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Total or ionized serum level of calcium and intact serum parathyroid hormone levels are measured and both should be elevated. The tumors are asymmetric in size and should be considered as independent clonal adenomas. Intraoperative parathyroid hormone level monitoring is recommended to be certain that sufficient abnormal parathyroid tissue has been removed. A viable 50 mg amount of normal parathyroid tissue should be left in the neck and marked with a hemoclip. Calcium-sensing receptor agonists (calcimimetics) are a new class of drugs that can act directly on the parathyroid gland, decrease parathyroid hormone release, and may even decrease parathyroid tissue growth. These agents may play an important role in the management of these patients in the future. Tumors vary from microadenomas to carcinomas with lymph node and liver metastases. Patients should be questioned for loss of peripheral vision and visual fields assessed formally if any suspicion. These tumors may spread to lymph nodes and liver and may require total gastrectomy. Pathology may include cortical adenoma, diffuse hyperplasia, nodular hyperplasia, and carcinoma. Some patients may present with Cushing syndrome secondary to an adrenal tumor, but adrenocorticotropic hormone from a bronchial carcinoid or a pituitary adenoma may also cause hypercortisolism. Patients have hypoglycemia and neuroglycopenic symptoms (altered mental status and seizures). Fasting hypoglycemia (glucose <45 mg/dl) and concomitant hyperinsulinemia (levels >5 uU/ml) are diagnostic. Tumors are generally small (<2 cm) and distributed uniformly throughout the pancreas. Several groups advocate that surgery should be avoided unless the tumor is 2 cm or growing. The standard operation is distal or subtotal (resection margin superior mesenteric vein) pancreatectomy with intraoperative ultrasound and enucleation of tumors from the pancreatic head and duodenum. Extensive pancreaticoduodenal procedures are associated with increased risk, thus the indication for the procedure, potential benefit, and surgeon experience must be considered. However, for patients with multiple primary endocrine tumors, vigilance must be taken when evaluating new findings on cross-sectional imaging to be certain which tumor is metastatic and/or progressing. This should be performed through a laboratory that analyzes exons 10, 11, 14, 14, 15, and 16. In this setting, central compartment lymph node dissection is unnecessary as it can increase the occurrence of postoperative hypoparathyroidism. Since these patients commonly have a more aggressive tumor, central lymph node dissection should always be done. Note that the medullary thyroid cancer is bilateral and that the central lymph nodes are involved. The tumor is multicentric and occupies the superior and central portion of each lobe. The tumor is very firm and has a fibrous acellular stroma that has staining properties similar to amyloid, but it is immunohistochemically calcitonin. In this setting, the pheochromocytomas are benign and confined to the adrenal gland. Sixty-five percent of the time, these tumors are bilateral; with 10-year follow-up, patients with a unilateral pheochromocytoma will develop a contralateral tumor. It is critical to exclude the diagnosis of pheochromocytoma in these patients before doing any invasive procedure because sudden death may occur if a pheochromocytoma is not detected and the patient is not appropriately prepared with alpha-adrenergic blocking agent. Patients suspected of having a pheochromocytoma should have measurement of plasma-free metanephrine and normetanephrine levels or a 24-hour urine for vanillylmandelic acid, metanephrines, and total catecholamines. The sensitivity and specificity are similar for the two procedures, 90% to 100% and 70% to 80%, respectively. Preoperative preparation with an alpha-adrenergic blocking drug like phenoxybenzamine is done.

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The total number of glands lost in the central portion of the lower eyelid (of eight adjacent glands) was measured. Dimpling or notching of the posterior lid margin due to tissue absorption in the region of the orifices (courtesy of J. In the gestalt system, they estimated the fractional, (partial or total) gland loss on a 1 to 4 scale, where 1 was no gland loss and 2 was 25%, 3 was 25% to 75%, and 4 was 75% gland loss in the image with partial glands. It can be seen from Table 4, that for the gestalt system, using a weighted statistic, the method showed near perfect reliability within observers (0. For the individual gland counting system, using the 95% limits of agreement method, reliability was judged to be moderate within observers and fair between observers. The reader should consult the original article for details of the statistical treatment. However, overall this report appears to establish the method of meibography as a useful clinical tool. The scores for the upper and lower lid were summed to give a scale range of 0 to 6 for the two lids. This effect would be measured by gland loss from the upper and lower lids, and the combined dropout score from the upper and lower lids would be needed to reflect this most accurately. Scale ranges must be considered, to demonstrate the relationship between dropout and other parameters. Currently, there is no consensus as to the number of discrete increments that should be used in clinical grading. This approach has been used effectively for the grading of corneal staining on a 0. At present, sometimes for ease of performance or for operational reasons, measurements are made on a limited region of one lid and from either the upper or lower lid alone. In a recent study of meibomian gland function in blepharitis, a high correlation between measures, including gland dropout, was found between the upper and lower lids, with the lower lid offering the most effective single measure. There is a need to develop approaches that can assess the full extent of each tarsal plate, to produce an aggregate score. Noncontact meibography and confocal microscopy appear promising from this point of view. Meibography is attractive because it offers a permanent record and permits masking of scoring. Validation of Meibography107 Test Reliability Gestalt method: Within observer Between observer Intact gland counting Within observer Between observer clinical trials, it is likely that digital imaging techniques will be developed that will document gland dropout more accurately and permit a focus of attention on the terminal ductule, a region of strategic importance. Meibomian gland expression is used in diagnosis and to obtain meibomian samples for lipid analysis (Appendix 6; Table 5). It is common to express the glands by applying digital pressure through the substance of the lids, but methods to standardize the application of force have also been developed. When the lids are normal, light expression may be expected to expel secretion contained in the ducts. Grading Meibomian Gland Expression Technique Study Details Lid Region Grading Scheme Reference Meibum Characteristics Firm digital pressure Volume of expressed meibum Central eight glands of lower eyelid Central eight glands of lower eyelid Central eight glands of lower eyelid 0 Normal volume. Just covers orifice 1 increased to 2 to 3 times normal 2 increased more than 3 times 3 increased more than 10 times 1 normal, clear, may have a few particles 2 opaque with normal viscosity 3 opaque with increased viscosity 4 severe thickening (toothpaste) Obstructive: Viscosity 3 (1, clear; 2, slightly opaque; 3, thick, opaque; 4, toothpaste Avg. Expressibility is sometimes equated with functionality of the meibomian glands and they are likely to be closely related, but expression is not in itself a measurement of secretory activity, although it could be considered a surrogate measure of secretion. These qualities have been incorporated into various ordinal grading schemes75,96,97 (Table 5). The scores in these four-point systems are 0, clear (normal); 1, cloudy; 2, cloudy with particles; and 3, inspissated (like toothpaste). When the expression of a fixed number of glands is assessed, there are two ways of generating a score. One way is to record only the highest grade encountered from any of the expressed glands. The other is to record the sum of scores for each gland expressed, to achieve a composite score. However, a small caveat is that in long-term studies, inexpressibility encountered in normal lids is also a sign of total obstruction; an increase in the number of pathologically inexpressible glands with disease progression, would, paradoxically, lead to a fall in total score. To increase the scale range and reflect the status of the full length of the upper and lower lids, an aggregate score can be created from the summed expression grades from the nasal, central, and temporal regions of each lid. As noted earlier, even in young normal subjects, the expressibility, in terms of the fraction of glands from which fluid meibum may be expressed, varies for different regions of the lid and reduces progressively from the nasal to the temporal side.


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  • Naegeli Franceschetti Jadassohn syndrome
  • Silicosiderosis
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  • Rotor syndrome
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The presence of other fluid-filled structures in the pelvis, including urachal remnant, may be misleading in cases of bladder exstrophy. During the first trimester ultrasound, the diagnosis of bladder exstrophy can be easily missed if imaging of the lower anterior wall of the abdomen and the bladder with the surrounding umbilical arteries is not performed. Bladder exstrophy is a sporadic anomaly, which could be part of syndromic conditions and other more complex malformations, thus making fetal counseling difficult,30,31 especially in the first trimester. We recommend a close follow-up ultrasound examination at 16 weeks of gestation if the diagnosis of bladder exstrophy is suspected in the first trimester. This is important to confirm the diagnosis and to exclude additional urogenital, gastrointestinal, and other anomalies. The bladder could not be visualized in fetus B during the detailed ultrasound examination. When compared with the normal fetus A, note the presence of a low abdominal cord insertion (short arrow) in B. Also note the presence of irregular tissue inferior to the cord insertion in B, which represents bladder exstrophy. Cloacal abnormalities refer to a spectrum of anomalies where the gastrointestinal, urinary, and genital tracts share a common cavity for discharge. Embryologically, a cloaca persists beyond the fourth to sixth week of gestation when the partition of the cloaca into the urogenital sinus and the rectum fails to occur. The diagnosis of cloacal abnormalities is possible in the first trimester, especially in its severe forms. The presence of a cystic structure in the mid- or lower abdomen in the first trimester should alert for the possible presence of cloacal abnormalities, because the cystic structure may represent a communication between the bladder and bowel. Association of cloacal abnormalities with enlarged nuchal translucencies has been reported. Abnormal Genitalia There are currently no comprehensive studies or reports on the diagnosis of abnormal genitalia in the first trimester. As described earlier in this chapter, the reliable assessment of the normal genitalia can be achieved from 12 weeks onward in optimal imaging. It is, however, difficult to achieve a definitive diagnosis on any gender malformation in the first trimester, with the exception of cloacal abnormalities. Once a renal malformation is suspected in the first trimester, however, ultrasound assessment of the genitalia should be performed because this may help in confirming the diagnosis. The absence of one kidney, in combination with a single umbilical artery and abnormal genitalia, may raise the suspicion for a syndromic condition. Gender discrepancy between chorionic villous sampling and ultrasound in a male fetus could suspect the presence of sexual reversal, as in Smith­Lemli­Opitz syndrome, campomelic dysplasia, chodrodysplasia punctata, and others. Abnormal Adrenal Gland the adrenal gland appears as an anechoic structure between the kidney and diaphragm, with an adrenal length about half the length of the kidney. On the other hand, a flat adrenal gland can be a marker for the presence of an empty renal fossa. In addition, we reported on enlarged adrenal glands5 in a fetus with congenital adrenal hyperplasia and found the adrenals to be larger than the kidneys. It is important to note that most cases of congenital adrenal hyperplasia do not have significantly enlarged adrenal glands and remain undetected in utero. Note the presence of ventricular (A) and great vessel (B) disproportion, suggesting the diagnosis of an aortic coarctation. Also note in C the presence of a thickened nuchal translucency of 4 mm (asterisk). Note the enlarged size of the adrenal glands bilaterally (arrows) and compare with normal first trimester adrenal glands, shown in Figure 13. Megacystis at 10­14 weeks of gestation: chromosomal defect and outcome according to bladder length. Transvaginal sonographic assessment of the fetal urinary tract in early pregnancy.

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After 7 years of follow-up, the age-standardized rate of death due to cervical cancer was 39. Performance Characteristics of Cervical Cytology the sensitivity of cytology varies and is a function of the adequacy of the cervical specimen. Not surprisingly, sensitivity is improved by serial examinations over time versus a single screen. It is elevated in only about half of women with ovarian cancer and may be elevated in a number of nonmalignant diseases. Women under 21 years of age should not be screened regardless of their age of sexual initiation. Women who have undergone a hysterectomy for noncancerous conditions do not need to undergo cervical cancer screening. Participants were followed for a maximum of 13 years, with mortality from ovarian cancer as the main study outcome. At the conclusion of the study, the number of deaths from ovarian cancer was similar in each group. Women should be encouraged to immediately report these symptoms to their physician. Women at High Risk for Endometrial Cancer Women with a suspected autosomal-dominant predisposition to colon cancer. Lynch syndrome), should consider undergoing an annual endometrial biopsy to evaluate endometrial histology, beginning at age 35 years. Women should be informed about the potential benefits, harms, and limitations of testing for early endometrial cancer. These findings led many to advocate for mass lung cancer screening, whereas others called for a prospective, randomized trial with a lung cancer mortality endpoint. At 13 years of follow-up, there were more early stage cancers in the intensively screened arm (n = 99) than in the control arm (n = 51), but the number of advanced tumors was nearly identical (107 versus 109, respectively). There were 585 lung cancers diagnosed on the intensive screening arm versus 500 on the control arm (p = 0. However, a concomitant decrease in lung-cancer mortality did not emerge with long-term follow-up (4. All three studies evaluated different screening schedules rather than screening versus no screening. Paradoxically, a metaanalysis of the three studies found that more frequent screening was associated with an increase (albeit not statistically significant), rather than a decrease, in lung cancer mortality when compared with less frequent screening. This was a prospective, randomized trial of nearly 155,000 men and women, aged 55 to 74 years. With 13 years of follow-up, no significant difference in lung cancer mortality was observed. These studies also demonstrated that 5-year survival rates were increased in screened compared to unscreened populations. Eligible participants were current and former smokers between 55 and 74 years of age at the time of randomization with at least a 30 pack-year smoking history; former smokers were eligible if they had quit smoking within the previous 15 years. These diagnostic procedures are associated with anxiety, expense, and complications. Although it is not known whether these deaths were directly caused by the invasive procedure, such findings do give pause. The possibility of this long-term phenomenon will have to be assessed in future analyses. This protein was discovered in the late 1970s, and a serum test to measure circulating levels was developed in the early 1980s. The prostate cancer conundrum was best summarized by the distinguished urologist, Willet Whitmore when he said, "Is cure necessary for those in whom it is possible? In a landmark analysis with 20-year follow-up, only a small proportion of 767 men, diagnosed with localized prostate cancer in the 1970s and early 1980s and followed expectantly, died from prostate cancer: 4% to 7% of those with Gleason 2 to 4 tumors, 6% to 11% of those with Gleason 5 disease, and 18% to 30% of men with Gleason 6 cancer. This is illustrated by an examination of the prostate cancer incidence and mortality rates in Washington state and Connecticut. However, mortality rates remained similar throughout the decade and, in fact, have remained similar to this day. Men were screened annually during this trial, and those who had not been diagnosed with prostate cancer after 7 years on-study were asked to undergo an end-of-study prostate biopsy. Given that the lifetime risk of prostate cancer mortality in the United States is less than 3%, it is clear that many men harbor indolent prostate cancer and, therefore, are at risk of being overdiagnosed.

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Many of these patients have addictions to tobacco and/or alcohol at presentation and may lack social support. All these issues should be comprehensively addressed, and in so doing, the provider and the patient are often rewarded by the productive role the patient assumes for him or herself, as well as within his or her family and in the workplace. Each team member has a specific, yet overlapping, role in preparing the patient for his or her intervention. The physicians are essential for providing information to the patient with respect to diagnosis, prognosis, and treatment options. This includes providing education to the patient on his or her specific treatment plan. Patients who are previously untreated and receive single modality treatment are going to do much better than patients who are recurrent or are going to undergo multimodality therapy. In order to design the best intervention for the patient, the physicians must also remain flexible and integrate feedback from the team. Once the plan is established, the physician team has to clearly communicate the treatment plan to the remaining members of the team so they can provide appropriate counseling. The placement of a gastrostomy or a tracheotomy tube is associated with the poorest patient-reported quality of life. Preoperative counseling with the speech pathologist is another essential part of patient education and shaping expectations. The speech pathologist is often regarded by the patient as the individual who will restore communication and swallowing function posttreatment. The greatest counseling challenge for the team when working with this patient group is overcoming poor coping skills. Speech pathologists often provide psychological counseling on an ad hoc basis, and this has shown to benefit head and neck cancer patients when compared to controls. This is a central piece of the rehabilitation efforts that ideally should be handled by a cessation specialist. Smoking cessation interventions, particularly those that take into consideration alcohol intake and depression, have been shown to be efficacious for this patient population. Therefore, the patient must understand that continuation of addictive behaviors represents the greatest risk to patient survival and future function. It is important to emphasize to the patient that there are many different ways to quit smoking. The patient should understand that alcohol is a facilitator and nicotine is a lower level carcinogen than tobacco products. Involvement of social work is important to address psychosocial and economic issues that impact cancer treatment and rehabilitation. The use of patient volunteers who have completed treatment is an invaluable resource. They provide education and experience with regard to what one may experience during treatment, posttreatment recuperation, and long-term quality of life to patients who are preparing for treatment. After treatment, there can be stiffness, edema, fibrosis, xerostomia, and stenosis. The severity of these effects is proportional to the aggressiveness of the treatment. To help reduce the effects of chemotherapy and radiation therapy, mobility of the aerodigestive tract should be maintained during treatment. Newer radiotherapy techniques that spare the swallowing-related structures have resulted in substantial improvements of long-term dysphagia. There are many different recipes for mouthwashes, but the common components are an antifungal such as nystatin (Mycostatin), an antihistamine such as diphenhydramine (Benadryl), and a barrier agent such as an antacid. The approach to analgesia is a sustained release agent that covers 80% to 90% of the analgesia needs and a shorter acting agent to cover breakthrough pain. Recent efforts to identify newer agents that may reduce mucositis during radiotherapy include amifostine13 and palifermin (keratinocyte growth factor).

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The biallelic expression of imprinted genes in germ cell tumors has been reported, showing that they likely arose from primordial germ cells where the genomic imprinting is temporarily erased. There is evidence that epigenetic regulation of gene expression plays a role in the pathogenesis of germ cell tumors. Thus, embryonal carcinoma can be thought of as the transformed counterpart of embryonic stem cells, displaying self-renewal, pluripotency, and lineage differentiation. These observations point to the likely existence of a hereditary germ cell tumor subset. The inheritable effect is mild, and the most common number of affected relatives in a family is two. The age at diagnosis among familial cases is 2 to 3 years younger than sporadic cases, and there is a higher incidence of bilateral tumors. The gr/gr deletion on chromosome Y, common among infertility patients and associated with a two- to threefold increased risk of testicular cancer, was studied as a candidate region for hereditary risk. Patterns of Metastasis Testicular cancers can undergo both lymphatic and hematogenous dissemination. The lymphatics arising from the testicle accompany the gonadal vessels in the spermatic cord. Some follow the gonadal vessels to their origin while others diverge and drain into the retroperitoneum. The landing zone for metastasis from the right testicle is in the interaortocaval lymph nodes just inferior to the renal vessels. The landing zone from the left testicle is in the para-aortic lymph nodes just inferior to the left renal vessels. Large volume disease tends to progress in retrograde fashion to the aortic bifurcation and below, along the iliac vessels. Seminoma Seminoma can spread extensively through the lymphatic system to include retroperitoneal, retrocrural, mediastinal, supraclavicular, and cervical lymph nodes, often in the absence of hematogenous metastasis. Stage groupings depend on both the anatomic extent of disease and serum tumor markers. Serum tumor Markers Serum tumor markers are an important part of the staging system for germ cell tumors. Markers that are elevated prior to orchiectomy and then normalize appropriately have no prognostic significance. Intratubular germ cell neoplasia (carcinoma in situ) Tumor limited to the testis and epididymis without vascular/lymphatic invasion. Tumor limited to the testis and epididymis with vascular/lymphatic invasion or tumor extending through the tunica albuginea with involvement of the tunica vaginalis. Distant metastasis Nonregional nodal or pulmonary metastases Distant metastasis other than to nonregional lymph nodes and lungs Regional lymph nodes cannot be assessed. No regional lymph node metastasis Metastasis with a lymph node mass 2 cm or less in greatest dimension and 5 nodes positive; none >2 cm in greatest dimension. Metastasis with a lymph node mass >2 cm but not >5 cm in greatest dimension, or >5 nodes positive, none >5 cm, or evidence of extranodal extension of tumor. No regional lymph node metastasis Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph nodes; none >2 cm in greatest dimension. Metastasis with a lymph node mass >2 cm but not >5 cm in greatest dimension, or multiple lymph nodes, any one mass >2 cm but not >5 cm cm in greatest dimension. Postchemotherapy resection showed metastatic teratoma with somatic transformation to primitive neuroectodermal tumor. Involvement of rete testis has not been validated as a risk factor, although it is often mentioned. These prognostic groupings are used to make treatment decisions and are discussed in the following sections. Pathologic Staging the T classification is determined by pathology of the orchiectomy specimen.

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With earlier diagnosis of many cancers and a longer length of life after diagnosis and treatment, an increasing number of survivors remain under the care of cancer specialists and primary care physicians. Wide variations in recommended practice have led to the development of guidelines by various organizations. Approximately 4% to 10% of patients who present with renal masses will have a concomitant tumor thrombus. A tumor thrombus should be suspected in patients with a renal tumor who also have new onset lower extremity edema, an isolated right-sided varicocele or one that does not collapse with recumbency, dilated superficial abdominal veins, proteinuria, pulmonary embolism, right atrial mass, or nonfunction of the involved kidney. Interestingly, many patients with vena cava extension will present active Surveillance of clinically localized renal cell carcinoma the concept of overdiagnosis and overtreatment of kidney cancers is a relatively new concept. While early detection leads to "cure," lead time biases in reported surgical series and the growing recognition that some localized renal tumors exhibit an indolent natural history have challenged the "find it, excise it" practice pattern. Authors at the Mayo Clinic found that patients with non­clear cell histology presented with a significantly larger tumor size, greater rate of lymph node disease, higher nuclear grade, and more frequent sarcomatoid differentiation. In this series of 1,774 patients, the overall 5-year cancer-specific survival was 53. Despite the fact that multiple prior studies have shown a survival benefit with a lymph node dissection performed at the time of nephrectomy,75,176,177 a recent randomized trial failed to show a distinct advantage. Of greater impact is the study from Blute and colleagues164 who elucidated pathologic features associated with increased risk for nodal metastases: tumor grade (grade 3 or 4), presence of a sarcomatoid component, tumor size 10 cm, tumor stage pT3 or pT4, and histologic tumor necrosis. Based on this study and a subsequent prospective evaluation of this approach, patients with two or more of these risk factors should be considered for extensive lymph node dissection incorporating the ipsilateral renal hilar region, the ipsilateral great vessel, and the interaortocaval region. This dissection should extend from the crus of the diaphragm to the common iliac artery. In a retrospective study, 45% of patients had positive lymph nodes outside of the renal hilar region, mandating a broader template. Prior trials have evaluated hormone therapy, radiotherapy, immunotherapy, and tumor vaccines, all with essentially negative results. Combining the survival data from all these trials resulted in a median survival of 13. Renal cell carcinoma with tumor thrombus: is cytoreductive nephrectomy for advanced disease associated with an increased complication rate? A similar analysis was conducted by Trinh et al193 using the Nationwide Inpatient Sample registry. Also, there were eight perioperative deaths, accounting for 19% of patients who did not receive systemic treatment. In patients with diffuse metastatic disease, metastatectomy is not routinely used for therapeutic purposes. However, for the subset of patients who either present with or develop low-volume, radiographically solitary, or limited metastases, whether it be synchronous or metachronous, resection is often an integral part of the treatment paradigm and can confer a survival advantage. However, these data must be interpreted in the context that only a small subset of patients will be optimal candidates for surgical extirpation of metastatic lesions. Of this large cohort, only 125 (14%) patients underwent a complete resection of their metastatic disease, whereas 698 (78. Also, patients experienced an improved survival if they underwent complete surgical resection regardless of metastatic sites (lung versus nonlung, p <0. In these series, 24% to 100% of patients were disease free 1 to 4 years postsurgery. However, not all patients will ultimately be optimal surgical candidates and the ability to achieve a complete surgical resection is paramount in helping to guide preoperative surgical decision making. Most studies have found that patients with higher number of metastatic sites (more than two) are independently associated with at least twofold greater probability of death. Erythrocyte sedimentation rate, C-reactive protein, hemoglobin, white blood cell, and platelet parameters have been evaluated. Elevated erythrocyte sedimentation rate and C-reactive protein were consistently found to be independent poor prognostic factors.

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Despite this, the cells fill with lipids; therefore, the resources for producing the lipids must be accessible to the central acinar cells. There are also questions about hormonal regulation of the lipid production process, because insulin and glucagon are typically involved with fat and sugar metabolism. By contrast, steroid hormones (particularly androgens) are known to influence the acinar cells, and their lipid solubility would give them access to the maturing acinar cells. In addition to the synthesis of meibomian lipids, the ultrastructure of meibocytes indicates that there are special features of stacked membrane arrays and peroxisomes, which means that these cells must also have the machinery to synthesize polar lipids, such as phospholipids and cholesterol, for synthesis of their internal membranes. There remains the possibility, however, that some of these polar lipids and others, such as (Oacyl)- -hydroxy fatty acids, are specifically synthesized for secretion. Before the puzzle of how the synthesis of these lipids is controlled versus those specifically destined for secretion can be systematically considered, a consensus must be reached on the composition of normal meibomian secretions. It is also highly likely that some of the enzymes associated with the lipid synthesis are membrane bound, which makes them difficult to study. Immunohistochemical studies may resolve this dilemma, because they will help determine the compartmentalization of the enzymes-an important factor, in that enzyme location is A Skeletal Overview of Lipid Synthesis Fatty acid synthesis catalyzed by fatty acid synthase occurs in the cytoplasm, but the carbons come from the mitochondria. Therefore, mitochondria are necessary, not only for generating the large amounts of energy needed for lipid synthesis, but also for the carbons of lipids. This fact is enigmatic in the context of meibomian glands, where the more mature acinar cells continue to plump up with lipids, but at the same time their mitochondrial number decrease, and they are further displaced from their oxygen source. Fatty Acid Synthesis the carbon chain of the fatty acids is built two carbons at a time after repeated enzymatic cycles. As part of this process, the acetyl-CoA has to be activated to a higher energy level. This activation is induced by adding carbon dioxide to it to form malonyl-CoA. Instead, it is more desirable to store the carbons as fats until the energy is needed. The acetyl group (2C) of acetyl-CoA is passed to oxaloacetate (4C) to form citrate (6C), and citrate is transferred across the mitochondrial membrane into the cytoplasm. It is then lysed (citrate lyase) and coupled to cytoplasmic CoA to form cytoplasmic acetyl-CoA, which is used for fatty acid synthesis, and oxaloacetate, which is cycled back (indirectly) to the mitochondrial matrix. The result is an even-numbered fatty acid, typically 16C long (palmitic acid), which is cleaved from the enzyme by a thiolase. Many of the fatty acids in the meibomian gland are much longer than 16C, and the further elongation requires different enzymes. Then, elongation (C18 ­C28) occurs in the endoplasmic reticulum,121 and some of these are converted by additional enzymes into fatty alco- hols. The elongation process occurs in the same way as described above, except that in this case, CoA is the carrier. Two new carbons are loaded from malonyl-CoA onto palmitoyl-CoA, followed by reduction, dehydration, and reduction to form the new saturated chain extended by 2C. In forming the most prominent fatty acid in meibomian gland secretions, oleic acid, the palmitic acid (16C), has to be elongated and then desaturated. Fatty acyl-CoA desaturase catalyzes the introduction of a double bond into the acyl chain (bond 9 of stearic acid), to form oleic acid. This enzyme in mammals readily desaturates the bond between C9 and C10 but does not desaturate the bonds between C10 and the terminal methyl group. These fatty acids have been detected in human meibomian gland secretions, albeit in small amounts. One example of such enzymatic activity is the product of the gene fat-1, which has been found in animals. The presence of large numbers of ordered peroxisomes in more mature cells in the meibomian gland acini34 may be the location of these enzymes, but this still has to be demonstrated. That these enzymes are membrane bound means that they are very difficult to purify, and therefore searching for their gene expression is more likely to reveal their presence. Another important highlight of plant membrane-bound desaturases is that they use glycerolipids as their substrates and not acyl-CoA.

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A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. Morbidity and functional outcomes of salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Bisphosphonates to prevent skeletal complications in men with metastatic prostate cancer. Magnetic resonance imaging for predicting prostate biopsy findings in patients considered for active surveillance of clinically low risk prostate cancer. Active surveillance versus surgery for low risk prostate cancer: a clinical decision analysis. Multiparametric magnetic resonance imaging findings in men with low-risk prostate cancer followed using active surveillance. Pelvic lymph node dissection for prostate cancer: frequency and distribution of nodal metastases in a contemporary radical prostatectomy series. Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. Indications for and anatomical extent of pelvic lymph node dissection for prostate cancer: practice patterns of uro-oncologists in North America. Pathological features of lymph node metastasis for predicting biochemical recurrence after radical prostatectomy for prostate cancer. Radical prostatectomy: long-term cancer control and recovery of sexual and urinary function ("trifecta"). Cancer control and functional outcomes after radical prostatectomy as markers of surgical quality: analysis of heterogeneity between surgeons at a single cancer center. The surgical learning curve for prostate cancer control after radical prostatectomy. Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. Downsides of robot-assisted laparoscopic radical prostatectomy: limitations and complications. Individualized estimation of the benefit of radical prostatectomy from the Scandinavian Prostate Cancer Group randomized trial. Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. Secondary therapy, metastatic progression, and cancer-specific mortality in men with clinically highrisk prostate cancer treated with radical prostatectomy. Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer.

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The anatomic orientation of the genitalia in relation to the spine (white arrow) in the first trimester is helpful in that regard. In female fetuses (A and B), the developing labia and clitoris have an orientation that is parallel (pink arrow) to the longitudinal spine. In male fetuses (C and D), the developing penis has an orientation that is almost perpendicular (blue arrow) to the spine. Sex determination is more reliable after the 12th weeks of gestation, when the crown-rump length is >65 mm. Dilation of the bladder in the first trimester fetus is defined by a longitudinal diameter of 7 mm or greater and is referred to as megacystis or megavesica (see text for details). The presence of megacystis with bladder longitudinal diameter between 7 and 15 mm is associated with fetal aneuploidy, renal abnormalities, albeit a large number of fetuses with bladder diameter between 7 and 15 mm are normal. The presence of megacystis with bladder longitudinal diameter of greater than 15 mm is associated with fetal aneuploidy and renal abnormalities, along with distension of the anterior abdominal wall. Megacystis is defined in the first trimester by a longitudinal bladder diameter of 7 mm or more obtained on a midline sagittal plane of the fetus. In contrast, in all fetuses with a bladder diameter >15 mm and normal chromosomes, megacystis progressed into obstructive uropathy. B: the corresponding axial plane at the level of the pelvis at 12 weeks of gestation showing the presence of a keyhole sign, suggesting a posterior urethral valves. C: the follow-up ultrasound at 14 weeks of gestation showing resolution of the megacystis with a longitudinal bladder diameter of 6 mm. D: An axial plane of the pelvis in color Doppler at 18 weeks of gestation showing normal bladder and umbilical arteries with no bladder wall hypertrophy, as evidenced by the proximity of the umbilical arteries to the internal bladder wall (arrows). Urethral atresia on the other hand occurs in males and females and is extremely rare. Ultrasound Findings Megacystis is probably the easiest and most commonly diagnosed abnormality of the genitourinary system in the first trimester. It is based on the identification of a large bladder, measuring 7 mm or more in sagittal view. In some cases of resolving megacystis, a thickened bladder wall may still be observed. The presence of progressive obstructive uropathy is common when the longitudinal bladder length measures greater than 15 mm. B: A parasagittal plane of the same fetus at 13 weeks of gestation demonstrating a normal bladder size and echogenic bladder wall. C: An axial plane of the pelvis at 13 weeks of gestation showing bladder wall hypertrophy, with bladder wall thickness of 1. D: An axial plane of the pelvis in color Doppler at 13 weeks of gestation confirming the presence of bladder wall hypertrophy as evidenced by the distance between the umbilical arteries and the internal bladder wall (double headed arrow). This finding is associated with significant risk for aneuploidy and renal abnormalities. Amniotic fluid appears normal in all fetuses, as expected in the first trimester in the presence of significant uropathy, and oligohydramnios is not expected before 16 weeks of gestation. Follow-up ultrasound examinations often demonstrate the presence of renal abnormalities and underdeveloped lungs, expected here in fetuses B, C, and D because of significant megacystis with abdominal wall distention. In B, the anterior abdominal wall and bladder were opened digitally using postprocessing volume cutting tools to provide an insight into the dilated bladder. C: Postprocessing with transparency tool (silhouette ), thus facilitating the visualization of the megacystis. In this case, it is not feasible to relate the presence of increased renal parenchyma echogenicity to urologic obstruction or trisomy 13. Associated Malformations Megacystis in the first trimester has been associated with chromosomal malformations, primarily trisomy 13 and 18. In a recently published large study on 108,982 first trimester fetuses including 870 fetuses with abnormal karyotypes, megacystis was found in 81 fetuses for a prevalence of 1:1,345. The rate of aneuploidy in megacystis was 18% (15/81) and, in this study, was similar in both subgroups. Note the presence of a massively distended bladder (megacystis) in A and B and a keyhole sign (circle in B) typical for the presence of urethral obstruction.


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