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Introduction: Chronic viral hepatitis is a condition of hepatotropic viral infection associated with chronic inflammation, hepatocyte injury and progressive fibrosis. Non-invasive assessment of liver fibrosis in chronic hepatitis B and C patients has been increasing and used instead of liver biopsy. Aim: To assess the diagnostic performance of ElastPQ Point Shear Wave Elastography (ElastPQ PSWE) with liver biopsy as the gold standard and comparing these results with other serum fibrosis markers namely Aspartate to Platelet Ratio Index (APRI), Fibrosis-4 Score (FIB4). Materials and Methods: A cross-sectional study was carried out in which 73 patients underwent ElastPQ PSWE and Histopathological Examination (HPE) with METAVIR Scoring system staging. Serum fibrosis indices including APRI and FIB4 values were calculated. The diagnostic performance of ElastPQ PSWE, APRI and FIB4 was evaluated using Area Under Receiver Operating Characteristic (AUROCAUROC) curve analysis, correlations of ElastPQ PSWE, APRI and FIB4 ratio index with histopathological findings (as the reference standard) were determined using Spearman’s correlation coefficient. Results: Study included 73 patients with chronic hepatitis B and hepatitis C, of which 8 (10.96%) were no/early fibrosis (F0- F1); 20 (27.40%) were significant fibrosis (F2); 22 (30.13%) were severe fibrosis (F3), and 23 (31.51%) were cirrhosis (F4). There was a significant positive correlation between different stages of liver fibrosis by liver biopsy and liver stiffness detected by ElastPQ PSWE (r=0.912, p

Introduction: Hazardous alcohol use and diabetes are the major risk factors for development of liver cirrhosis. The presence and progression of hepatic fibrosis into cirrhosis is a prognostic variable having impact on survival in people with hazardous alcohol use and Type 2 Diabetes Mellitus. Liver biopsy is an invasive method for diagnosis and staging of hepatic fibrosis. Shear Wave Elastography (SWE) is a non-invasive method for assessing and staging hepatic fibrosis. Aim: To evaluate SWE as a non-invasive technique along with biomarker parameters as an algorithm for early detection of liver fibrosis in Type 2 Diabetes and hazardous alcohol use patients and to compare the results of shear wave ultrasound elastography in liver fibrosis with AST/ALT ratios, AST Platelet Ratio Index (APRI scores), and Fibrosis-4 (FIB-4) scores. Materials and Methods: A prospective cross-sectional study was conducted in a tertiary care hospital attached to Mysore Medical College and Research Institute, Mysore, Karnataka, India, from July 2018 to June 2019. Based on inclusion and exclusion criteria 460 patients were recruited for the study. For each patient, AST, ALT, platelet count and SWE values were measured. Patients with normal serum biomarkers and elevated SWE results were subjected to liver biopsy to confirm the diagnosis. Student’s t-test, Analysis of Variance (ANOVA), Chi-square/fisher-exact test was used to find the significance of study parameters. ANOVA was used to compare the SWE findings with the biochemical parameters. Results: SWE identified 75 patients with normal values, 2.2 m/sec (Group C). SWE showed positive correlation with APRI (p

An overview of the conditions underlying the flourlshing Bangladeshi trafficking trade. Cross-border sales of women and girls are common, and prostitution is said to function on a scale comparable to other domestic industry. However, gaining an accurate understanding of the magnitude of traficking is made very difficult by a lack of proper documentation. Despite legal provisions prohibiting the flesh trade, the abuse of well-intentioned laws results in a successful evasion of penalization by the many who benefit from the trafficking of women and girls.

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal-Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3-4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: This was a single-arm, phase 2 clinical trial of Bavarian Nordic (BN)-Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression-free survival (PFS), and safety of the combination in chordoma., Methods: A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients., Results: Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study., Conclusions: This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity., (© 2024 American Cancer Society.)

Cardiac tumors are rare and encompass a variety of presentations. Clinica symptoms are usually nonspecific, but they can present as obstructive, embolic, or constitutional symptoms. Treatment options and prognosis vary highly depending on the subtype, tumor size, and location. Surgical resection is usually the first-line therapy, except for cardiac lymphomas, and provides favorable long-term prognosis in most benign tumors. Cardiac sarcomas, however, are usually diagnosed in advanced stages, and the treatment relies on a multimodal approach with chemotherapy and radiotherapy. Metastatic cardiac tumors are usually related to advanced disease and carry an overall poor prognosis.

Background: Undifferentiated small round-cell sarcomas (uSRCSs) are a subgroup of sarcomas that are difficult to diagnose. Some uSRCSs have specific gene re-arrangements, but others do not. Currently, there is no specific treatments for advanced uSRCSs, and its treatment is largely based on general experience with sarcomas, which includes chemotherapy, targeted therapy, and immunotherapy. In this article, we report a patient with uSRCS who responded to treatment with anti-VEGF inhibitor surufatinib and anti-PD-1 inhibitor camrelizumab after progression on first-line chemotherapy, second-line anlotinib combined with immunotherapy, and third-line chemotherapy., Case Description: In July 2020, a 37-year-old female patient was diagnosed with advanced uSRCS. Results for the Ewing sarcoma RNA binding protein 1 and Wilms tumor suppressor (EWSR1/WT1) fusion gene were negative. The patient was also negative with BCOR (BCL6 co-repressor) and CIC (capicua transcriptional repressor) fusion gene. The next-generation sequencing results revealed point mutations on Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Beta (PIK3CB), Transcription Factor Binding To IGHM Enhancer 3 (TFE3), Mucin 16 (MUC16), and AXL (Axl, also called UFO, ARK, and Tyro7, is part of a family of receptor tyrosine kinases). The patient received 4 cycles of the Ifosfamide and epirubicin hydrochloride regimen, and her best objective response was stable disease. On November 3, 2020, a computed tomography (CT) scan revealed progressive disease (PD). Two cycles of camrelizumab (a programmed death-1 inhibitor) plus anlotinib (an anti- vascular endothelial growth factor drug) were administered, but PD was again observed. Thus, a regimen of gemcitabine plus docetaxel was adopted. Unfortunately, the disease progressed once again after two cycles of the treatment. On February 4, 2021, the patient began to receive targeted therapy with surufatinib combined with camrelizumab. A CT scan showed that the tumor achieved a partial response. As of April 2023, the patient had a progression-free survival time of 26 months., Conclusions: Surufatinib in combination with camrelizumab could be effective in the treatment of advanced uSRCSs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Huang, Chen, Ye, Du, Voutsadakis, Seetharam, Zhang and Lu.)

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth., Patients and Methods: NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m 2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay., Results: Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51., Conclusion: Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Vesiculoviruses are attractive oncolytic virus platforms due to their rapid replication, appreciable transgene capacity, broad tropism, limited preexisting immunity, and tumor selectivity through type I interferon response defects in malignant cells. We developed a synthetic chimeric virus (VMG) expressing the glycoprotein (G) from Morreton virus (MorV) and utilizing the remaining structural genes from vesicular stomatitis virus (VSV). VMG exhibited in vitro efficacy by inducing oncolysis in a broad range of sarcoma subtypes across multiple species. Notably, all cell lines tested showed the ability of VMG to yield productive infection with rapid replication kinetics and induction of apoptosis. Furthermore, pilot safety evaluations of VMG in immunocompetent, non-tumor-bearing mice showed an absence of toxicity with intranasal doses as high as 1e10 50% tissue culture infectious dose (TCID 50 )/kg. Locoregional administration of VMG in vivo resulted in tumor reduction in an immunodeficient Ewing sarcoma xenograft at doses as low as 2e5 TCID 50 . In a murine syngeneic fibrosarcoma model, while no tumor inhibition was achieved with VMG, there was a robust induction of CD8+ T cells within the tumor. The studies described herein establish the promising potential for VMG to be used as a novel oncolytic virotherapy platform with anticancer effects in sarcoma., Competing Interests: M.J.B. has received grants to their institution from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Five Prime Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun Biopharma, Isis Pharmaceuticals, Redhill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, Sillajen, ARIAD Pharmaceuticals, PUMA Pharmaceuticals, Novartis Pharmaceuticals, QED Pharmaceuticals, and Pieris Pharmaceuticals; consultancy fees from ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, and Lynx Group; and travel support from Astra Zeneca. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. M.J.B. and B.M.N. declare that they filed a patent application for the vectors and their derivatives included in this manuscript., (© 2023 The Author(s).)

Abstract: A 39-year-old man presented with progressive dyspnea and lower extremity edema. Doppler ultrasound demonstrated bilateral leg partially occluded venous thromboses. A V/Q scan revealed a mismatched perfusion defect involving the entire right middle and lower lobes. Subsequent CT pulmonary angiogram revealed a mass lesion occluding the right interlobar pulmonary artery. Endobronchial ultrasound-guided fine-needle aspiration of the mass was concerning for neoplasm. 18 F-FDG PET/CT demonstrated marked hypermetabolism of the mass lesion. Patient underwent transmediastinal right pneumonectomy with histopathologic diagnosis of pulmonary artery angiomatoid fibrous histiocytoma, a rare etiology mimicking large pulmonary artery embolism., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In patients with extremity soft tissue sarcoma (eSTS), we describe outcomes of preoperative external beam radiation therapy (EBRT), limb-sparing surgery (LSS), and intraoperative electron radiation therapy (IOERT)., Methods: One hundred and eighteen patients with eSTS treated between October 17, 2002 and July 28, 2021 were identified. EBRT was delivered preoperatively followed by LSS and IOERT., Results: The median follow-up was 24.9 months. The presentation was primary in 102 (94%) patients and recurrent in 6 (6%) patients. Tumor location was lower extremity in 82 (76%) patients and upper extremity in 26 (24%) patients. Stage distribution was as follows: 3 (3%) IA, 24 (22%) IB, 31 (29%) II, 24 (22%) IIIA, and 25 (23%) IIIB. Final surgical margins were negative in 96 (89%) patients. The 5-year local control, failure-free survival, and overall survival were 94%, 75%, and 64%, respectively. Univariate analysis identified age >50, lower extremity, and higher grade as significant negative prognostic factors for overall survival. Grade 3 fracture or osteoradionecrosis requiring surgical fixation, neuropathy, and lymphedema occurred in 7 (6%), 1 (1%), and 0 patients, respectively., Conclusions: This study represents one of the largest series using preoperative EBRT, LSS, and IOERT for eSTS, with high local control and a low rate of late severe toxicity., (© 2022 Wiley Periodicals LLC.)

Oncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW ( NCT03037385 , ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET-altered solid tumors. Twenty-nine patients with 12 different RET fusion-positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35-77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib's potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion-positive solid tumors., (© 2022. The Author(s).)

Purpose: Proton beam therapy (PBT) may provide an advantage when planning well-selected patients with extremity soft tissue sarcoma (eSTS), specifically for large, anatomically challenging cases. We analyzed our early experience with PBT on toxicity and outcomes., Materials and Methods: A retrospective study was performed for eSTS treated between June 2016 and October 2020 with pencil beam scanning PBT at 2 institutions. Diagnostic, treatment, and toxicity characteristics were gathered from baseline to last follow-up or death. Wound complications were defined as secondary operations for wound repair (debridement, drainage, skin graft, and muscle flap) or nonoperative management requiring hospitalization. Statistical analysis was performed with R software., Results: Twenty consecutive patients with a median age 51.5 years (range, 19-78 years) were included. Median follow-up was 13.7 months (range, 1.7-48.1 months). Tumor presentation was primary (n = 17) or recurrent after prior combined modality therapy (n = 3). Tumor location was either lower extremity (n = 16) or upper extremity (n = 4). Radiation was delivered preoperatively in most patients (n = 18). Median pretreatment tumor size was 7.9 cm (range, 1.3 -30.0 cm). The 1-year locoregional control was 100%. Four patients (20%) had developed metastatic disease by end of follow-up. Maximum toxicity for acute dermatitis was grade 2 in 8 patients (40%) and grade 3 in 3 patients (15%). After preoperative radiation and surgical resection, acute wound complications occurred in 6 patients (35%). Tumor size was larger in patients with acute wound complications compared with those without (medians 16 cm, range [12-30.0 cm] vs 6.3 cm, [1.3-14.4 cm], P = .003)., Conclusion: PBT for well selected eSTS cases demonstrated excellent local control and similar acute wound complication rate comparable to historic controls. Long-term follow-up and further dosimetric analyses will provide further insight into potential advantages of PBT in this patient population., Competing Interests: Conflicts of Interest: The authors have no relevant conflicts of interest to disclose., (©Copyright 2022 The Author(s).)

Background: Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)-targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone., Methods: In this phase I/II study, patients received intravenous enoblituzumab (3-15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non-small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]-naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts., Results: Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC., Conclusions: Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC., Trial Registration Number: NCT02475213., Competing Interests: Competing interests: CA reports personal fees from AstraZeneca, BluPrint Oncology, Celgene, Eli Lilly, Merck, Daiichi Sankyo for advisory boards, and research funding to the institution from Merck, MacroGenics, Novartis, and AstraZeneca; SA reports consulting fees from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, GlaxoSmithKline, Amgen, travel expenses from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, and grants from Novartis; VA reports personal fees and non-financial support from Bristol-Myers Squibb, and personal fees from Merck, MSD, Novartis, QBiotics, Nektar, Roche, Pierre Fabre; RC reports grants paid to the institution from MacroGenics, Merck, personal fees from AstraZeneca, grants to the institution and personal fees from Innate Pharma, Genocea Biosciences, Heat Biologics, advisory boards for Innate Pharma, Genocea Biosciences, AstraZeneca, Heat Biologics, Cantargia, research funding from Celldex, Kyn Therapeutics, Merck, Genocea Biosciences, Xencor, Innate Pharma, Heat Biologics, and travel expenses from Heat Biologics, Innate Pharma, Genocea Biosciences; RLF reports consulting fees from Aduro Biotech, Novasenta, Sanofi, Zymeworks, honoraria from Bristol-Myers Squibb, EMD Serono, MacroGenics, Merck, Numab Therapeutics, Pfizer for advisory boards, research funds to institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Novasenta, Tesaro, clinical trial support from AstraZeneca/MedImmune, Bristol-Myers Squibb, Merck, and stocks in Novasenta; VG reports honoraria from AstraZeneca, Roche/Genentech; ARK reports holding stocks in ECOM Medical, receiving consulting fees from Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, Bristol-Myers Squibb, EMD Serono, serving on Speakers’ Bureau at Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, Bristol-Myers Squibb, Amgen, Exelixis, EMD Serono, Merck, Seattle Genetics/Astellas, receiving research funding to the institution from Genentech, Exelixis, Janssen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, MacroGenics, Astellas Pharma, beyond spring, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics, Epizyme, and receiving travel expenses from Genentech, Prometheus Laboratories, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis, AstraZeneca; SK reports consulting fees from MacroGenics and is a stock holder of Abbott, Aqua, Bank of America, Baxter, Betterment, Bristol-Myers Squibb, Etrade, ExxonMobil, Invesco, Johnson & Johnson, Lockheed Martin Corp, Marathon Oil, Marathon Petroleum, Pfizer, Takeda Pharm Co, Verizon, Welltower, Vanguard; NL reports research funding from ALX Therapeutics, Ascentage, Asana, BeiGene, Constellation Pharma, Alexion, Cerulean, Forty Seven, Alpine, Merck, Pfizer, Regeneron, TaiRx, Apexian, Formation Biologics (Forbius), Symphogen, CytomX, InhibRx, Incyte, Jounce, Livzon, Northern Biologics, Innovent Biologics, Ikena, Odonate, Loxo, Alpine Biosciences, Ikena, Mersana, and serves on advisory boards for Innovent Biologics; YL reports research funding from Merck, MacroGenics, Tolero Pharmaceuticals, AstraZeneca, Vaccinex, Blueprint Medicines, Harpoon Therapeutics, Sun Pharma Advanced Research, Kyowa Pharmaceuticals, Tesaro, Bayer HealthCare, honorarium from Clarion Healthcare, served on the advisory board for AstraZeneca, Novocure, and consultant for AstraZeneca; OR reports research support from Merck, Speakers’ Bureau activities supported by educational grants from Bristol-Myers Squibb and Merck, and honoraria for consulting activities for Merck, Celgene, Five Prime, GlaxoSmithKline, Bayer, Roche/Genentech, Puretech, Imvax, Sobi. In addition, OR has a patent pending for 'Methods of using pembrolizumab and trebananib'; MS received honoraria from Deciphera Pharmaceuticals and Daiichi Sankyo for serving on advisory boards; AT reports consulting fees from AbbVie, Adagene, Agenus, Aro Biotherapeutics, Ascentage, Aximmune, Bayer, BioInvent, Birdie, Cello Health, Ellipses, EMD Serono, Five Prime, Forbius, Gilde Healthcare Partners, HBM Partners, Immunomet, Karma Oncology, Mekanistic, Menarini, Mersana, Nanobiotix, Nuvalent, OSI, Partner Therapeutics, Pfizer, Pieris, Pierre Fabre, Ridgeway, RYVU Therapeutics, Scitemex, Seattle Genetics, Symphogen, Syneos, TFS Trial Form Support, and Trillium Therapeutics, and honoraria from Abgenomics, Adagene, ADC Therapeutics, Aro Biotherapeutics, BioInvent, Elucida, Immunome, Jazz, NBE Therapeutics, Pelican, Innate Pharma, TFS Trial Form Support International, and Zymeworks for serving on advisory boards. In addition, AT serves on the Independent Data Monitoring Committees for Mirati and Genentech; NV reports non-financial support for conducting trials with Amgen, Aravive, Arrowhead, Arvinas, AstraZeneca, Bayer, Bristol-Myers Squibb, Calithera, Clovis, Corvus, Dendreon, eFFECTOR, Eisai, Endocyte, Epizyme, ESSA, Exelixis, Genentech, Immunomedics, Kangpu, Kinter Suzhou, MacroGenics, Merck, Mirati, Nektar, Novartis, Seattle Genetics, Tolero, advisory boards for Amgen, Astellas, AstraZeneca, Aveo, Caris, Clovis, Corvus, Eisai, Exelixis, GeneCentric, Genentech, Janssen, Merck, Myovant, OnQuality Pharma, Pfizer, Sanofi-Genzyme, Tolero, serves on the Speakers’ Bureau at Bayer, Caris, Clovis, Sanofi-Genzyme, Seattle Genetics, consulting services to Cancer Expert Now, vice-chair responsibilities at SWOG, section editor at Up-To-Date, and legal defense advisor to Novartis, Sanofi-Genzyme; AW reports grants from Merck, grants and personal fees from Bristol-Myers Squibb, personal fees from Ipsen, Pfizer; DPZ received institutional research support from Merck, Bristol-Myers Squibb, GlaxoSmithKline, AstraZeneca, Aduro Biotech, Lilly, Astellas, MacroGenics for his role as a PI of clinical trials sponsored by these companies and received honoraria from Blueprint Medicines for serving on an advisory board; SMG is a former employee of MacroGenics serving as medical monitor; XZ, RC, and LP are employees of MacroGenics; JB was an employee of MacroGenics; PAM is an employee of MacroGenics, holds stock in MacroGenics, and holds a patent with all rights assigned to MacroGenics for 'Antibodies reactive with B7-H3, immunologically active fragments thereof' US Patent 9,150,656; EB is an employee of MacroGenics, holds stock in MacroGenics, and has a patent US20190389952 pending to MacroGenics; FA was an employee of MacroGenics and is now an employee of AstraZeneca; AP, AAA, AB, RH, and AMJ have nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Ocular melanoma (OM) is a rare noncutaneous malignancy and consists of 2 different subtypes based on the anatomic location in the eye: uveal melanoma and conjunctival melanoma. Like cutaneous melanoma, OM benefits from nuclear medicine and molecular imaging in nodal staging and clinical management. Through the illustration of 2 distinctive cases, we aim to demonstrate the complementary roles of standard lymphoscintigraphy, advanced SPECT/CT, 18 F-FDG PET/CT, and 18 F-FDG PET/MRI in accurate nodal staging and surveillance of OM. We also review the epidemiology, existing staging guidelines, and management of uveal melanoma and conjunctival melanoma., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Targeted therapy has shown to be a very effective treatment in tumors with specific genomic drivers. Trk has proven to be one such target. Efforts to target the Trk fusion with specific inhibitors have shown remarkable responses in a tumor agnostic fashion, with responses seen even in patients with intracranial metastasis. Entrectinib is a first-generation Trk inhibitor with impressive activity in early phase trials performed in patients with NTRK fusion positive solid tumors and ROS1 positive non-small-cell lung cancers with subsequent approval for those indications. Entrectinib was also found to be effective in treatment of brain metastasis and generally well tolerated.

Background: Cytotoxic chemotherapy remains the standard of care first-line treatment for advanced and metastatic soft-tissue sarcomas (STSs). Certain patients may not be chemotherapy candidates based upon age or co-morbidities, leaving limited treatment options. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA-approved for metastatic STS after the first line. We proposed a phase II study evaluating pazopanib as a first-line agent in patients with advanced disease who are deemed not to be candidates for chemotherapy., Methods: Eligible patients were at least 18 years old, not candidates for chemotherapyand were treatment naive. Pazopanib was titrated from 200 mg twice daily to a goal of 800 mg daily. The primary end point was the clinical benefit rate (CBR) (CBR = completed response + partial response + stable disease per Response Evaluation Criteria in Solid Tumours [RECIST 1.1]) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesised CBR of ≥35% against an unfavourable CBR of ≤20%. If ≥ 17 patients achieved benefit, the null CBR of 20% would be rejected at a nominal 5% alpha level. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life and serum biomarkers., Findings: Fifty-six patients were enrolled from May 2015 to February 2019 and are included in the intention-to-treat analysis. Median PFS was 3.67 (2.62-7.25) months. Median OS was 14.16 (95% confidence interval [CI]: 8.4-NR) months, CBR = 39.29% (22/56) (CI = 0.265-0.533, p = 0.0007). No new or unexpected adverse events were seen. The most common grade I-II events were diarrhoea, nausea and fatigue. The most common grade III-IV events were hypertension and liver function test abnormalities., Interpretation: These data suggest that there is a benefit to front-line pazopanib in patients with STS who are not candidates for cytotoxic chemotherapy., Competing Interests: Conflict of interest statement M.A. reports receiving consultation fees from Novartis, Lilly, Immune Design, Bayer; Speaker Bureau: Janssen, Eisai, BMS, Bayer. V.M. reports receiving travel funding from Deciphera; has received research funding from Immunocellular and Orbus Therapeutics. M.M. reports being a member of the consultant/advisory boards with Amgen, Trieza, Biontech, Blueprint Medicine, Immunocore, Array BioPharma, INC. S.R. reports receiving research support from TRACON Pharmaceutical; has been a member of the advisory boards with BTG International and the Society of Interventional Radiology Foundation; has received honoraria to institution; all outside the submitted work. S.A. has received research funding from Desmoid Tumor Research Foundation; has also received research funding to Institution from AB Science, TRACON Pharma, CytRx Corporation, Bayer, Novartis, Daiichi Sankyo, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics; has received travel fees, accommodation expenses and general expenses from Immune Design. B.V.T. has received Basic Science Grant Funding from Pfizer, Tracon and Merck; has received consulting fees from Epizyme, Lilly, CytRx, Janssen, Immune Design, Daiichi Sankyo, Plexxikon and Adaptimmune; has received speaking fees from Caris, Janseen and Lilly; and has received travel support from Adaptimmune and Lilly. All the authors have no conflict of interests to disclose., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients-72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS.

Background: Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials., Methods: In this multi-center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first-line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox regression., Results: At start of first-line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first-line therapy for SS was 24.7 months (95% CI, 20.9-29.4) and 7.5 months, respectively (95% CI, 6.4-8.4). Median OS and median PFS from start of first-line therapy for MRCL was 29.9 months (95% CI, 27-44.6) and 8.9 months (95% CI 4.5-12.0)., Conclusions: To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real-world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature., (© 2020 The Authors and Merck Sharp & Dohme Corp. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors., Methods: All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (QuadWT). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and QuadWT., Results: A total of 102 patients were included in this study of which 14 had mutations of CDKN2A (CDKN2Amut), 21 had TP53 mutations (TP53mut), and 12 were QuadWT. TP53mut, CDKN2Amut and QuadWT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2Amut cohort and a trend towards worsened median TTP in the QuadWT cohort., Conclusion: Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used., Competing Interests: The authors have declared that no competing interests exist.

Trichoblastic carcinoma is an uncommon malignant neoplasm arising from follicular germinative cells. The high-grade trichoblastic carcinoma has been reported with lymphatic and hematogenous dissemination. The authors present a 59-year-old man with gluteal cleft trichoblastic carcinoma and highlight the useful role of serial F-FDG PET/CT examinations in the demonstration of initial and subsequent nodal metastasis in the inguina and pelvis.

Opinion Statement: Soft tissue sarcomas are rare cancers with an expected incidence of about 14,000 new cases in 2018, and account for less than 1% of all cancers. It includes in excess of 75 heterogeneous subtypes with varying biology, molecular aberrations, and variable response to treatment. Because of the rarity of these tumors and the many different subtypes, there is no large-scale data to guide treatment, and hence the need for a multidisciplinary individualized approach to treatment, preferably at a high-volume tertiary referral center. For localized disease, surgery with or without radiation is the preferred treatment. In metastatic disease, the longest track record is with use of anthracyclines, either alone or in combination with ifosfamide, but the median overall survival even with combination was just over a year. There have been recent advances in understanding the heterogeneity of these tumors and the need for an individualized approach. With that new knowledge, recent approvals of trabectedin, eribulin, and pazopanib have been limited to some select histologic subtypes with improved outcomes. More recently, immunotherapy has been tested in select histotypes of sarcoma with encouraging activity and has led to further evaluation in combination with immunotherapeutic agents, as well as with chemotherapy and radiation treatments. Here, in this article, we summarize the data of the currently approved therapies in metastatic soft tissue sarcoma, with the principal focus on first-line therapies. We also review the recent encouraging data with PDGFR-targeted antibody (olaratumab) with doxorubicin which showed an impressive improvement in overall survival in phase II study. Molecular characterization of sarcoma subtypes will likely improve understanding of these very diverse tumors and improve target characterization. The ongoing efforts in better understanding these rare tumors hold the key to make a difference in the outcome of these patients.

Soft tissue sarcomas are a group of rare tumors of mesenchymal origin, and account for less than 1% of all cancers. The most commonly used drug for the treatment of soft tissue sarcoma is anthracycline chemotherapeutic agent, doxorubicin. The major limitation for doxorubicin is cardiotoxicity. Hence, to overcome this limitation and to increase efficacy, aldoxorubicin was developed, which has demonstrated activity in soft tissue sarcomas without much cardiotoxicity. In this review article, we discuss mechanism of action, pharmacokinetics, preclinical studies, clinical trial data and safety profile of aldoxorubicin and its potential applicability in the future of sarcoma treatment.

Eribulin is a structurally simplified, synthetic macrocyclic ketone analog of halichondrin B, which is a natural, polyether macrolide derived from marine sponges. Eribulin exerts its cytotoxicity by its unique microtubule dynamics inhibitory action. Eribulin was approved in 2010 by the US FDA as a third-line therapy for metastatic breast cancer patients previously treated with an anthracycline and a taxane. In 2016, it was approved for treatment of metastatic liposarcoma for patients who have progressed with anthracycline treatment. In this article, we review the pharmacokinetics, mechanism of action of eribulin with focus on preclinical and clinical data in sarcoma and also the role of miRNAs in soft tissue sarcomas.

Esthesioneuroblastoma (ENB) is an uncommon sinonasal tract tumor, and it is even more uncommon among all neoplasms. Literature regarding the incidence and spread of the disease is limited. The prognosis of metastatic disease is poor. In this report, we present a case of recurrent ENB in a young woman involving metastasis to the neck, lungs, and ovary. Metastasis to the cervical lymph nodes is relatively common, but metastasis to the lungs is rare. Furthermore, to our knowledge, no cases of ovarian metastases of ENB have been reported. This case highlights the potential for widespread metastatic disease, suggesting the need for more frequent and thorough surveillance of patients diagnosed with recurrences of this tumor.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare microvascular occlusive disorder characterized by systemic intravascular aggregation of platelets, thrombocytopenia, and mechanical injury to red blood cells. We report a rare case of pernicious anemia presenting as TTP in a Jehovah's Witness., Case Report: A 46-year-old Jehovah's Witness female presented with epigastric pain, vomiting, and diarrhea for 2 days and fatigue and paresthesias for 4 weeks. Initial laboratory evaluation showed severe anemia and thrombocytopenia with elevated total bilirubin and lactate dehydrogenase. Peripheral blood smear showed schistocytes, macroovalocytes, and hypersegmented neutrophils. TTP was suspected and plasmapheresis was offered. The patient refused it due to her religious beliefs. Due to the presence of macroovalocytes and hypersegmented neutrophils, vitamin B12 level was checked and found to be extremely low. Anti-intrinsic factor antibodies and anti-parietal cell antibodies were also positive; hence a diagnosis of pernicious anemia was established. Treatment with intramuscular vitamin B12 was initiated, which resulted in dramatic neurologic and hematologic improvement., Discussion: Vitamin B12 deficiency can lead to elevated levels of homocysteine in the blood. Homocysteine can cause endothelial dysfunction, which can lead to formation of microvascular thrombi. Due to this phenomenon, vitamin B12 deficiency can rarely present with schistocytes and thrombocytopenia, which combined with other stigmata of vitamin B12 deficiency, can be misdiagnosed as TTP., (© 2015 AABB.)

Objectives: The 2008 World Health Organization (WHO) classification system grouped bilineal and biphenotypic acute leukemias together under a new heading of mixed phenotype acute leukemia (MPAL). The lineage-specific marker criteria have also changed for a diagnosis of MPAL. The goal of this study was to characterize clinical significance of this new group., Methods: Sixty-one patients diagnosed with MPAL using either European Group for the Immunological Classification of Leukaemias (EGIL) criteria or 2008 WHO criteria were included in this study., Results: Sixteen patients (26%) diagnosed with acute biphenotypic leukemia using EGIL criteria did not fulfill 2008 WHO criteria for MPAL. Cytogenetic data were available for 32 patients, and the most common abnormality was t(9;22) (five of 32 cases). Clinical outcome data suggested that younger patients with MPAL (≤21 years) had better overall survival (OS) in both the EGIL and WHO groups (EGIL, P = .0403; WHO, P = .0601). Compared with 177 patients with acute myeloid leukemia (AML), MPAL patients had better OS (P = .0003) and progression-free survival (P = .0001). However, no difference in OS between MPAL and 387 patients with acute lymphoblastic leukemia was present (P = .599)., Conclusions: As defined by the 2008 WHO classification, fewer patients are now classified as having MPAL than with the EGIL criteria. In this study, patients with MPAL have a better clinical outcome compared with patients with AML., (Copyright© by the American Society for Clinical Pathology.)

Objectives: Acute myeloid leukemia (AML) with monosomal karyotype (MK) recently has been reported to be associated with worse outcome than the traditional complex karyotype., Methods: In this retrospective study of 111 patients with AML, we identified 14 patients with MK (13% of all patients with AML) using the definition proposed by Breems et al., Results: Five (36%) of these 14 patients had a loss of a single chromosome in the presence of other structural abnormalities, and nine (64%) had a loss of two or more autosomal chromosomes. Patients with AML-MK presented at an older age, with lower bone marrow blasts, and their blasts less frequently expressed CD34. Most patients with AML-MK had morphologic multilineage dysplasia and were predominantly subclassified as having AML with myelodysplasia-related changes (AML-MRC). Molecular analysis showed a significant absence of NPM1 and FLT3 in patients with AML-MK., Conclusions: Outcome data showed that patients with AML-MK had significantly worse overall survival, disease-free survival, and complete response compared with the rest of the patients with AML as well as within the AML-MRC group., (Copyright© by the American Society for Clinical Pathology.)

To determine the role of DNA methylation in the progression of acute myeloid leukaemia (AML), we analysed the methylation status of ALOX12, GSTM1, HS3ST2 and FZD9 in 127 AML patients. Aberrant methylation of ALOX12 was associated with the subcategory AML with myelodysplasia-related changes (P = 0·0439) and specifically with megakaryocytic dysplasia (P = 0·0003). An association between HS3ST2 and AML patients with favourable cytogenetic risk was identified (P = 0·0469). In univariate and multivariate analysis, methylation of GSTM1 was associated with worse overall survival (OS) and disease-free survival (DFS), with hazard ratios of 2·57 and 1·86, respectively. Furthermore, the significance of methylation of GSTM1 in predicting poor prognosis was maintained within the subcategories of AML not otherwise specified (NOS), AML with intermediate cytogenetic risk and normal karyotype AML. Finally, patients with both GSTM1 and ALOX12 methylated, demonstrated worse outcomes when all AML patients were assessed (OS; P = 0·000411) as well as within AML NOS (DFS; P = 0·0023), AML with intermediate cytogenetic risk (OS; P = 0·0104) and normal karyotype AML (OS; P = 0·00636). This study implicates methylation of specific genes in the classification and prognostication of AML and suggests that the morphological feature of multilineage dysplasia may be a surrogate marker of gene methylation in at least a subset of AML cases., (© 2012 Blackwell Publishing Ltd.)

In a Phase I/II clinical trial, 13 higher risk red blood cell-dependent myelodysplastic syndrome (MDS) patients unresponsive to hypomethylating therapy were treated with the multikinase inhibitor ON 01910.Na. Responses occurred in all morphologic, prognostic risk and cytogenetic subgroups, including four patients with marrow complete responses among eight with stable disease, associated with good drug tolerance. In a subset of patients, a novel nanoscale immunoassay showed substantially decreased AKT2 phosphorylation in CD34+ marrow cells from patients responding to therapy but not those who progressed on therapy. These data demonstrate encouraging efficacy and drug tolerance with ON 01910.Na treatment of higher risk MDS patients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Although some studies have validated the 2001 World Health Organization (WHO) classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification has expanded this category into "AML with myelodysplasia-related changes" (AML-MRC). We evaluated the clinical, pathologic, cytogenetic, and molecular features of 100 AML patients using the 2008 WHO criteria. Patients underwent genetic screening for NPM1, FLT3-ITD, FLT3-D835, and CEBPA mutations. Compared with patients with AML, not otherwise specified, patients with AML-MRC were significantly older (P= .014), presented with a lower hemoglobin (P= .044), more frequently expressed CD14 (P= .048), and exhibited a decreased frequency of CEBPA mutations (P= .001). Multivariate analysis indicated that patients with AML-MRC had a significantly worse overall survival, progression-free survival, and complete response compared with AML-not otherwise specified (all P< .001). These data support the clinical, morphologic, and cytogenetic criteria for this 2008 WHO AML category.

Purpose: The primary objective of this phase I study was to evaluate the clinical safety of a vaccine using recombinant vaccinia virus (prime) and recombinant fowlpox virus (boost) in combination with granulocyte-macrophage colony-stimulating factor in patients with prostate cancer. The vaccines contained transgenes for prostate specific antigen, a triad of co-stimulatory molecules and a tumor antigen whose amino acid sequence had been modified to enhance its immunogenicity. Secondary end points were immunological and clinical responses, changes in prostate specific antigen velocity, and the kinetics of vaccinia virus clearance from the vaccination site, serum, peripheral blood mononuclear cells, urine and saliva., Materials and Methods: The 15 patients enrolled in this study had metastatic prostate cancer. Patients were given recombinant fowlpox-prostate specific antigen/triad of co-stimulatory molecules alone or recombinant vaccinia-prostate specific antigen/triad of co-stimulatory molecules followed by recombinant fowlpox-prostate specific antigen/triad of co-stimulatory molecules on a prime and boost schedule with or without recombinant-granulocyte-macrophage colony-stimulating factor protein or recombinant fowlpox-granulocyte-macrophage colony-stimulating factor vector. Prostate specific antigen specific immune responses were measured using an enzyme-linked immunosorbent spot assay for interferon-gamma production. Polymerase chain reaction for vaccinia DNA and a plaque assay for live virus were also used., Results: Some grade 2 toxicity was seen in patients who received a higher dose of recombinant fowlpox-granulocyte-macrophage colony-stimulating factor but no toxicity exceeded grade 2. Viable vaccinia was detected after vaccination at the site swab of 1 of 4 patients analyzed. Prostate specific antigen specific immune responses were seen in 4 of 6 patients who were HLA-A2+ and decreases in serum prostate specific antigen velocity were observed in 9 of 15., Conclusions: Based on the safety and preliminary immunogenicity results of this trial we recommend initiating a randomized, phase II study of prostate specific antigen/triad of co-stimulatory molecules vaccines in patients with less advanced prostate cancer.

Transforming growth factor-beta (TGF-beta) is an important physiologic regulator of cell growth and differentiation. TGF-beta has been shown to inhibit the proliferation of quiescent hematopoietic stem cells and stimulate the differentiation of late progenitors to erythroid and myeloid cells. Insensitivity to TGF-beta is implicated in the pathogenesis of many myeloid and lymphoid neoplasms. Loss of extracellular TGF receptors and disruption of intracellular TGF-beta signaling by oncogenes is seen in a variety of malignant and premalignant states. TGF-beta can also affect tumor growth and survival by influencing the secretion of other growth factors and manipulation of the tumor microenvironment. Recent development of small molecule inhibitors of TGF-beta receptors and other signaling intermediaries may allow us to modulate TGF signaling for future therapeutic interventions in cancer.

Carbamazepine is an effective antiepileptic drug for the treatment of partial and convulsive generalised epilepsy in adults and children. The pharmacokinetic profile in children is similar to that in adults, but the half-life in long term paediatric therapy is between 6 and 12 hours, compared with 15 hours in adults. Autoinduction is present. The most common adverse effects are neurological and dose-related, and occur in up to 50% of patients treated, usually on dosage initiation or dose elevation. Most dissipate over time and require no alteration in dosage. Idiosyncratic effects include hypersensitivity, hepatic and haematological reactions. A benign leucopenia occurs in 10 to 12% of adults and children and appears to be unrelated to aplastic anaemia which occurs in approximately 1 in 575,000 treated patients per year. Carbamazepine is reported to have cognitive and behavioural advantages over other antiepileptic drugs. Overall, carbamazepine has become a major antiepileptic drug in children as well as adults.