Extremity Soft Tissue Sarcoma: A Multi-Institutional Validation of Prognostic Nomograms.

BACKGROUND: Prognostic nomograms for patients with resected extremity soft tissue sarcoma (STS) include the Sarculator and Memorial Sloan Kettering (MSKCC) nomograms. We sought to validate these two nomograms within a large, modern, multi-institutional cohort of resected primary extremity STS patients. METHODS: Resected primary extremity STS patients from 2000 to 2017 were identified across nine high-volume U.S. institutions. Predicted 5- and 10-year overall survival (OS) and distant metastases cumulative incidence (DMCI), and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated with Sarculator and MSKCC nomograms, respectively. Predicted survival probabilities stratified in quintiles were compared in calibration plots to observed survival assessed by Kaplan-Meier estimates. Cumulative incidence was estimated for DMCI. Harrell's concordance index (C-index) assessed discriminative ability of nomograms. RESULTS: A total of 1326 patients underwent resection of primary extremity STS. Common histologies included: undifferentiated pleomorphic sarcoma (35%), fibrosarcoma (13%), and leiomyosarcoma (9%). Median tumor size was 8.0 cm (IQR 4.5-13.0). Tumor grade distribution was: Grade 1 (13%), Grade 2 (9%), Grade 3 (78%). Median OS was 172 months, with estimated 5- and 10-year OS of 70% and 58%. C-indices for 5- and 10-year OS (Sarculator) were 0.72 (95% CI 0.70-0.75) and 0.73 (95% CI 0.70-0.75), and 0.72 (95% CI 0.69-0.75) for 5- and 10-year DMCI. C-indices for 4-, 8-, and 12-year DSS (MSKCC) were 0.71 (95% CI 0.68-0.75). Calibration plots showed good prognostication across all outcomes. CONCLUSIONS: Sarculator and MSKCC nomograms demonstrated good prognostic ability for survival and recurrence outcomes in a modern, multi-institutional validation cohort of resected primary extremity STS patients. External validation of these nomograms supports their ongoing incorporation into clinical practice.

ALK rearrangements in infantile fibrosarcoma-like spindle cell tumours of soft tissue and kidney.

AIMS: Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated 'NTRK-rearranged' spindle cell neoplasms. These two groups of tumours demonstrate overlapping morphologies and harbour alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1 and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of paediatric tumours with clinicopathological features not typical for inflammatory myofibroblastic tumour, but rather with similarities to cCMN/IFS harbouring ALK fusions. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumours occurred in patients aged from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumours arose in soft tissues and two in the kidney. Morphological features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenised stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of anaplastic lymphoma kinase (ALK) and one case demonstrated co-expression of CD34 and S100. CONCLUSIONS: This series of ALK-rearranged IFS-like tumours expands the spectrum of targetable kinases altered in these tumours and reinforces the potential overlap between IFS/cCMN-like tumours and the provisional entity of 'NTRK-rearranged' spindle cell neoplasms.

A multi-institutional validation study of prognostic nomograms for retroperitoneal sarcoma.

BACKGROUND AND OBJECTIVES: Prognostic nomograms for patients undergoing resection of retroperitoneal sarcoma (RPS) include the Sarculator and Memorial Sloan Kettering (MSK) sarcoma nomograms. We sought to validate the Sarculator and MSK nomograms within a large, modern multi-institutional cohort of patients with primary RPS undergoing resection. METHODS: Patients who underwent resection of primary RPS between 2000 and 2017 across nine high-volume US institutions were identified. Predicted 7-year disease-free (DFS) and overall survival (OS) and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated from the Sarculator and MSK nomograms, respectively. Nomogram-predicted survival probabilities were stratified in quintiles and compared in calibration plots to observed survival outcomes assessed by Kaplan-Meier estimates. Discriminative ability of nomograms was quantified by Harrell's concordance index (C-index). RESULTS: Five hundred and two patients underwent resection of primary RPS. Histologies included leiomyosarcoma (30%), dedifferentiated liposarcoma (23%), and well-differentiated liposarcoma (15%). Median tumor size was 14.0 cm (interquartile range [IQR], 8.5-21.0 cm). Tumor grade distribution was: Grade 1 (27%), Grade 2 (17%), and Grade 3 (56%). Median DFS was 31.5 months; 7-year DFS was 29%. Median OS was 93.8 months; 7-year OS was 51%. C-indices for 7-year DFS, and OS by the Sarculator nomogram were 0.65 (95% confidence interval [CI]: 0.62-0.69) and 0.69 (95%CI: 0.65-0.73); plots demonstrated good calibration for predicting 7-year outcomes. The C-index for 4-, 8-, and 12-year DSS by the MSK nomogram was 0.71 (95%CI: 0.67-0.75); plots demonstrated similarly good calibration ability. CONCLUSIONS: In a diverse, modern validation cohort of patients with resected primary RPS, both Sarculator and MSK nomograms demonstrated good prognostic ability, supporting their ongoing adoption into clinical practice.

Donor-derived herpes simplex virus hepatitis in a kidney transplant recipient and review of the literature.

Donor-derived (DD) herpes simplex virus (HSV) hepatitis in solid organ transplant (SOT) recipients is extremely uncommon but carries a high mortality rate. The diagnosis is challenging due to the non-specific presentation and lack of clinical suspicion. We report a case of DDHSV hepatitis in a HSV2 pre-transplant seronegative kidney recipient who received the organ from a HSV2 seropositive donor. The case is highlighted by a few unusual features, namely severe thrombocytopenia and the development of cutaneous, oral and esophageal HSV lesions several weeks after symptom onset while recovering on appropriate treatment. A review of nine proven and probable DDHSV hepatitis cases (including eight previously published ones) showed that fever is a common presenting feature while gastrointestinal symptoms and cutaneous manifestations are uncommon. The symptoms almost always occurred within 2 weeks of transplant. Six out of the nine DDHSV hepatitis patients, including five patients who were on appropriate treatment, died within a month after transplant.

Malignant Tenosynovial Giant Cell Tumor: The True "Synovial Sarcoma?" A Clinicopathologic, Immunohistochemical, and Molecular Cytogenetic Study of 10 Cases, Supporting Origin from Synoviocytes.

We present our experience with ten well-characterized malignant tenosynovial giant cell tumors, including detailed immunohistochemical analysis of all cases and molecular cytogenetic study for CSF1 rearrangement in a subset. Cases occurred in 7 M and 3 F (mean age: 52 years; range: 26-72 years), and involved the ankle/foot (n = 1), finger/toe (n = 3), wrist (n = 1), pelvic region (n = 3), leg (n = 1), and thigh (n = 1). There were eight primary and two secondary malignant tenosynovial giant cell tumors. Histologically, all cases showed definite areas of typical tenosynovial giant cell tumor. The malignant areas varied in appearance. In some cases, isolated malignant-appearing large mononuclear cells with high nuclear grade and mitotic activity were identified within otherwise-typical tenosynovial giant cell tumor, as well as forming larger masses of similar-appearing malignant cells. Occasionally, these nodules of malignant large mononuclear cells showed transition to pleomorphic spindle cell sarcoma, with varying degrees of collagenization and myxoid change. One malignant tenosynovial giant cell tumor was composed of sheets of monotonous large mononuclear cells with high nuclear grade, growing in a hyalinized, osteoid-like matrix, with areas of heterologous osteocartilaginous differentiation. Mitotic activity ranged from 2 to 34 mitoses per 10 HPF (mean 18/10 HPF). Geographic necrosis was observed in four cases. The malignant-appearing large mononuclear cells were consistently positive for clusterin and negative for CD163, CD68, and CD11c. Desmin was positive in a small minority of these cells. Areas in malignant tenosynovial giant cell tumor resembling pleomorphic spindle cell sarcoma or osteo/chondrosarcoma showed loss of clusterin expression. RANKL immunohistochemistry was positive in the large mononuclear cells in eight cases. Two cases showed an unbalanced rearrangement of the CSF1 locus. Follow-up (nine patients; range 0.5-66 months; mean 20 months) showed three patients dead of disease, with three other living patients having lung and lymph node metastases; three patients were disease-free. We conclude that malignant tenosynovial giant cell tumors are highly aggressive sarcomas with significant potential for locally destructive growth, distant metastases, and death from disease. The morphologic and immunohistochemical features of these tumors and the presence of CSF1 rearrangements support origin of malignant tenosynovial giant cell tumor from synoviocytes.

MiR-122 decreases HCV entry into hepatocytes through binding to the 3' UTR of OCLN mRNA.

BACKGROUND & AIMS: Analysis in silico suggests that occludin (OCLN), a key receptor for HCV, is a candidate target of miR-122; the most abundant hepatic micro RNA. We aimed to determine if miR-122 can decrease HCV entry through binding to the 3' UTR of OCLN mRNA. DESIGN: Huh7.5 cells were cotransfected with luciferase construct containing 3' UTR of OCLN (pLuc-OCLN) and with selected miRNAs (0-50 nM) and luciferase activity was measured. Huh7.5 cells were also infected by viral particles containing lenti-miR122 genome or control virus. After 48 h, the cells were infected with HCV pseudo-particles (HCVpp) and VSV pseudo-particles (VSVpp). After 72 h of infection, luciferase activity was measured and HCVpp activity was normalized to VSVpp activity. RESULTS: miR-122 binds to the 3'-UTR of OCLN and down-regulates its expression; cotransfection of miR-122 mimic with pLuc-OCLN resulted in a significant decrease in luciferase activity [by 55% (P < 0.01)], while a non-specific miRNA and a mutant miR-122 did not have any effect. miR-122 mimic significantly down-regulated [by 80% (P < 0.01)] OCLN protein in Huh7.5 cells. Accordingly, patients with chronic hepatitis C and higher levels of hepatic miR-122 have lower hepatic expression of OCLN. Immuno-fluorescence imaging showed a decrease in colocalization of OCLN and CLDN following miR-122 over-expression in HCV infected cells. Huh7.5 cells transiently expressing Lenti-miR122 system showed 42% (P < 0.01) decrease in HCV entry. CONCLUSION: This study uncovers a novel antiviral effect of miR-122 on human liver cells and shows that over-expression of miR-122 can decrease HCV entry into hepatocytes through down-regulation of OCLN.

Sevelamer-Induced Gastrointestinal Disease in 12 Patients with End-Stage Renal Disease: A Case Series.

INTRODUCTION: Isolated case reports and case series have linked the use of sevelamer to severe gastrointestinal (GI) inflammation and perforation among patients with end-stage renal disease. METHODS: In this study, we identified 12 cases of biopsy-proven sevelamer-induced gastrointestinal disease from a large urban community hospital over the course of 5 years. We described baseline characteristics, sites and types of injury, histological findings, timing and dosing of sevelamer initiation compared with symptom onset, and in a smaller subset, endoscopic resolution post drug cessation. We also reviewed preexisting conditions to identify trends in populations at risk. RESULTS: Several of the patients reviewed had preexisting conditions of decreased motility and/or impaired mucosal integrity. The presentation of disease was broad and included both upper-GI and lower-GI pathologies and in varying severity. DISCUSSION: There is a broad phenotypic range of sevelamer-induced gastrointestinal disease. As this becomes a more frequently recognized pathology, clinicians should be aware of how it may present and which populations may be more susceptible.

Lysophosphatidic acid receptor expression and function in human hepatocellular carcinoma.

BACKGROUND: Lysophosphatidic acid (LPA) is a ubiquitously expressed phospholipid that regulates diverse cellular functions. Previously identified LPA receptor subtypes (LPAR1-5) are weakly expressed or absent in the liver. This study sought to determine LPAR expression, including the newly identified LPAR6, in normal human liver (NL), hepatocellular carcinoma (HCC), and non-tumor liver tissue (NTL), and LPAR expression and function in human hepatoma cells in vitro. METHODS: We determined LPAR1-6 expression by quantitative reverse transcriptase polymerase chain reaction, Western blot, or immunohistochemistry in NL, NTL, and HCC, and HuH7, and HepG2 cells. Hepatoma cells were treated with LPA in the absence or presence of LPAR1-3 (Ki16425) or pan-LPAR (α-bromomethylene phosphonate) antagonists and proliferation and motility were measured. RESULTS: We report HCC-associated changes in LPAR1, 3, and 6 mRNA and protein expression, with significantly increased LPAR6 in HCC versus NL and NTL. Analysis of human hepatoma cells demonstrated significantly higher LPAR1, 3, and 6 mRNA and protein expression in HuH7 versus HepG2 cells. Treatment with LPA (0.05-10 µg/mL) led to dose-dependent HuH7 growth and increased motility. In HepG2 cells, LPA led to moderate, although significant, increases in proliferation but not motility. Pretreatment with α-bromomethylene phosphonate inhibited LPA-dependent proliferation and motility to a greater degree than Ki16425. CONCLUSIONS: Multiple LPAR forms are expressed in human HCC, including the recently described LPAR6. Inhibition of LPA-LPAR signaling inhibits HCC cell proliferation and motility, the extent of which depends on LPAR subtype expression.

The use of a novel MUC1 antibody to identify cancer stem cells and circulating MUC1 in mice and patients with pancreatic cancer.

BACKGROUND AND OBJECTIVES: MUC1 is over-expressed and aberrantly glycosylated in >60% of human pancreatic cancer (PC). Development of novel approaches for detection and/or targeting of MUC1 are critically needed and should be able to detect MUC1 on PC cells (including cancer stem cells) and in serum. METHODS: The sensitivity and specificity of the anti-MUC1 antibody, TAB 004, was determined. CSCs were assessed for MUC1 expression using TAB 004-FITC on in vitro PC cell lines, and on lineage(-) cells from in vivo tumors and human samples. Serum was assessed for shed MUC1 via the TAB 004 EIA. RESULTS: In vitro and in vivo, TAB 004 detected MUC1 on >95% of CSCs. Approximately, 80% of CSCs in patients displayed MUC1 expression as detected by TAB 004. Shed MUC1 was detected serum in mice with HPAF-II (MUC1(high) ) but not BxPC3 tumors (MUC1(low)). The TAB 004 EIA was able to accurately detect stage progression in PC patients. CONCLUSIONS: The TAB 004 antibody may be explored as a therapeutic targeting agent for CSCs in PC. The TAB 004 EIA detected circulating MUC1 in a stage-dependent manner in patients with PC and thus may be explored as a PC stage diagnostic biomarker.

Intestinal spirochetosis: an enigmatic disease.

INTRODUCTION: Intestinal spirochetosis (IS) is a condition in which colonic and appendiceal epithelial cells are colonized by one of two anaerobic spirochetes, either the Brachyspira aalborgi or Brachyspira pilosicoli. There is much debate in the literature as to whether IS is a pathogen or a commensal inhabitant. A recent case of IS at our institution prompted a retrospective database search and review of the literature. METHODS: A pathology database search for IS was performed at Carolinas Medical Center from 2003 through 2007. After patient identification, a retrospective review of the endoscopic record and the pathology report was performed. Pathology slides were reviewed for accuracy and special silver stains and/or immunostains were performed if needed. The following data were collected for each patient when available: age, gender, nationality, HIV status, and other co-morbid conditions when noted. We attempted to determine whether patients were treated for spirochetosis and if so, the treatment regimen used as well as the results. RESULTS: The database search detected 29 patients with biopsies showing IS. Three patients were subsequently removed due to incorrect identification. A total of 26 patients with an average age of 45 years were reviewed. The most common symptoms were abdominal pain, diarrhea, and rectal bleeding. Most patients did not exhibit inflammatory changes despite the presence of spirochetosis. Pathologic examination revealed a relative increase in intra-epithelial lymphocytes in a subset of cases, a non-specific finding. Acute colitis or architectural distortion was not seen in any of the study cases. We were only able to obtain follow-up of two patients after treatment with metronidazole and both responded to therapy. CONCLUSIONS: To date, our study is the largest case series that includes both endoscopic and pathologic descriptions and confirms the "bland" nature of the condition. In <20 % of our patients inflammation was present microscopically and it did not correlate well with endoscopic appearance. Symptoms reported by our patients were similar to those reported in previous studies, although our lack of endoscopic changes was different from one previous paper. There is no established standard of care for the treatment of IS and our study, reflects the enigmatic nature of IS as a disease process. In the absence of rigorous literature, physicians will need to use a logical and pragmatic approach to the evaluation and treatment of IS.

Invasive biliary mucinous cystic neoplasm: a review.

OBJECTIVES: Biliary mucinous cystic neoplasms (BMCNs) are recently redefined rare liver tumours in which insufficient recognition frequently leads to an incorrect initial or delayed diagnosis. A concise review of the subtle, sometimes non-specific, clinical, serologic and radiographic features will allow for a heightened awareness and more comprehensive understanding of these entities. METHODS: Literature relating to the presentation, diagnosis, treatment, pathology and outcomes of BMCNs and published prior to March 2012 was reviewed. RESULTS: Biliary mucinous cystic neoplasms most commonly occur in females (≥60%) in the fifth decade of life. Clinical symptoms, serologic markers and imaging modalities are unreliable for diagnosis of BMCNs, which leads to misdiagnosis in 55-100% of patients. Perioperative cyst aspiration is not recommended as invasive BMCNs can only be differentiated from non-invasive BMCNs by microscopic evaluation for the presence of ovarian-type stroma. Intraoperative biopsy and frozen section(s) are essential to differentiate BMCNs from other cystic liver lesions. The treatment of choice is complete excision and can result in excellent survival with initial correct diagnosis. CONCLUSIONS: A low threshold for considering BMCN in the differential diagnosis of cystic liver lesions and increased attentiveness to its subtle diagnostic characteristics are imperative. The complete surgical resection of BMCNs and the use of appropriate nomenclature are necessary to improve outcomes and accurately define prognosis.

Subcellular tissue proteomics of hepatocellular carcinoma for molecular signature discovery.

Hepatocellular carcinoma (HCC) is one of the leading causes of mortality from solid organ malignancy worldwide. Because of the complexity of proteins within liver cells and tissues, the discovery of therapeutic targets of HCC has been difficult. To investigate strategies for decreasing the complexity of tissue samples for detecting meaningful protein mediators of HCC, we employed subcellular fractionation combined with 1D-gel electrophoresis and liquid chromatography-tandem mass spectrometry analysis. Moreover, we utilized a statistical method, namely, the Power Law Global Error Model (PLGEM), to distinguish differentially expressed proteins in a duplicate proteomic data set. Mass spectrometric analysis identified 3045 proteins in nontumor and HCC from cytosolic, membrane, nuclear, and cytoskeletal fractions. The final lists of highly differentiated proteins from the targeted fractions were searched for potentially translocated proteins in HCC from soluble compartments to the nuclear or cytoskeletal compartments. This analysis refined our targets of interest to include 21 potential targets of HCC from these fractions. Furthermore, we validated the potential molecular targets of HCC, MATR3, LETM1, ILF2, and IQGAP2 by Western blotting, immunohistochemisty, and immunofluorescent microscopy. Here we demonstrate an efficient strategy of subcellular tissue proteomics toward molecular target discovery of one of the most complicated human disease, HCC.

A Normal FGF23 Does Not Preclude Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte-derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45-year-old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44-215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate-regulating endopeptidase homolog, X-linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma.

PURPOSE: Doxorubicin is standard therapy for advanced soft-tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings of advanced STS. PATIENTS AND METHODS: This single-center, single-arm, phase II trial enrolled patients with unresectable or metastatic STS with no prior anthracycline therapy. Patients received pembrolizumab 200 mg i.v. and doxorubicin (60 mg/m2 cycle 1 with subsequent escalation to 75 mg/m2 as tolerated). The primary endpoint was safety. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) based on RECIST v1.1 guidelines. RESULTS: Thirty patients were enrolled (53.3% female; median age 61.5 years; 87% previously untreated) with 4 (13.3%) patients continuing treatment. The study met its primary safety endpoint by prespecified Bayesian stopping rules. The majority of grade 3+ treatment-emergent adverse events were hematologic (36.7% 3+ neutropenia). ORR was 36.7% [95% confidence interval (CI), 19.9-56.1%], with documented disease control in 80.0% (95% CI, 61.4-92.3%) of patients. Ten (33.3%) patients achieved partial response, 1 (3.3%) patient achieved complete response, and 13 (43.3%) patients had stable disease. Median PFS and OS were 5.7 months (6-month PFS rate: 44%) and 17 months (12-month OS rate: 62%), respectively. Programmed cell death ligand-1 (PD-L1) expression was associated with improved ORR, but not OS or PFS. CONCLUSIONS: Combination pembrolizumab and doxorubicin has manageable toxicity and preliminary promising activity in treatment of patients with anthracycline-naive advanced STS.

Pulmonary Carcinosarcoma: A Surveillance, Epidemiology, and End Results (SEER) Analysis.

INTRODUCTION: Pulmonary carcinosarcoma (PC) is a rare malignant neoplasm composed of epithelial and mesenchymal components. It accounts for < 1% of thoracic cancers and is not fully understood. This study examined Surveillance, Epidemiology, and End Results (SEER) data to describe demographic and clinical characteristics of patients with PC and assessed survival outcomes by treatment modality and stage. PATIENTS AND METHODS: SEER data were reviewed to identify patients diagnosed with primary PC (1973-2012). Overall survival (OS) and disease-specific survival (DSS) were analyzed by univariate/multivariable Cox proportional hazards models and Kaplan-Meier methods. RESULTS: A total of 411 patients were included. Median age was 67 (range, 24-96) years. Disease stage at the time of initial diagnosis was known for 74.7% of the identified patients (307/411). Of these patients, 23.1% had localized disease. Survival was significantly better for patients with localized disease (OS: 31 vs. 6 months, P < .001; DSS: 54 vs. 8 months, P < .001). Additionally, patients who received surgery alone had significantly improved OS (20 months; P < .001) and DSS (32 months; P < .001) compared to patients who received combined surgery and radiotherapy (OS: 7 months; DSS: 8 months) or radiotherapy alone (OS: 4 months; DSS: 4 months). CONCLUSION: Treatment with surgery alone resulted in superior survival outcomes compared to other treatment modality combinations, regardless of patient age and disease stage. Within the limitations of this study, providers may wish to consider these findings when devising patient treatment plans.

Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil.

Mycophenolate mofetil, an immunosuppressive agent, is frequently used following bone marrow and solid organ transplantation. Diarrhea is a commonly seen side effect of mycophenolate mofetil, which may necessitate colonic biopsy in some patients. The histologic changes found in this setting have been reported to mimic self-limited colitis, graft-vs-host disease or inflammatory bowel disease in isolated case reports, and could pose diagnostic and management difficulties. The goal of this study is to define the spectrum of histologic changes in colonic biopsies associated with mycophenolate mofetil usage. All solid organ transplant patients who received mycophenolate mofetil and underwent colonic biopsy for gastrointestinal symptoms from 1999 to 2007 were included in the study. Patients who did not receive mycophenolate mofetil were used as controls. Various histologic features including architectural distortion, apoptosis, inflammatory infiltrate, Paneth cell metaplasia and mucin depletion were subjectively evaluated and scored (scale: 0-3) by two independent reviewers in a blinded fashion. Forty solid organ transplant patients underwent colonic biopsy for gastrointestinal symptoms during the study period. Biopsies from 69% of patients on mycophenolate mofetil showed histologic changes. Apoptosis (41%) and architectural distortion (66%) were seen more frequently in patients receiving mycophenolate mofetil as compared to the control group (13%). The histologic changes in patients receiving mycophenolate mofetil were categorized as normal/near normal (31%), inflammatory bowel disease-like (28%), graft-vs-host disease-like (19%), ischemia-like (3%) and self-limited colitis-like (16%) changes. Of the controls, only one patient showed a graft-vs-host disease-like histologic pattern. In conclusion, histologic changes are frequently associated with mycophenolate mofetil use and can resemble self-limited colitis, graft-vs-host disease and inflammatory bowel disease leading to diagnostic difficulties. Increased awareness of the histologic spectrum of mycophenolate mofetil-induced changes is required by the pathologist to avoid diagnostic errors.

Anatomical, histologic, and genetic characteristics of congenital chest wall deformities.

There is a large and diverse group of congenital abnormalities of the thorax that manifest as deformities and/or defects of the anterior chest wall and, depending on the severity and concomitant anomalies, may have cardiopulmonary implications. Pectus excavatum, the most common anterior chest deformity, is characterized by sternal depression with corresponding leftward displacement and rotation of the heart. Pectus carinatum, the second most common, exhibits a variety of chest wall protrusions and very diverse clinical manifestations. The cause of these conditions is thought to be abnormal elongation of the costal cartilages. Collagen, as a major structural component of rib cartilage, is implicated by genetic and histologic analysis. Poland syndrome is a unique unilateral chest/hand deficiency that may include rib defects, pectoral muscle deficit, and syndactyly. Cleft sternum is a rare congenital defect resulting from nonfusion of the sternal halves, which leaves the heart unprotected and requires early surgical intervention.