Hector I. Cohen

Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability.

&NA; The phenotypic markers of colorectal carcinomas with microsatellite instability have been widely studied and include mucinous or poor differentiation, prominent host response, a circumscribed growth pattern, histologic heterogeneity, and right‐sided location. As part of a population‐based case–control study of colorectal cancer in northern Israel, we reviewed the pathology and microsatellite status of 528 consecutively diagnosed colorectal cancers. Phenotypic analysis was performed by one pathologist (J.K.G.) and included assessment of grade, mucinous histology (>50%, or focal), histologic heterogeneity, growth pattern, necrosis, and host response. Microsatellite status was determined on microdissected portions of formalin‐fixed, paraffin‐embedded tissue using a panel of 5 NCI consensus primers. Fifty‐two of 528 colorectal carcinomas were microsatellite unstable (9.85%). Multivariate analysis found that >2 tumor infiltrating lymphocytes per high power field (p <0.0001), the lack of dirty necrosis (p = 0.0054), a Crohns‐like host response (p = 0.0064), right‐sided location (p = 0.032), well or poor differentiation (p = 0.037), and any mucinous differentiation (p = 0.039) were independent predictors of microsatellite instability. Tumor infiltrating lymphocytes were the single best histologic predictor of microsatellite instability. The absence of dirty necrosis and the presence of well‐differentiated tumors and tumors with only focal mucinous differentiation were also important markers for microsatellite instability that have not been emphasized previously. The combination of >2 tumor infiltrating lymphocytes per high power field and/or any mucinous differentiation and/or the absence of dirty necrosis identified all MSI‐H tumors in this study.

Pathologic Predictors of Microsatellite Instability in Colorectal Cancer

Identification of microsatellite unstable (MSI-H) colorectal cancers (CRCs) is important not only for the identification of hereditary nonpolyposis colorectal cancer syndrome but also because MSI-H CRCs have a better prognosis and may respond differently to 5-fluorouracil–based chemotherapy. We present 2 nearly equivalent logistic regression models for clinical use that predict microsatellite instability based on the review of 1649 CRCs from patients of all ages collected in a population-based case control study in northern Israel. One hundred ninety-eight of these 1649 tumors demonstrated a high degree of microsatellite instability (12%). Multivariate analysis found that >2 tumor-infiltrating lymphocyte (TIL) cells per high-powered field, the lack of dirty necrosis, the presence of a Crohn-like reaction, right-sided location, any mucinous differentiation (mucinous or focally mucinous) and well or poor differentiation, and age less than 50 were all independent predictors of MSI-H. We developed 2 logistic regression models that differ only by the statistical approach used to analyze the number of TIL cells per high-powered field, where the slightly more accurate (and complex) model uses the log of the total number of TIL cells. The simpler clinical model uses a cut-off of 2>TIL cells per high-powered field. The accuracy of both models is high, with an 85.4% versus 85.0% probability of correctly classifying tumors as MSI-H. By employing the simpler model, pathologists can predict the likelihood of microsatellite instability by compiling the MSI probability score (Table 4 and Fig. 1) from simple histologic and clinical data available during sign-out. Our model shows that approximately 43% of CRCs have a MSI probability score of 1 or less and hence have little likelihood (<3%) of being MSI-H. Although this model is not perfect in predicting microsatellite instability, its use could improve the efficiency of expensive diagnostic testing.

Gene Expression Differences between Colon and Rectum Tumors

Purpose: Colorectal cancer studies typically include both colon and rectum tumors as a common entity, though this assumption is controversial and only minor differences have been reported at the molecular and epidemiologic level. We conducted a molecular study based on gene expression data of tumors from colon and rectum to assess the degree of similarity between these cancer sites at transcriptomic level. Experimental Design: A pooled analysis of 460 colon tumors and 100 rectum tumors from four data sets belonging to three independent studies was conducted. Microsatellite instable tumors were excluded as these are known to have a different expression profile and have a preferential proximal colon location. Expression differences were assessed with linear models, and significant genes were identified using adjustment for multiple comparisons. Results: Minor differences at a gene expression level were found between tumors arising in the proximal colon, distal colon, or rectum. Only several HOX genes were found to be associated with tumor location. More differences were found between proximal and distal colon than between distal colon and rectum. Conclusions: Microsatellite stable colorectal cancers do not show major transcriptomic differences for tumors arising in the colon or rectum. The small but consistent differences observed are largely driven by the HOX genes. These results may have important implications in the design and interpretation of studies in colorectal cancer. Clin Cancer Res; 17(23); 7303–12. ©2011 AACR.

Intrapulmonary solitary fibrous tumors: clinicopathologic and immunohistochemical study of 24 cases.

Solitary fibrous tumor (SFT) is a ubiquitous neoplasm that arises most commonly from the pleura. SFT arising within lung parenchyma (intrapulmonary SFT) has been rarely reported and is therefore not well recognized. We present a clinicopathologic and immunohistochemical study of 24 cases of primary intrapulmonary SFT. Patients’ ages ranged from 44 to 83 years (mean, 58 y). None of the patients had evidence or history of a similar tumor elsewhere. Tumor size ranged from 2.3 to 22 cm (mean, 8.5 cm). On the basis of the degree of cytologic atypia, cellularity, mitotic activity, and areas of necrosis, the lesions were divided into low-grade, intermediate-grade, and high-grade histology. Twenty-one tumors showed the conventional features of SFT of low-grade histology (<5 mitoses per 10 high-power fields), with alternating bands of rope-like collagen flanked by a bland-appearing spindle cell proliferation. Hemangiopericytic, angiofibromatous, and a neural-like plexiform growth pattern were also observed. Five of 21 cases showed an “adenofibromatous” appearance imparted by entrapped normal airspaces at the advancing edges of the lesion. One intermediate-grade tumor showed overall increased cellularity with plump, pleomorphic nuclei, 5 to 10 mitoses per 10 high-power fields, and focal areas of classic SFT. Two cases showed high-grade features at initial presentation, with areas resembling a pleomorphic high-grade sarcoma admixed with foci of conventional, low-grade SFT. Immunohistochemical staining analyses performed in 13 cases showed positivity of the tumor cells for CD34, bcl-2, and CD99 in the majority of cases tested. Clinical follow-up was available in 18 patients, with long-term follow-up (>5 y) in 6. Fourteen (14/18) patients were alive and well without evidence of disease 1 month to 14 years after initial diagnosis. Three patients died of their tumors after 4, 5, and 7 years; in 2 of them the initial tumor was of low-grade histology, but the recurrence/metastases showed a high-grade histology; the third fatal case showed a tumor with high-grade histology at initial diagnosis. One patient with intermediate-grade histology also had chest wall metastases at 5 years but was subsequently lost to follow-up. The results of our study indicate that although tumors with overtly malignant histologic features can be expected to behave as high-grade sarcomas, tumors with bland-appearing morphologic features at presentation may also follow an aggressive behavior. Adequate excision with close clinical follow-up, thus, appears to be the most prudent course of action for the management of primary intrapulmonary fibrous tumors.

A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis

Background Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. Methods The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. Results The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. Conclusions The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.

Nimesulide-Induced Acute Hepatitis

OBJECTIVE: To report the occurrence of nimesulide-induced acute hepatitis confirmed by biopsy and an in vitro lymphocyte toxicity assay. CASE SUMMARY: A 54-year-old Arabic woman treated with nimesulide for chronic low back pain was admitted to the hospital with acute hepatitis confirmed by biopsy. Her liver function test results returned to normal within one month after nimesulide discontinuation. An in vitro lymphocyte toxicity assay confirmed that the liver injury was due to nimesulide exposure. DISCUSSION: A case of acute hepatitis secondary to nimesulide, confirmed by biopsy and a laboratory in vitro assay, is described. Although the occurrence of clinically significant liver damage due to nonsteroidal antiinflammatory drugs (NSAIDs) is low, the enormous consumption of these drugs has made them an important cause of liver damage. Nimesulide, a relatively new NSAID commonly used in Europe, with a relative selectivity to cyclooxygenase type 2, can cause a wide range of liver injuries, from mild abnormal liver function to severe liver injuries. These effects are usually reversible on discontinuation of the drug, but occasionally can progress to fatal hepatic failure. CONCLUSIONS: Drug-induced acute hepatitis is a well-recognized adverse effect of many drugs, including nimesulide. Identification of a drug as a cause for this life-threatening disease is important because the discontinuation of it may be life saving. This article confirms the occurrence of nimesulide-induced hepatitis. It also highlights the importance of monitoring liver function test results after initiating therapy with such a drug.

Effect of the Antioxidant Mesna (2-Mercaptoethane Sulfonate) on Experimental Colitis

Reactive oxygen species play a key role in intestinal inflammation, although interventional studies using antioxidants have shown only weak beneficial effects both in humans and animals. Hence, our aim was to examine the possible beneficial effect of the antioxidant 2-mercaptoethane sulfonate (Mesna) on experimental colitis. Colitis was induced in rats by intrarectal instillation of trinitrobenzene sulfonic acid (TNB) followed immediately by intrarectal Mesna or saline, administered for 14 days, twice daily. A beneficial effect of Mesna was observed, resulting in a significant reduction in inflammation followed by almost full recovery. iNOS mRNA expression and myeloperoxidase (MPO) activity were significantly increased in the TNB-Mesna group. These results suggest that the induction of iNOS in the presence of Mesna reduced intestinal inflammation. Mesna probably resolved this inflammation by scavenging reactive oxygen species generated by the augmented infiltration of polymorphonuclear leukocytes.

The Impact of Endoscopic Ultrasonography on the Management of Suspected Pancreatic Cancer-a Comprehensive Longitudinal Continuous Evaluation

Objectives: Between 1997 and 2001, a single-center chart review demonstrated significant impact of endoscopic ultrasonography (EUS) in evaluating suspected pancreatic cancer (PCA). Repeating and comparing this review with that from 2001 to 2004 was performed to determine whether increased use of EUS results in more patients being accurately chosen for curative versus palliative procedures, and for surgical versus nonsurgical oncotherapy. Methods: The complete systematic review was made up of electronic files from the gastroenterology, oncology, and pathology departments of patients presenting with suspected PCA. Results were compared with those obtained in 1997-2001. Results: From 2001 to 2004, 72 patients had PCA. Seven tumor types were identified. Forty-seven percent (34/72) of patients with suspected PCA were preoperatively staged by EUS; 24% (17/72) of all patients underwent surgery. Comparatively, from 1997 to 2001, only 32% (20/62) of patients were evaluated by EUS (P = 0.056) and 45% (28/62) of all patients underwent surgery (P < 0.01). The EUS detected a tumor in 32 of 34 cases. The EUS-guided fine-needle aspiration cytology identified PCA in 14 of 18 cases. F-18-deoxyglucose-positron emission tomography and magnetic resonance imaging were not used. Endoscopic retrograde cholangiopancreatography was performed in 29% (21/72) of patients, with 15 stents inserted. Conclusions: Increased EUS use for diagnosing and staging PCA resulted in fewer patients undergoing futile surgery. The EUS plays a pivotal role in the management of patients with PCA.

Gastrointestinal β2microglobulin amyloidosis in hemodialysis patients: biochemical analysis of amyloid proteins in small formalin-fixed paraffin-embedded tissue specimens

We present here a first report on the biochemical analysis of intestinal amyloid deposits found in two cases of hemodialysis-related amyloidosis. A new microtechnique was applied for extraction and immunochemical/chemical characterization of amyloid proteins in small amounts of fixed tissue, thus allowing precise identification of β2microglobulin amyloid (Aβ2M) in both cases studied. The molecular mass of the identified amyloid β2M was close to that of intact β2M (12 kDa), with no evidence of the products of proteolytic fragmentation of these molecules. The isoelectrofocusing of the purified Aβ2M demonstrated a shift to more acidic pI as compared to the normal β2M analyzed under the same experimental conditions. The obtained data suggest that the intestinal amyloid deposits in dialysis-related amyloidosis contain disease-specific β2M isoforms, which could play a role in the pathogenesis of amyloid disease. The new methodology used might be useful in obtaining precise diagnosis of amyloidosis that is necessary for appropriate therapy, and also provide new important information on the chemical structure of amyloid proteins.

Imaging of primary sternal osteomyelitis in a patient with Crohn's disease

A 41-year-old man with known Crohns disease presented with chest pain and fever. Plain film and CT of the chest were normal, but bone scan and gallium scans showed intense sternal uptake. Surgery revealed staphylococcal osteomyelitis of the sternum. Following appropriate antibiotic treatment, the patients symptoms resolved and follow-up gallium scans became normal. This is the first report of the association of sternal osteomyelitis and Crohns disease, although other sites have been described. Sternal osteomyelitis has a high morbidity and the index of suspicion for this condition must be high even in the face of initially negative imaging.