistency, multi-lobed, and a yellowish interior greasy material. Microscopically the tumor is delimited with a firm capsule composed of a hyaline-fibrous tissue, lined by squamous keratinized epithelium, with multiple layers of keratin. This anato-pathologic finding is diagnostic of retroperitoneum mature teratoma.

[Benign mature teratomas of the mediastinum].

Mature teratomas of the mediastinum are rare. However, they represent the most common mediastinal germ cell tumours. The aim of this study is to describe their clinical and pathological characteristics. Fourteen cases of mediastinal mature teratoma, diagnosed between January 1992 and December 2006, were reviewed retrospectively, noting the clinical, radiological, surgical, and pathological findings. The patient population consisted of 10 females and 4 males with mean age of 29 years (5-56 years). Chest pain was the main symptom. Imaging features comprised a heterogeneous anterior mediastinal mass containing soft-tissue, fluid, fat, or calcium attenuation, or any combination of the four. Macroscopically all the tumours were cystic, or predominantly cystic, containing mostly grumous material. The mean size was 9 cm (5-12 cm). Histological examination constantly revealed skin with or without appendages. Other components identified were bronchial mucosa (12 cases), fat (12 cases), muscle (10 cases), cartilage (8 cases), bone (7 cases), gastrointestinal mucosa (7 cases), pancreas (5 cases), urothelial epithelium (3 cases), nervous and prostatic tissues (one case each). All the teratomas were mature, and 7 of them were intrathymic. Every form of teratoma occurs in the mediastinum (mature, immature and with malignant transformation) but, in our study, they were exclusively mature. The histology is essentially similar to that of teratomas of gonads. However, pancreatic tissue occurs frequently in mediastinum (54% in literature, 25% in our study) but not in the gonads. On the other hand, thyroid follicles have not yet been seen in mediastinal teratomas.

Ovarian germ cell tumors

Teratomas Teratoma are most common germ cell tumor of ovary. Teratomas can be divided into two types: mature teratoma (benign) and immature teratoma (malignant). Immature teratomas contain immature or embryonic tissue which significantly differentiates them from mature teratomas as they carry dermoid cysts. It is commonly observed in 15 to 19-year-old women and rarely in women after menopause. Immature teratomas are characterized with a diameter of 14–25 cm, encapsulated mass, cystic areas, and occasional appearance of hemorrhagic areas. The stage of immature teratomas is determined depending on the amount of immature neuroepithelium tissue detected. Yolk sac tumor

Dermoid cyst

A dermoid cyst is a teratoma of a cystic nature that contains an array of developmentally mature, solid tissues. It frequently consists of skin, hair follicles, and sweat glands, while other commonly found components include clumps of long hair, pockets of sebum, blood, fat, bone, nail, teeth, eyes, cartilage, and thyroid tissue. As dermoid cysts grow slowly and contain mature tissue, this type of cystic teratoma is nearly always benign. In those rare cases wherein the dermoid cyst is malignant, a squamous cell carcinoma usually develops in adults, while infants and children usually present with an endodermal sinus tumor. Location Due to its classification, a dermoid cyst can occur wherever a teratoma can occur. Vaginal and ovarian dermoid cysts

Adenocarcinoma arising from respiratory ciliated epithelium in mature ovarian cystic teratoma.

Malignant transformation of a mature cystic teratoma of the ovary is rare, that of an adenocarcinoma is extremely rare. A 32-year-old woman was suspected as having a malignant transformation of her mature cystic teratoma of the ovary because the preoperative level of carcinoembryonic antigen (CEA) was extremely high. Resections of her ovarian cysts were performed, and this particular tumor was histopathologically diagnosed as an adenocarcinoma arising from a mature cystic teratoma of the left ovary. Because adenocarcinomas arising from mature cystic teratomas of the ovary are extremely rare, we report this case with a review of some of the literature.

Immature teratoma

Ovarian cancer is staged using the FIGO staging system and uses information obtained after surgery, which can include a total abdominal hysterectomy via midline laparotomy, unilateral (or bilateral) salpingo-oophorectomy, pelvic (peritoneal) washings, assessment of retroperitoneal lymph nodes and/or appendectomy. The AJCC staging system, identical to the FIGO staging system, describes the extent of tumor (T), the presence of absences of metastases to lymph nodes (N), the presence or absence of distant metastases (M). Pathology An immature teratoma contains varying compositions of adult and embryonic tissue. The most common embryonic component identified in immature teratomas is the neuroectoderm. Occasionally, tumors may present neuroepithelium that resemble neuroblasts. Tumors may also present embryonic components such as immature cartilage and skeletal muscle of mesodermal origin. Immature teratomas composed of embryonic endodermal derivatives are rare.

Pathology_Robbins

Benign (mature) cystic teratomas are marked by the presence of mature tissues derived from all three germ cell layers: ectoderm, endoderm, and mesoderm. Usually these tumors contain cysts lined by epidermis replete with adnexal appendages—hence the common designation dermoid cysts. Most are discovered in young women as ovarian masses or are found incidentally on abdominal radiographs or scans because they contain foci of calcification produced by toothlike structures contained within the tumor. About 90% are unilateral, with the right side more commonly affected. Rarely do these cystic masses exceed 10 cm in diameter. On cut section, they often are filled with sebaceous secretion and matted hair that, when removed, reveal a hair-bearing epidermal lining ( Fig. 19.18 ). Sometimes there is a nodular projection from which teeth protrude. Occasionally, foci of bone and cartilage, nests of bronchial or gastrointestinal epithelium, or other tissues are present.

Teratoma

Types Mature teratoma A mature teratoma is a grade 0 teratoma. They are highly variable in form and histology, and may be solid, cystic, or a combination of the two. A mature teratoma often contains several different types of tissue such as skin, muscle, and bone. Skin may surround a cyst and grow abundant hair (see dermoid cyst). Mature teratomas generally are benign, with 0.17-2% of mature cystic teratomas becoming malignant. Immature teratoma Immature teratoma is the malignant counterpart of the mature teratoma and contains immature tissues which typically show primitive or embryonal neuroectodermal histopathology. Immature teratoma has one of the lowest rates of somatic mutation of any tumor type and results from one of five mechanisms of meiotic failure.

[Laparoscopic extirpation of retroperitoneal bronchogenic cyst].

The retroperitoneal bronchogenic cyst is an extremely rare anomaly. During the examination of an 18-year-old female patient due to her extreme thinness, the abdominal ultrasound and later the CT indicated as an accidental finding--a left side adrenal/suprarenal adenoma, which turned out to be hormonally inactive. But while we were doing a laparoscopic surgical intervention we found a 6-8-cm cyst in the retroperitoneum, between the greater curvature and the spleen. It contained light grey, mucinous liquid. The left suprarenal gland had normal size and appearance. During the microscopic examination the removed terime showed cystic structures, which were covered inside with multilayer ciliated columnar epithelium, mucous excretory glands, a whole layer of connective/interstitial and smooth muscle tissue. Neither cartilage, nor gastrointestinal epithelium was found. Only a few publications have reported about retroperitoneal bronchogenic cyst so far. These lesions occur very rarely at the greater curvature. Although this alteration is really unusual, bronchogenic cysts have to be expected in the differential diagnostics of the retroperitoneal tumors.

Pulmonary blastoma. Comparison between its epithelial components and fetal bronchial epithelium.

Three cases of pulmonary blastoma exhibiting biphasic epithelial and stromal patterns, and a case of fetal lung-type adenocarcinoma, were examined by immunohistochemistry and electron microscopy (EM) and compared with fetal bronchial epithelium in order to explore the multidirectional differentiation of their epithelial components. The glandular cells of all four tumors resembled fetal bronchial epithelial cells in the pseudoglandular stage. Neuroendocrine (NE) cells were also present; they were argyrophilic and expressed pan-NE markers, neurosecretory granules and peptide hormones. The neural cell adhesion molecule (NCAM) was strongly expressed on the cell membranes of glandular cells, as in the case of proximal bronchial epithelial cells at the pseudoglandular stage in fetal lung. Sialosylated Lewis X was also expressed, indicating that the epithelial cells were possibly of endodermal origin. Two of the four cases showed considerable immunoreactivity for alpha-fetoprotein (AFP). The epithelial cells of pulmonary blastomas may occasionally de-differentiate into cells functionally resembling fetal hepatic, foregut and yolk sac cells expressing AFP. Tumor examination by immunohistochemistry and EM suggested that the glandular cells of the tumors may differentiate to some extent like those of fetal large bronchi at the pseudoglandular stage, but there was concordance and discordance in the expression of neuroendocrine and oncofetal markers between blastomatous tumors and fetal bronchial epithelium.

Primary Mature Teratoma of the Rectum: A Case Report.

BACKGROUND Teratomas are embryonal neoplasms that contain tissues derived from 1 or more of the 3 germ layers. They commonly are found in the sacrococcygeal-gonadal location, sometimes in midline locations such as the mediastinum, retroperitoneum, and head and neck region. Primary rectal teratomas are extremely rare. Extragonadal teratomas can originate from pluripotent germ cells present in abnormal embryonic rests. CASE REPORT Here, we report a rare case of a primary mature, solid teratoma of the rectum. A 68-year-old woman presented with hematochezia and denied any history of abdominal pain or a change in bowel habits. Colonoscopy revealed a 4-cm pedunculated polyp in the rectum. No hair was present on its surface. The polyp was completely removed by polypectomy. Histologically, the tumor consisted of mature components from all 3 germ layers. Its surface was covered by squamous epithelium with hair follicles and sweat glands. Adipose tissue, blood vessels, bone, and glandular epithelium were present inside the mass. No evidence was found of immature elements or malignant features. CONCLUSIONS When polypoid lesions are found in the rectum, teratoma should be considered in the differential diagnosis. Histopathological confirmation is necessary to diagnose teratoma. Primary rectal teratomas should be distinguished from other neoplastic polyps as well as from local spread of teratomas arising in adjacent organs. These neoplasms are usually mature (benign) but may undergo malignant transformation. Therefore, complete resection is recommended to alleviate symptoms and avoid the risk of malignancy.

Clinicopathological observation of mature teratoma with malignant transformation, a single center retrospective study.

To investigate the clinicopathological features of mature teratoma with malignant transformation. Retrospectively analysis of 1179 cases mature teratoma was done from August 1999 to December 2019 in Institution. 14 cases of mature teratoma with malignant transformation were discussed mainly for the pathological characteristics and clinical manifestations. 4 of them were less than 40 years old. All but one occurred in the ovaries, and the one was in the left anterior mediastinum which was the only male. The clinical manifestations of the patients were atypical. Imaging showed cystic solid mass. Surgery was performed. Polypoid mass, solid nodule and thickened area of cyst wall can be seen on the section of tumor. Pathological results show that there were 5 cases of squamous cell carcinoma, 3 cases of carcinoid, 2 cases of serous carcinoma and 2 cases of thyroid papillary carcinoma, 1 case of carcinosarcoma and 1 case of strumal carcinoid. Two cases of squamous cell carcinoma had pelvic and abdominal metastasis. Immunohistochemistry of case 14 showed that AE1/AE3, CD56, SYN, NSE, PSAP, CDX2 were positive in carcinoid. EMA and CK20 were positive in mucinous glands around carcinoid. Calretinin and inhibin were positive in the mesenchyme adjacent to intestinal mucinous gland. Teratoma with malignant transformation is a rare malignancy, although teratoma is a common germ cell tumor. And it's more common in patients over 40 years, especially those patients who were in menopause. Squamous cell carcinoma is the most common type and prone to metastasis. Strumal carcinoid was well-defined, but as an endocrine tumor, it may cause a series of digestive, respiratory or hormonal disorders. Therefore, the mature teratomas should be removed in time after detection.

Testicular Teratoma -- Histopathology

Microscopy : Any epithelial, mesenchymal, or neural-derived tissue can be seen. Less common are tissues derived from the respiratory, gastrointestinal, or genitourinary tract. Skin-derived structures such as epithelial-derived (epidermoid cyst) or appendages is a quite common finding, especially in prepubertal-type teratomas, while postpubertal-type teratomas tend to appear as multiloculated cysts lined by other tissue types such as glandular epithelium and contain solid areas formed by parenchymal structure or mesenchymal tissues. A certain element of immature tissues can also be encountered, consisting of ectodermal, endodermal, or mesenchymal structures. Neuroectodermal tissue is the most common immature type and often has several differentiation stages of embryonic/fetal nervous system tissue. Historically teratoma has been differentiated into mature and immature, but this distinction is not recommended any more due to the lack of a prognostic significance. Teratoma can occur paired with other histotypes of germ cell neoplasia, such as yolk sac tumor or embryonal carcinoma.

International Classification of Diseases for Oncology

M9064/3 Germinoma Germ cell tumor, NOS M9065/3 Germ cell tumor, nonseminomatous M9070/3 Embryonal carcinoma, NOS Embryonal adenocarcinoma M9071/3 Yolk sac tumor Endodermal sinus tumor Polyvesicular vitelline tumor Orchioblastoma Embryonal carcinoma, infantile Hepatoid yolk sac tumor M9072/3 Polyembryoma Embryonal carcinoma, polyembryonal type M9073/1 Gonadoblastoma Gonocytoma M9080/0 Teratoma, benign Adult cystic teratoma Adult/cystic teratoma, NOS Teratoma, differentiated Mature teratoma M9080/1 Teratoma, NOS Solid teratoma M9080/3 Teratoma, malignant, NOS Embryonal teratoma Teratoblastoma, malignant Immature teratoma, malignant or NOS M9081/3 Teratocarcinoma Mixed embryonal carcinoma and teratoma M9082/3 malignant teratoma, undifferentiated Malignant teratoma, anaplastic M9083/3 Malignant teratoma, intermediate M9084/0 Dermoid cyst, NOS Dermoid, NOS

An intrapulmonary teratoma associated with bronchiectasia containing various kinds of primordium: a case report and review of the literature.

An intrapulmonary teratoma (IPT), multiloculated and bronchiectatic, with two polyps inside a 23-year-old man is reported. The IPT, a very rare benign cystic lesion, was communicating with segmental bronchus and was removed by a segmental resection from the upper lobe of the left lung. The teratoma contained various kinds of primordial derivatives, such as mesoderm, ectoderm, and endoderm. Though 65 cases of IPT have been reported in the literature (1839-1996), in the present case there were over 15 germ derivatives, the largest number reported to date. The tumor contained thymic tissue, apart from mediastinum, which may be significant in relation to the pathogenesis of IPT. Clinical manifestations, age, and gender distributions and the kind of germ cell derivatives are discussed.

[Mature cystic teratoma of the ovary with a small ganglioneuroma].

A case of ganglioneuroma arising within a cystic mature teratoma of the ovary in a 34-year-old woman is reported. Patient underwent right adnexectomy. The ovary was completely replaced by a bilocular cystic lesion, measuring 8 cm in diameter and filled with adipose tissue and pilosebaceous material. Microscopically the cyst was composed by a mature cystic teratoma containing skin with dermal appendages, fatty tissue and bronchial epithelium. Furthermore a nodule (0.5 cm in size) composed of mature ganglion cells, axons and Schwann cells, was identified. Ganglion cells were positive for NSE and synaptophysin, while Schwann cells stained positively with S100 protein and GFAP. To the best of our knowledgment this is the first reported cases of ganglioneuroma arisen within a cystic mature teratoma of the ovary.

Cystic Teratoma -- Introduction

Ovarian teratomas are broadly classified histologically into monodermal teratomas (carcinoid tumors, neural tumors, struma ovarii), immature teratomas, and mature cystic teratomas. The most common type among these tumors is mature cystic teratoma, also known as "Dermoid cyst." Cystic teratomas constitute about 20% of ovarian germ cell tumors. The most common site of occurrence is in the ovaries and testes. However, they can rarely be seen in the anterior mediastinum, sacrococcygeal region, or neck. Mature cystic teratoma is always benign with a slow growth rate of 1.8 mm/year; however, in rare circumstances, it can undergo malignant transformation.

Retroperitoneal bronchogenic cyst: a case report.

Bronchogenic cysts are among developmental disorders of the primitive foregut which are typically found above the diaphragm. Bronchial cysts discovered in the abdominal cavity or retroperitoneum are extremely rare. We present a rare case of a retroperitoneal bronchogenic cyst which was incidentally detected after a wrestling injury in a 23-year-old man who had a negative medical history. Although initial imaging studies suggested an adrenal tumor, histopathological analysis provided a definite diagnosis of bronchogenic cyst. Though rare, bronchogenic cysts must be considered in the differential diagnosis of retroperitoneal cystic lesions. This is the first case of a retroperitoneal bronchogenic cyst reported in Iran.

Benign cystic teratoma of the parotid gland: a case report.

Mature cystic teratomas of the major salivary glands are rare. This report describes a case of a mature cystic teratoma of the left parotid gland, including the cytologic and histopathologic findings. A 17-year-old young woman presented with a slow-growing left parotid mass that had been present for 4 years. Preoperative fine needle aspiration cytology showed the presence of acinar and ductal cells, foamy cells and multinucleated giant cells. Imprint cytology of the surgical material showed the presence of some squamous cells and sebaceous gland-like cells with hair shafts. Cellular atypia was inconspicuous. Grossly, the 3-cm lesion was unicystic and embedded within the parotid gland parenchyma. Microscopically, the inner surface of the cyst was lined with keratinized squamous epithelium. The cyst wall contained skin adnexa such as sebaceous, eccrine and apocrine glands, as well as hair follicles. Some mature cartilage tissue was also detected. Foreign body granulomatous change was seen focally. No immature tissue or malignant transformation was found. There is no previous report describing the cytologic findings of a mature cystic teratoma of the parotid gland. Mature cystic teratomas should therefore be considered in the differential diagnosis of a cystic lesion of the parotid

A bronchogenic cyst, presenting as a retroperitoneal cystic mass.

Bronchogenic cysts are mostly benign, congenital abnormalities originating from the remnants of the primitive foregut. A retroperitoneal location is rare. Due to the mostly asymptomatic behavior and the historical confusion regarding histology, an exact prevalence is not known. We present here a case report of a retroperitoneal bronchogenic cyst. A literature review was performed for cases of retroperitoneal bronchogenic cysts written in English. Anatomopathological criteria for inclusion were pseudo stratified, ciliated, columnar epithelium together with the presence of at least one of the following: cartilage, smooth muscle or seromucous glands. In addition, the embryology, pathogenesis, radiological, clinical and suggested treatment modalities are reviewed. We report the surgical excision of a retroperitoneal bronchogenic cyst that presented as a non-functioning left adrenal mass. Our review of literature revealed only 62 potential cases of retroperitoneal bronchogenic cysts. After applying the strict anatomopathological criteria, only 30 cases of true retroperitoneal bronchogenic cysts could be identified. Retroperitoneal location of a bronchogenic cyst is rare. Despite the rarity of this pathologic entity, bronchogenic cysts should be considered in the differential diagnosis of retroperitoneal cystic lesions. Only histology can confirm definitive diagnosis. Surgery remains the recommended treatment of choice.

[Bronchogenic cyst of the tongue].

Bronchogemc cyst is a rare aberration secondary to abnormal detachment of accessory lung buds from the primitive foregut. Through one case of bronchogenic cyst of the tongue, the authors made a review of this exceptional localisation. We report one case of bronchogenic cyst of the tongue treated in the Ibn Sina Hospital. Our patient was a new born admitted in our formation for a voluminous cystic mass ot the tongue, responsible of difficulty for mouth occlusion and feeding The radiology I confirms the liquid nature of this mass. The treatment was surgical, and the diagnosis of bronchogenic cyst was histological. Bronchogenic cysts are generally intrathoracic. The localization in the cervico-facial area is rare, and only 4 cases of bronchogenic cyst of the tongue were described in the literature. The clinical presentation is non specific, depending on the volume of the cyst. Radiology permits to confirm the nature of the mass. The certitude diagnosis is histological: bronchogenic cysts are lined by pseudostratified ciliated columnar epithelium with accessory tissues in the cyst wall, smooth muscle, seromucinous glands and cartilage, simulating a bronchus. Complete surgical excision is the base of the treatment.