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Background: Atypical intradermal smooth muscle neoplasm, also commonly termed cutaneous leiomyosarcoma, is a soft tissue tumor with a low risk of aggressive behavior. These lesions arise in the dermis with possible superficial subcutaneous extension, demonstrate cytologic atypia, and often show mitotic activity., Methods: A retrospective review of patient demographics, tumor characteristics, and treatment methods was conducted in a consecutive series of patients presenting to MD Anderson Cancer Center (MDACC) from 2002 to 2021 (n = 95). All pathology was reviewed by MDACC pathologists and determined to be atypical intradermal smooth muscle neoplasm., Results: Median age at diagnosis was 58 years (range 22-86), and 74% were male. Ninety-five percent (n = 90) of patients identified as White, non-Hispanic. Most tumors were slow-growing, solitary, and painless nodules. Tumors were in the lower extremities (44.2%), followed by the upper extremity (28.4%), trunk (22.1%), and head and neck (5.2%). All patients (n = 44, 46.3%) who had a punch/incisional biopsy for diagnostic purposes had a subsequent tumor excision. Unplanned excision or excisional biopsy was performed on the remaining 46 (48%) patients. Of this subset, 41 of the 46 aforementioned patients (89%) had positive margins and underwent re-excision. Final pathology in 25/38 (66%) re-excision specimens was negative for residual tumor despite an initial positive margin. Two patients in the cohort had local recurrence 2 and 3 years after initial surgery. Both patients had positive margins, underwent excision of the recurrent tumor, and remain free of disease. After median follow-up of 6.9 years (range 1 day-18 years), 5-year recurrence-free survival was 96% and overall survival (OS) of the entire cohort was 78%., Conclusion: In this study of consecutive patients presenting with atypical intradermal smooth muscle neoplasm, we found good OS and local control after definitive surgical excision with negative margins, including excisional biopsy with close margins. Atypical intradermal smooth muscle neoplasm is unlikely to metastasize and has an excellent prognosis. Guidelines to determine optimal surveillance strategies for these patients should be revisited., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly aggressive malignant neoplasm characterized by high-grade undifferentiated morphologic features and recurrent inactivating mutations of SMARCA4 . These tumors consistently exhibit loss of SMARCA4 (BRG1) while displaying variable expression of other nonspecific markers. Recently, we encountered a SMARCA4-UT demonstrating immunoreactivity for GATA3, and we sought to characterize this phenomenon in a larger series., A total of nine SMARCA4-UTs were examined from 3 large academic institutions. The clinicopathologic and molecular characteristics were studied and GATA3 immunohistochemistry was performed., The cohort included 5 male and 4 female patients, with a median age of 54 years and a median smoking history of 37 pack-years. At initial diagnosis, mediastinal lymph node involvement was observed in 5 patients (56%) while distant metastases were present in 7 patients (78%). The median survival was 6 months. Histologically, the tumors were characterized by sheets of undifferentiated epithelioid and/or rhabdoid cells, accompanied by frequent mitotic figures and necrosis. Immunohistochemically, all tumors displayed a complete loss of BRG1 expression. Notably, 4 of 9 tumors (44%) were positive for GATA3 expression, including one tumor that exhibited strong and diffuse immunoreactivity., GATA3 expression in SMARCA4-UT may pose diagnostic challenges, requiring differentiation from other GATA3-positive tumors. This distinction is crucial for accurate prognostication and treatment decisions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that express smooth muscle and melanocytic makers. Diagnosis of PEComas can be challenging due to focal or lost expression of traditional immunohistochemical markers, limited availability of molecular testing, and morphological overlap with much more common smooth muscle tumors. This study evaluates the use of glycoprotein nonmetastatic melanoma protein B (GPNMB) immunohistochemical staining as a surrogate marker for TSC1/2/MTOR alteration or TFE3 rearrangement to differentiate PEComas from other mesenchymal tumors. Cathepsin K was also assessed for comparison. A total of 399 tumors, including PEComas, alveolar soft part sarcomas, and other histologic PEComa mimics, were analyzed using GPNMB and cathepsin K immunohistochemistry. GPNMB expression was seen in all PEComas and alveolar soft part sarcomas with the majority showing diffuse and moderate-to-strong labeling, whereas other sarcomas were negative or showed focal labeling. When a cutoff of diffuse and at least moderate staining was used, GPNMB demonstrated 95% sensitivity and 97% specificity in distinguishing PEComas from leiomyosarcoma, well-differentiated/dedifferentiated liposarcomas, and undifferentiated pleomorphic sarcomas. Cathepsin K with a cutoff of any labeling had lower sensitivity (78%) and similar specificity (94%) to GPNMB. This study highlights GPNMB as a highly sensitive marker for PEComas and suggests its potential use as an ancillary tool within a panel of markers for accurate classification of these tumors., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm 2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, "distinctive nested glomoid neoplasm." Tumors were consistently positive for CD56 (n = 5/5). A subset was stained with S100 protein (n = 7/13), SMA (n = 6/13), keratin (n = 2/9), EMA (n = 3/7), and CD99 (n = 2/6). Tumors harbored ACTB::GLI1 (n = 15) or PTCH1::GLI1 (n = 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n = 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n = 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Distinguishing sarcomatoid carcinoma from primary sarcoma is clinically important. We sought to characterize metastatic sarcomatoid bone disease and its management., Methods: We analyzed the characteristics of all cases of sarcomatoid carcinoma to bone at a single institution from 2001 to 2021, excluding patients with nonosseous metastases. Survival was evaluated using the Kaplan-Meier method., Results: We identified 15 cases of metastatic sarcomatoid carcinoma to bone. In seven cases the primary cancer was unknown at presentation. Renal cell carcinoma was suspected or confirmed in nine cases. Nine patients presented with pathologic fracture and two with concomitant visceral metastases. All patients underwent image-guided core needle or open biopsy. Ten required surgery for discrete osseous metastases; in four cases definitive surgery was delayed (median delay, 19 days) due to inability to rule out sarcoma with frozen section. No patients required reoperation or had construct failure. Thirteen died of disease; median survival was 17.5 months (interquartile range, 6.2-25.1)., Conclusions: Metastatic sarcomatoid carcinoma is a clinically challenging entity. Multidisciplinary input and communication are key to identifying the primary carcinoma, locating osseous metastases, and defining an operative fixation that will survive the remainder of the patient's life., (© 2023 Wiley Periodicals LLC.)

Aims: NUTM1-rearranged sarcoma is an emerging entity that differs from NUT carcinoma at the molecular level, with most of the former tumours harbouring fusions involving genes in the MYC-associated factor X dimerization (MAD) transcription family (MXD1, MXD4, MXI1 [or MXD2], and MGA). MGA::NUTM1 is one of the most recently described novel gene fusions associated with NUTM1-rearranged sarcoma. Herein we describe the clinicopathologic features of three sarcomas with an MGA::NUTM1 fusion., Methods and Results: The three study patients were male, with an age range of 10-28 years. The tumour sites were deep soft tissue of the thigh, the chest wall, and the pelvis. All three tumours were aggressive, with multiple recurrences and metastases. Histologically, the tumours were composed of monotonous spindle, round, or epithelioid cells in variably hyalinized stroma and prominent aggregates of amianthoid fibre-like collagen or collagen rosettes. Mitotic activity was relatively low (5-12 mitotic figures per 10 hhpf). All tumours tested expressed NUT, with one tumour having S100 protein expression and two tumours having CD99 and CD56 expression. The genetic breakpoints were MGA exon 21, MGA exon 22, and NUTM1 exon 3., Conclusion: MGA::NUTM1 sarcoma often exhibits hyalinized stroma with amianthoid fibre-like collagen or collagen rosettes in the presence of monotonous round, epithelioid, or spindle cell morphology. NUT immunohistochemistry and molecular testing can help confirm the diagnosis., (© 2023 John Wiley & Sons Ltd.)

Aims: Cutaneous syncytial myoepithelioma (CSM) is a rare myoepithelioma variant of skin, characterized by intradermal syncytial growth of spindle cells with a distinct immunophenotype of EMA and S100 positivity and infrequent keratin expression. While CSM was first described as a cutaneous tumor, singular non-cutaneous cases have since been reported in bone. We aimed to investigate the clinicopathological features of this variant across all anatomic sites through a large multi-institutional study., Methods and Results: We complied a total of 24 myoepitheliomas with syncytial growth from our files. The tumors occurred in 12 male and 12 female patients (M:F = 1:1), with a median age of 31 years (range, 9-69 years). While the majority of tumors (75%, n = 18) occurred in skin, a significant subset (25%, n = 6) arose in non-cutaneous sites, including bone (n = 3), bronchus/trachea (n = 2), and interosseous membrane of tibia/fibula (n = 1). Tumor size ranged from 0.4 to 5.9 cm. Clinical follow-up (7 patients; range 14-202 months; median 56.5 months) showed a single local recurrence 8 years after incomplete skin excision but no metastases; all patients were alive at the time of last follow-up without evidence of disease. Histologically, all tumors were pink at low-power and characterized by a syncytial growth of bland ovoid, spindled, or histiocytoid cells with eosinophilic cytoplasm and prominent perivascular lymphoplasmacytic inflammation. One-third displayed adipocytic metaplasia (8/24). Rare cytologic atypia was seen but was not associated with increased mitotic activity. All tumors expressed S100, SMA, and/or EMA. Keratin expression was absent in most cases. Molecular analysis was performed in 16 cases, all showing EWSR1-rearrangments. In total, 15/15 (100%) harbored an EWSR1::PBX3 fusion, whereas 1 case EWSR1 FISH was the only molecular study performed., Conclusion: Syncytial myoepithelioma is a rare but recognizable morphologic variant of myoepithelioma which may have a predilection for skin but also occurs in diverse non-cutaneous sites. Our series provides evidence supporting a reappraisal of the term "cutaneous syncytial myoepithelioma," as 25% of patients in our series presented with non-cutaneous tumors; thus, we propose the term "syncytial myoepithelioma" to aid pathologist recognition and avoidance of potentially confusing terminology when referring to non-cutaneous examples. The behavior of syncytial myoepithelioma, whether it arises in cutaneous or non-cutaneous sites, is indolent and perhaps benign with a small capacity for local recurrence., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A subset of clear cell chondrosarcomas may contain focal areas of low-grade conventional chondrosarcoma; however, it is rare to find foci resembling clear cell chondrosarcoma admixed with areas otherwise typical conventional chondrosarcoma. We report two patients with conventional chondrosarcoma with clear cell features occurring in the rib, one in the setting of multiple hereditary exostoses (MHE) and the other without MHE. Both patients were found to have a destructive rib mass with a soft tissue component and underwent en bloc resection. Histologic examination revealed predominantly grade 2 conventional chondrosarcomas; however, multiple foci containing large cells with pale eosinophilic to clear cytoplasm, distinct cell borders, centrally located nuclei, and conspicuous nucleoli, resembling clear cell chondrosarcoma were identified throughout the specimen. The significance of clear cell features in an otherwise typical conventional chondrosarcoma, to our knowledge, is unknown and deserves recognition. Finally, these tumors highlight the need for careful histologic examination and proper classification as unexpected findings may impact management.

Pericytes are multipotent mesenchymal precursor cells that demonstrate tissue-specific properties. In this study, by comparing human adipose tissue- and periosteum-derived pericyte microarrays, we identified T cell lymphoma invasion and metastasis 1 (TIAM1) as a key regulator of cell morphology and differentiation decisions. TIAM1 represented a tissue-specific determinant between predispositions for adipocytic versus osteoblastic differentiation in human adipose tissue-derived pericytes. TIAM1 overexpression promoted an adipogenic phenotype, whereas its downregulation amplified osteogenic differentiation. These results were replicated in vivo, in which TIAM1 misexpression altered bone or adipose tissue generation in an intramuscular xenograft animal model. Changes in pericyte differentiation potential induced by TIAM1 misexpression correlated with actin organization and altered cytoskeletal morphology. Small molecule inhibitors of either small GTPase Rac1 or RhoA/ROCK signaling reversed TIAM1-induced morphology and differentiation in pericytes. In summary, our results demonstrate that TIAM1 regulates the cellular morphology and differentiation potential of human pericytes, representing a molecular switch between osteogenic and adipogenic cell fates.

Aims: Glomus tumours are neoplasms with perivascular smooth muscle differentiation, which rarely occur in the oesophagus and may behave aggressively in this site based upon prior case reports. This study describes the clinicopathologic features of three oesophageal glomus tumours diagnosed at two large academic institutions between 1984 and 2022., Methods and Results: Three cases of oesophageal glomus tumours were identified. Patients included two females and one male, with an age range of 19-65 years. All three tumours behaved in a malignant fashion, with metastases to various sites (lymph nodes, lung, pericardium, pleura, diaphragm, scalp). One patient developed an aorto-oesophageal fistula, resulting in a fatal haemorrhage. Tumours ranged in size from 4.5 to 8.1 cm. Histologically, all tumours had a multinodular, perivascular growth pattern. The neoplasms showed varying degrees of cytologic atypia and spindling, elevated mitotic activity (2-12 mitotic figures per 10 high-power fields), and necrosis was seen in in two cases. All tumours expressed smooth muscle actin by immunohistochemistry, and harboured NOTCH gene alterations (MIR143::NOTCH2 fusion in two cases; NOTCH3 rearrangement and NOTCH1 point mutation in one case). An ATRX splicing mutation in exon 10 was also identified in one case., Conclusion: Oesophageal glomus tumours pose diagnostic challenges, given their rarity at this site, but can be recognised by their characteristic perivascular growth pattern, round central nuclei, and supportive ancillary studies. Given the propensity for aggressive behaviour in this location, we recommend management by a multidisciplinary sarcoma team for optimal outcome., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Dermatofibrosarcoma protuberans (DFSP) is a dermal malignant mesenchymal tumor. Most variants are associated with a high risk of local recurrence and a low risk of metastasis. The classic histomorphology of this tumor is made up of uniform, spindle-shaped cells, arranged in a storiform pattern. Tumor cells characteristically infiltrate the underlying subcutis in a honeycomb pattern. Less common variants of DFSP have been identified: myxoid, pigmented, myoid, granular cell, sclerosing, atrophic, and fibrosarcomatous. Only the fibrosarcomatous variant has been shown to differ significantly from classic DFSP in terms of clinical outcome; fibrosarcomatous DFSP has been shown to be associated with a greater risk of local recurrence and metastatic potential than classic DFSP. However, the other variants may pose diagnostic difficulty as they resemble other types of spindle cell neoplasms, especially in small biopsy specimens. This article reviews the clinical, histologic, and molecular features of DFSP variants, as well as possible pitfalls in their diagnosis and how to resolve them.

Introduction: In children and adolescents, most sarcoma subtypes have a simple karyotype with a single genetic alteration; cytologic findings combined with ancillary testing can lead to a specific diagnosis. The goal of this study was to review the use of fine-needle aspiration in conjunction with immunohistochemistry and molecular studies as a part of an integrated, multidisciplinary diagnostic workup for bone and soft tissue sarcomas in this population., Materials and Methods: We searched for cases aged ≤18 years old with a malignant bone or soft tissue tumor that had corresponding cytology specimens from 3 institutions. Clinical data, cytologic findings and diagnoses, histologic diagnoses, and ancillary testing were documented., Results: Of 99 cases, 55% were male with a mean age of 12 years. Ninety-four cases (95%) had a specific histologic diagnosis, and 84 cases (85%) were primary neoplasms. Ninety-four cases (95%) had a malignant cytologic diagnosis, and 71 cases (72%) had a specific cytologic diagnosis concordant with the histologic diagnosis. Among primary tumors with a specific histologic diagnosis, a specific cytologic diagnosis was made in 63 cases (79%). After excluding osteosarcoma, 74% of the tumors (n = 50) had molecular studies. Specific genetic alterations supporting a definitive diagnosis were found in 42 cases (84%), the majority of which were demonstrated using Fluorescence In Situ Hybridization (n = 33, 79%)., Conclusions: We found that fine-needle aspiration in conjunction with core needle biopsy, immunohistochemistry, and molecular studies allowed cytopathologists to accurately classify sarcomas in a pediatric age group., (Copyright © 2022 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Annotating cancerous regions in whole-slide images (WSIs) of pathology samples plays a critical role in clinical diagnosis, biomedical research, and machine learning algorithms development. However, generating exhaustive and accurate annotations is labor-intensive, challenging, and costly. Drawing only coarse and approximate annotations is a much easier task, less costly, and it alleviates pathologists' workload. In this paper, we study the problem of refining these approximate annotations in digital pathology to obtain more accurate ones. Some previous works have explored obtaining machine learning models from these inaccurate annotations, but few of them tackle the refinement problem where the mislabeled regions should be explicitly identified and corrected, and all of them require a - often very large - number of training samples. We present a method, named Label Cleaning Multiple Instance Learning (LC-MIL), to refine coarse annotations on a single WSI without the need for external training data. Patches cropped from a WSI with inaccurate labels are processed jointly within a multiple instance learning framework, mitigating their impact on the predictive model and refining the segmentation. Our experiments on a heterogeneous WSI set with breast cancer lymph node metastasis, liver cancer, and colorectal cancer samples show that LC-MIL significantly refines the coarse annotations, outperforming state-of-the-art alternatives, even while learning from a single slide. Moreover, we demonstrate how real annotations drawn by pathologists can be efficiently refined and improved by the proposed approach. All these results demonstrate that LC-MIL is a promising, lightweight tool to provide fine-grained annotations from coarsely annotated pathology sets.

Background: Pleomorphic liposarcoma (PLPS) is the least common but most aggressive of all forms of liposarcoma (LPS). Its diagnosis relies on the recognition of pleomorphic lipoblasts (PLBs), whose numbers vary considerably. Because few large fine-needle aspiration (FNA) biopsy studies exist, the authors review their experience with PLPS., Methods: The authors' cytopathology files were searched for PLPS with histopathologic verification. FNA biopsy smears were performed via standard techniques., Results: Twenty cases from 20 patients (male/female ratio, 2.3/1; age range, 22-77 years; mean age, 58 years) met the inclusion criteria. All had tissue confirmation. Biopsy sites included the following: thigh (11 [55%]), upper extremity (4 [20%]), axilla (2 [10%]), neck (1 [5%]), chest wall (1 [5%]), and mediastinum (1 [5%]). Aspirates were from primary (17 [85%]), locally recurrent (2 [10%]), and metastatic neoplasms (1 [5%]). The FNA diagnoses were PLPS (10 [50%]), myxofibrosarcoma (4 [20%]), LPS (2 [10%]), sarcoma (2 [10%]), and high-grade malignant neoplasm (2 [10%]). Smears showed thick cell clusters and dissociated single forms. Pleomorphic, epithelioid, and bizarre cell/nuclear shapes were common. PLBs were absent, rare, or unnoticed in 45%. In 25%, smears dominated by myxoid stroma were diagnosed as high-grade myxofibrosarcoma or myxoid LPS. Ancillary testing performed in 5 cases had limited diagnostic efficacy., Conclusions: FNA biopsy of PLPS, although able to successfully recognize malignancy, suffers from a sampling bias due to an inability to capture or recognize PLBs in a significant proportion of cases secondary to the heterogeneous composition of this neoplasm., (© 2022 American Cancer Society.)

Background: Ancillary studies are commonly performed on cell blocks prepared from fine-needle aspiration (FNA) specimens. There are limited studies in application of ancillary studies on cell blocks from salivary gland (SG) FNAs. This multi-institutional study evaluates the role of ancillary studies performed on cell blocks in the diagnosis of SG lesions, and their impact on clinical management., Method: The electronic pathology archives of three large academic institutions were searched for SG FNAs with ancillary studies performed on cell blocks. The patient demographics, FNA site, cytologic diagnosis, ancillary studies, and surgical follow-up were recorded. If needed, the cytologic diagnoses were reclassified as per the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC)., Results: 117 SG FNA cases were identified including 3, 10, 11, 6, 23, 4, and 60 cases in MSRSGC categories I, II, III, IVa, IVb, V, VI, respectively with surgical follow-up available ranging from 27% to 100% within each category. Ancillary studies including histochemistry, immunocytochemistry (IHC), and in situ hybridization (ISH) were beneficial in 60%-100% of cases in each category. Risk of malignancy was 100% in both the suspicious for malignancy (V) and malignant (VI) categories. Ancillary studies improved diagnosis in 60% of non-neoplastic cases (II, 6/10), 100% of benign neoplasm cases (IVa, 6/6), and 98.3% of malignant cases (VI, 59/60)., Conclusion: Judicious and case-based ancillary studies performed on SG FNA cell blocks with sufficient material can improve the diagnostic yield by further characterization of the atypical/neoplastic cells, particularly in MSRSGC categories IVa-VI., (© 2022 The Authors. Diagnostic Cytopathology published by Wiley Periodicals LLC.)

The term "Atypia" has been employed to describe a wide spectrum of cytomorphologic features associated with reactive/inflammatory processes as well as those suspicious for neoplasms in cytology. Similar to other cytopathology reporting systems, the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has reserved the atypical category for cytology specimens lacking quantitative and/or qualitative cytomorphologic features to be diagnosed with confidence as either non-neoplastic or neoplastic. In MSRSGC, the atypical category is associated with a risk of malignancy and recommendation for clinical management. In this review, we discuss the value of atypical diagnostic category of MSRSGC in both cystic and non-cystic salivary gland lesions by evaluating our institutional case cohort., (© 2022 Wiley Periodicals LLC.)

Background: Solitary fibrous tumour (SFT) is a unique mesenchymal neoplasm with classic features on histology and is characterised by the NAB2-STAT6 gene fusion. There are rare reports of SFTs with pancreatic involvement and only two cases in the literature reporting its features by preoperative fine needle aspiration (FNA). Herein, we characterise the cytomorphological features of four SFTs involving the pancreas by FNA to establish a preoperative diagnostic approach., Methods: The anatomic pathology archives of two academic medical centres were searched to identify patients with a pancreatic FNA cytology specimen and a confirmed diagnosis of SFT by surgical resection. The clinical history, pathological diagnosis, cytomorphological findings, and results of immunohistochemistry (IHC) were reviewed., Results: Four SFTs were identified from four patients with a median age of 59 years. The morphological features were variable but most frequently showed a bland spindled-to-epithelioid proliferation in fragments and single cells with small, oval, elongated, and hypochromatic nuclei in a haphazard arrangement with or without dense collagen. One tumour presented with a concurrent metastasis and showed a pure epithelioid component with necrosis and enlarged, hyperchromatic nuclei with conspicuous nucleoli and scattered mitoses. IHC was necessary for all diagnoses which were confirmed by surgical resection., Conclusions: SFTs with pancreatic involvement are rare, and non-specific features and tumour heterogeneity can pose a diagnostic challenge on FNA; however, IHC can be used to make a definitive diagnosis. As a result, FNA is a simple, safe, cost-effective, and accurate approach that can be used to diagnose SFT in the pancreas., (© 2021 John Wiley & Sons Ltd.)

Anaplastic lymphoma kinase (ALK) rearrangement-associated renal cell carcinoma ( ALK -rearranged RCC) is a new provisional entity that has been included in the 2016 World Health Organization classification of RCCs. We report 2 cases of ALK -rearranged RCC, 1 with a vinculin-ALK ( VCL-ALK ) fusion and the other with an EML4-ALK fusion. The VCL-ALK RCC occurred in a 14-year-old girl with sickle cell trait and showed features similar to previously described VCL-ALK RCCs, including medullary epicenter, solid architecture, and polygonal cells with cytoplasmic vacuoles. The EML4-ALK RCC occurred in a 14-year-old boy with no evidence of sickle cell trait and had multiple less-specific growth patterns comprising tubular, solid, and tubulopapillary architectures in the desmoplastic stroma, reminiscent of collecting duct carcinoma. Both tumors demonstrated cytoplasmic and membranous ALK protein expression by immunohistochemistry. Fluorescence in situ hybridization confirmed the ALK gene rearrangements in both cases. On review in the literature, we found that solid architecture and cytoplasmic vacuoles were present significantly more frequently in VCL-ALK RCC than in non- VCL-ALK RCC, supporting the distinctive nature of the former.

Introduction: Chondromyxoid fibroma is a rare bone tumor characterized by immature myxoid mesenchymal tissue showing early primitive cartilaginous differentiation. There have been limited case reports describing the cytologic features of chondromyxoid fibroma. Herein, we reported cytologic features of chondromyxoid fibroma on fine-needle aspiration (FNA)., Materials and Methods: We performed a retrospective search in our cytopathology and surgical pathology database for cases diagnosed as chondromyxoid fibroma that had corresponding cytology specimens from three medical institutions. All available cytopathology specimens were reviewed., Results: Eight cases were retrieved from patients aged 16-77 years (mean, 51 years), and M:F ratio of 1.7:1. Seven tumors (88%) were primary, and most (62%) occurred in flat bones. Cytologic diagnoses were made in 6 cases with cytologic slides not available to review in 1 case. All cases showed metachromatic matrix in the background, while hyaline cartilage fragments were absent. All cases had two cell populations comprising oval to round cells and stellate to spindle cells. The spindle to stellate cells were more commonly embedded in matrix material. Moderate atypia (hyperchromasia and moderate anisonucleosis) was present in 4 cases (80%), while no mitotic figure was present in all cases., Conclusions: Our study highlights common cytologic features of chondromyxoid fibroma, including the presence of the spindle or stellate cells embedded in matrix material. Hyaline cartilage is uncommon and, if present, diagnostic considerations should include enchondroma or low-grade chondrosarcoma. A specific cytologic diagnosis primarily using FNA samples can be challenging but possible when evaluated in conjunction with clinical and radiologic data., (Copyright © 2021 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma presenting as a slow-growing mass that occurs mainly in the distal extremities of adults. Relatively little is known about the cytopathology of MIFS. We evaluated cytologic characteristics of MIFS on fine-needle aspiration (FNA)., Materials and Methods: A search was made of our cytopathology and surgical pathology databases for cases diagnosed as MIFS. FNA biopsy smears and cell-block were performed and examined using standard technique., Results: Eight cases were retrieved from patients aged 22-90 years (mean, 56 years), and M:F ratio of 1:1. Six tumors (75%) were primary, and 2 (25%) locally recurrent. Distal lower limb was involved in all but one case (88%). One (13%) recurrent case was correctly diagnosed cytologically as MIFS; remaining single diagnoses were varied: myxofibrosarcoma, low-grade sarcoma, malignant neoplasm, myxoid neoplasm, atypical fibrohistiocytic neoplasm, atypical cells with chronic inflammation, and spindle cells with atypia. Among 7 cases with available cytologic slides for review, common features were spindle cells with variable atypia (100%), rare virocyte/Reed-Sternberg -like cells (86%), background mixed inflammation (71%), and variable myxoid stroma (57%). Pseudolipoblasts and multinucleated giant cells were rare. Hemosiderin and branching capillaries were largely absent. Immunohistochemistry was non-specific., Conclusion: MIFS was accurately interpreted in only 13% of cases; remaining cases were diagnosed as atypical or malignant, which would lead to proper management. A specific cytologic diagnosis of MIFS using FNA is extremely difficult in our experience due to an absence of distinctive cytomorphology and specific immunophenotype., (Copyright © 2021 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Chondroblastoma is a rare benign tumor of immature cartilage cells that generally occurs in an epiphyseal location of skeletally immature individuals. However, a few studies have reported cases in older patients. The purpose of this study was to evaluate the clinical, radiographic, and pathologic features of chondroblastoma in an adult population. The pathology archives of our institution were searched for cases of chondroblastoma diagnosed in patients ≥25 years of age. Of 14 patients identified, 8 were male and 6 were female with a median age of 34 years (range = 29-54 years). Most lesions occurred in short bones of hands and feet (N = 7, 50%), followed by the long tubular bones (N = 4, 28%). All demonstrated typical histologic features of chondroblastoma, but more extensive calcification, necrosis, and degenerative changes were also seen. At follow-up (median = 73.5 months), 2 patients (17%) had local recurrence. None had metastasis. In summary, chondroblastoma in adults tends to involve the short bones of the hands and feet and demonstrate histologic changes associated with long-standing growth of a benign tumor.

SMARCA4-deficient neoplasms are recently characterized high-grade malignancies associated with a poor prognosis. The SMARCA4 gene encodes BRG1, which is part of the SWI/SNF complex. SMARCA4-deficient neoplasms have an undifferentiated, often rhabdoid morphology, and demonstrate loss of BRG1 nuclear expression on immunohistochemistry. These neoplasms have become increasingly recognized and diagnosed in tissue specimens, but their features in cytologic specimens are poorly defined in the literature. The review is introduced by a diagnostically challenging case of a SMARCA4-deficient carcinoma involving a pleural fluid specimen in which the carcinoma cells demonstrated greatly reduced claudin-4 expression in the setting of strong, diffuse BerEP4 expression. Most of the malignant cells also demonstrated positive cytoplasmic staining for PAS and all were PAS-diastase negative, suggesting that the cytoplasm contained glycogen granules., (Copyright © 2021 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Perivascular epithelioid cell tumor (PEComa) is a family of rare mesenchymal tumors consisting of histologically and immunohistochemically distinctive perivascular epithelioid cells. Relatively little is known about the cytopathology of extra-renal PEComas. Because of a considerable range of morphology and their rarity, accurate cytologic classification can be challenging. We evaluated cytologic characteristics and diagnostic pitfalls of extra-renal PEComas on fine-needle aspiration (FNA)., Materials and Methods: We performed a retrospective search in our cytopathology and surgical pathology database for cases diagnosed as PEComa that had corresponding cytology specimens from 3 medical institutions. All available cytopathology specimens were reviewed. We evaluated cytologic characteristics and recorded histologic diagnoses and immunohistochemical stains., Results: Seven FNA specimens from 6 patients were identified, and cytologic diagnoses were made in all cases as follows: PEComa (4 cases), most consistent with PEComa (1 case), malignant neoplasm (1 case), and hepatocellular carcinoma (1 case). Most specimens were moderately to highly cellular. Cell distribution occurred as tissue fragments with background proliferating capillaries. Most smears were composed of epithelioid cells showing mild to moderate anisonucleosis, abundant eosinophilic cytoplasm, well-defined borders, intranuclear pseudoinclusions, and prominent nucleoli. A combination of myoid and melanocytic markers was expressed in 6 cases except 1 case, which was called hepatocellular carcinoma., Conclusions: This was the largest FNA series for extra-renal PEComas to date. Our study highlights some common cytomorphologic characteristics of PEComa with which cytopathologists should be familiar. In the right clinical and radiologic context, and with the aid of immunohistochemistry, a definitive diagnosis can be achieved., (Copyright © 2021 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Background: Atypia of undetermined significance (AUS) is a category of the Milan System for Reporting Salivary Gland Cytopathology that refers to salivary gland fine-needle aspiration (FNA) specimens that cannot be definitively diagnosed as neoplastic or nonneoplastic., Methods: The AUS FNA samples were selected from a large academic institution from 2008 through 2018. The AUS cases were divided into 6 subgroups. The risk of malignancy (ROM), risk of neoplasm (RON), and clinical outcomes for each subgroup were evaluated., Results: A total of 123 cases were found (76 males and 47 females with a mean age of 62 years [range, 6-94 years]). The parotid gland was the most common FNA site (103 cases), followed by the submandibular gland (9 cases). The overall RON and ROM were 63% and 47%, respectively. Among the subgroups, salivary gland lymph nodes or lymphoid lesions was the most common diagnosis (42%), whereas mucinous cystic lesions with no or a scant epithelial component was the least common (2%). The specimens with preparation artifacts category had the highest RON and ROM (100% for both), whereas the reactive and reparative atypia indefinite for a neoplasm category had the lowest RON and ROM (7% for both). The salivary gland lymph nodes or lymphoid lesions indefinite for a lymphoproliferative disorder category had the second highest RON and ROM at 77% and 74%, respectively., Conclusions: The overall RON and ROM for the AUS category were 63% and 47%, respectively. The RON and ROM varied among the different AUS subgroups, being highest in the specimens with preparation artifacts category and lowest in the reactive and reparative atypia category, thereby demonstrating the importance of subgrouping in the AUS specimens., (© 2020 American Cancer Society.)

Liver metastasis is a recalcitrant disease that usually leads to death of the patient. The present study established a unique patient-derived orthotopic xenograft (PDOX) nude mouse model of a highly aggressive liver metastasis of colon cancer. The aim of the present study was to demonstrate proof-of-concept that candidate drug combinations could significantly inhibit growth and re-metastasis of this recalcitrant tumor. The patient's liver metastasis was initially established subcutaneously in nude mice and the subcutaneous tumor tissue was then orthotopically implanted in the liver of nude mice to establish a PDOX model. Two studies were performed to test different drugs or drug combination, indicating that 5-fluorouracil (5-FU) + irinotecan (IRI) + bevacizumab (BEV) and regorafenib (REG) + selumetinib (SEL) had significantly inhibited liver metastasis growth (p = 0.013 and p = 0.035, respectively), and prevented liver satellite metastasis. This study is proof of concept that a PDOX model of highly aggressive colon-cancer metastasis can identify effective drug combinations and that the model has future clinical potential.

Case Report: A 65-year-old Caucasian man presented with a debilitating anogenital lesion., Differential Diagnosis: The differential diagnosis of anogenital lesions includes infectious (syphilis, herpes simplex virus), noninfectious (hidradenitis suppuritiva, lymphedema), benign (condyloma acuminata), and malignant pathologies (squamous cell carcinoma, Kaposi sarcoma)., Diagnostic Assessment, Management, and Outcome: Biopsy of an anogenital lesion will determine any oncologic potential. Further imaging can better characterize the disease. Once in the operating room, oncologic principles should be adhered to and quality of life concerns prioritized. Reconstruction of large defects may require a multidisciplinary team. Genitourinary and gastrointestinal diversions should be considered to improve wound healing, decrease infection risk, and optimize graft take., Discussion: A multidisciplinary approach to medical and surgical reconstruction of anogenital lesions should be considered for extensive malformations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Follicular dendritic cell sarcoma (FDCS) is a very rare and highly recalcitrant disease. A patient's doxorubicin-resistant FDCS was previously established orthotopically on the right high thigh into the biceps femoris of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present manuscript was to identify an effective drug for this recalcitrant tumor. Here, we evaluated the efficacy of temozolomide (TMZ), trabectedin (TRAB) and pazopanib (PAZ) on the FDCS PDOX model. PDOX mouse models were randomized into five groups of eight to nine mice, respectively. Group 1, untreated control with PBS, i.p.; Group 2, treated with doxorubicin (DOX), 2.4 mg/kg, i.p., weekly for 3 weeks; Group 3, treated with PAZ, 50 mg/kg, oral gavage, daily for 3 weeks; Group 4, treated with TMZ, 25 mg/kg, oral gavage, daily for 3 weeks; Group 5, treated with TRAB, 0.15 mg/kg, i.v., weekly for 3 weeks. Body weight and tumor volume were assessed 2 times per week. TMZ arrested the FDCS PDOX model compared to the control group (p < 0.05). PAZ and TRAB did not have significant efficacy compared to the control group (p = 0.99, p = 0.69 respectively). The PDOX tumor was resistant to DOX (p= 0.99). as was the patient. The present study demonstrates that TMZ is effective for a PDOX model of FDCS established from a patient who failed DOX treatment, further demonstrating the power of PDOX to identify effective therapy including for tumors that failed first line therapy., (Published by Elsevier Ltd.)

Purpose: Ewing's sarcoma (ES) is a rare and recalcitrant disease which is in need of a development of a novel effective therapy. The aim of this study was to investigate the efficacy of regorafenib on an ES tumor in a patient-derived orthotopic xenograft (PDOX) model., Methods: The ES PDOX models were established orthotopically in the right chest wall of nude mice to match the site of the tumor in the donor patient. The ES PDOX models were randomized into three groups (G) when the tumor volume reached 75 mm 3 : G1: untreated control; G2: doxorubicin (DOX) (i.p., 3 mg/kg, weekly, 2 weeks); G3: regorafenib (REG) (p.o., 30 mg/kg, daily, 2 weeks). Tumor volume and body weight were measured twice a week. All mice were sacrificed on day 15., Results: DOX was ineffective compared to the control group (P = 0.229). REG regressed the tumor size (P < 0.001 and P < 0.001, relative to control and DOX, respectively)., Conclusions: Our findings suggest that REG has clinical potential for ES patients whose tumors respond to REG in a PDOX model.

Undifferentiated/unclassified soft-tissue sarcomas (USTS) is recalcitrant neoplasms that is usually treated with doxorubicin (DOX)-containing regimens as first-line therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a nanotechnology-based drug and is widely used in pancreatic cancer in combination with gemcitabine (GEM). The major goal of the present study was to determine the efficacy of nab-PTX in combination with GEM, compared to conventional drugs such as docetaxel (DOC), GEM combined with DOC, or first-line drug DOX on a USTS not-otherwise specified (USTS/NOS) from a striated muscle implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. USTS PDOX models were randomized into six groups: untreated control; DOX; DOC; nab-PTX; GEM combined with DOC; and GEM combined with nab-PTX. Tumor size and body weight were measured. Tumor growth was inhibited to the greatest extent by GEM combined with nab-PTX. Tumors treated with GEM combined with nab-PTX had the most necrosis. Body weight of the treated mice was not significantly different from the untreated controls. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the combination of GEM and nab-PTX for recalcitrant soft-tissue sarcomas. These results suggest that combination of GEM and nab-PTX could be a promising therapeutic strategy for USTS., (Published by Elsevier Masson SAS.)

There are no effective treatments for leiomyosarcoma (LMS) spreading intraabdominally. The aim of this study was to develop precision chemotherapy for recurrent peritoneal LMS metastases in a patient-derived orthotopic xenograft (PDOX) model. The LMS PDOX models were established orthotopically on the dome of the bladder of nude mice. The LMS PDOX models were randomized into 6 groups when the tumor volume reached 80 mm 3 : G1: untreated control; G2: doxorubicin (DOX) (DOX: i.p., 3 mg/kg, weekly, 3 weeks); G3: DOX combined with olaratumab (OLA) (DOX: i.p., 3 mg/kg, weekly, 3 weeks; OLA: i.p., 40 mg/kg, 3 times/week, 3 weeks); G4: gemcitabine (GEM) combined with docetaxel (DOC) (GEM: i.p., 100  mg/kg, weekly, 3 weeks; DOC: i.p., 20  mg/kg, weekly, 3 weeks); G5: pazopanib (PAZ) (PAZ: p.o., 100  mg/kg, daily, 3 weeks); G6: palbociclib (PAL) (PAL: p.o., 100  mg/kg, daily, 3 weeks). All mice were sacrificed on day 22. Body weight was assessed twice a week. Tumor volume was measured on day 0 and day 22. Although all regimens had a significant efficacy compared to the untreated group (P < 0.001), only GEM combined with DOC regressed the tumor significantly (P < 0.001), suggesting GEM combined with DOC has clinical potential for this LMS patient., (Copyright © 2019. Published by Elsevier Inc.)

Background/aim: Undifferentiated pleomorphic sarcoma (UPS) is a common soft tissue sarcoma and highly recalcitrant. We have previously developed patient-derived orthotopic xenograft (PDOX) mouse models of UPS and other major sarcoma types. Unlike PDOX models of other cancer types, it has been difficult to demonstrate metastasis in the sarcoma PDOX models., Materials and Methods: To visualize metastasis at high resolution in the UPS PDOX model, established tumor fragments were implanted in transgenic nude mice expressing red fluorescent protein (RFP) for one passage. The tumors acquired RFP-expressing stroma from transgenic host. UPS tumor with RFP stromal cells were harvested and implanted orthotopically in non-transgenic nude mice. After six weeks of UPS tumor growth in the PDOX model, the primary tumor was imaged non-invasively and lung, liver, and spleen were resected and imaged ex-vivo in order to visualize the presence of RFP, with a FluorVivo® imaging system and FV1000® confocal laser microscope, respectively., Results: The primary tumor was imaged non-invasively. Confocal microscopy visualized the presence of RFP in the lung and liver indicating metastases in these organs. This is the first report of metastasis in a sarcoma PDOX model., Conclusion: This study should prove very useful to screen for anti-metastatic drugs for the PDOX donor patients and to understand the metastatic process in sarcoma., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Image analysis systems are not currently commonly used for evaluating urinary cytology specimens. We evaluated whether the BestCyte Cell Sorter (CellSolutions, Greensboro, NC) imaging system can reliably identify atypical cells in urinary cytology specimens., Methods: Fifty-three consecutive urine cytology specimens underwent 2 preparations: one slide using SurePath (SP; BD Diagnostics, Sparks, MD) ™ for routine clinical evaluation, and a second slide using the CellSolutions F50 system for analysis by the BestCyte Cell Sorter (BCCS) scanning system. Eight observers reviewed atypical cells flagged by BCCS and assigned a BCCS diagnosis to each of the 53 specimens. The observers also blindly reviewed the SP preparation (when available) and assigned an SP diagnosis. The SP diagnoses given by one "expert" observer was considered as a reference diagnosis., Results: There was fair-to-moderate agreement among observers for identifying any atypia and high-grade atypia (Fleiss kappa: 0.417 and 0.338, respectively) using BCCS. Review of SP preparations had slightly better agreement (Fleiss kappa: 0.558 and 0.564, respectively). Intraobserver agreement between the two methods varied greatly between individuals (Cohen's kappa range: 0.260 to 0.647). When a consensus diagnosis could be reached among the observers for cases with surgical follow-up, the consensus diagnosis was concordant in 11 of 12 instances, with one instance being a one-step discrepancy., Conclusions: Specimen review by BCCS resulted in slightly greater interobserver variability than review of routine SP preparations. This may have been due to variations in observer experience and comfort with the use of a digital imaging system, which is further suggested by the wide range of intraobserver agreement among individuals., (Copyright © 2018 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS., (Published by Elsevier Inc.)

Cancer of unknown primary (CUP) is metastatic disease without a known primary and therefore very difficult to identify effective therapy. Previously, we demonstrated partial efficacy of Salmonella typhimurium A1-R (S. typhimurium A1-R) alone and carboplatinum alone (CAR) on a CUP patient tumor in the patient-derived xenograft (PDOX) model. The aim of the present study was to investigate the efficacy of S. typhimurium A1-R combined with CAR on the CUP PDOX model. The CUP tumors were implanted orthotopically into the left supraclavicular fossa of nude mice to match the site from which they were resected from the patient. CUP PDOX models were divided randomly into the following 4 groups after the tumor volume reached 100 mm 3 : G1: untreated group; G2: CAR (30 mg/kg, i.p., weekly, 2 weeks); G3: S. typhimurium A1-R (5x10 7 CFU/body, i.v., weekly, 2 weeks).; G4: S. typhimurium A1-R combined with CAR (S. typhimurium A1-R; 5x10 7 CFU/body, i.v., weekly, 2 weeks; CAR, 30 mg/kg, i.p., weekly, 2 weeks). Each group comprised 7 mice. All mice were sacrificed on day 15. Tumor volume and body weight were measured twice a week. S. typhimurium A1-R and CAR moderately inhibited tumor growth compared to the untreated group on day 15 (P < 0.001 and P < 0.001, respectively). S. typhimurium A1-R combined with CAR inhibited the tumor growth significantly more compared to S. typhimurium A1-R monotherapy or CAR monotherapy on day 15 (P = 0.004 and P = 0.001, respectively). The present report demonstrates that S. typhimurium A1-R can increase the efficacy of a standard drug used for CUP in a PDOX model., (Published by Elsevier Ltd.)

Recombinant methioninase (rMETase) was previously administered as an injectable drug to target methionine dependence of cancer. Recently, we observed that rMETase could be administered orally (o-rMETase) in a patient-derived orthotopic xenograft (PDOX) mouse model of melanoma. Here, we determined the efficacy of o-rMETase on a pancreatic cancer PDOX model. Forty pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each. o-rMETase was significantly more effective than i.p.-rMETase, but the combination of both was significantly more effective than either alone. Acquired gemcitabine resistance is a major factor in the recalcitrance of pancreatic cancer. We tested a human pancreatic cancer cell line, which has acquired >100-fold GEM-resistance (PK-9R) than its parental cell line PK-9. In contrast to GEM, both cell lines were very sensitive to rMETase. In orthotopic nude mouse models of PK-9 and PK-9R, GEM inhibited tumor growth in PK-9 but not PK-9R. In contrast, o-rMETase could inhibit both tumors. The combination of GEM + o-rMETase could regress the PK-9 tumor and inhibit PK-9R tumor growth. The present study shows that o-rMETase is effective and overcomes acquired GEM resistance in pancreatic cancer and demonstrates the clinical potential of this strategy., (Published by Elsevier B.V.)

Melanoma is a recalcitrant cancer. To improve and individualize treatment for this disease, we previously developed a patient-derived orthotopic xenograft (PDOX) model for melanoma. We previously reported the individual efficacy of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and recombinant methioninase (rMETase) for melanoma in the PDOX models of this disease. In the present study, we evaluated the efficacy of the combination of S. typhimurium A1-R with orally-administered rMETase (o-rMETase) for BRAF-V600E-negative melanoma in a PDOX model. Three weeks after implantation, 60 PDOX mouse models were randomized into six groups of 10 mice each: untreated control, temozolomide (TEM); o-rMETase; S. typhimurium A1-R; TEM + rMETase, S. typhimurium A1-R + rMETase. All treatments inhibited tumor growth compared to untreated control (TEM: p < 0.0001, rMETase: p < 0.0001, S. typhimurium A1-R: p < 0.0001, TEM + rMETase: p < 0.0001, S. typhimurium A1-R + rMETase: p < 0.0001). The most effective was the combination of S. typhimurium A1-R + o-rMETase which regressed this melanoma PDOX, thereby indicating a new paradigm for treatment of metastatic melanoma., (Published by Elsevier Inc.)

Cancer of unknown primary (CUP) is a recalcitrant disease with poor prognosis because it lacks standard first-line therapy. CUP consists of diverse malignancy groups, making personalized precision therapy essential. The present study aimed to identify an effective therapy for a CUP patient using a patient-derived orthotopic xenograft (PDOX) model. This paper reports the usefulness of the PDOX model to precisely identify effective and ineffective chemotherapy and to compare the efficacy of S. typhimurium A1-R with first-line chemotherapy using the CUP PDOX model. The present study is the first to use a CUP PDOX model, which was able to precisely distinguish the chemotherapeutic course. We found that a carboplatinum (CAR)-based regimen was effective for this CUP patient. We also demonstrated that S. typhimurium A1-R was more effective against the CUP tumor than first-line chemotherapy. Our results indicate that S. typhimurium A1-R has clinical potential for CUP, a resistant disease that requires effective therapy., Competing Interests: The authors declare no competing interests.

Background: Ewing's sarcoma (ES) is a recalcitrant disease in need of transformative therapeutics., Objectives: The aim of this study was to investigate the efficacy of tumor-selective Salmonella typhimurium A1-R combined with tumor metabolism targeting with oral administration of recombinant methioninase (o-rMETase), on an ES patient-derived orthotopic xenograft (PDOX) model., Methods: The ES PDOX models were previously established in the right chest wall. The ES PDOX models were randomized into 5 groups when the tumor volume reached 80 mm3: G1: untreated control; G2: doxorubicin; G3: S. typhimurium A1-R; G4: o-rMETase; G5: S. typhimurium A1-R combined with o-rMETase. All mice were sacrificed on day 15. Body weight and tumor volume were assessed twice a week., Results: S. typhimurium A1-R and o-rMETase respectively suppressed tumor growth as monotherapies (p = 0.050 and p = 0.032). S. typhimurium A1-R combined with o-rMETase regressed tumor growth significantly compared to untreated group on day 15 (p < 0.032). S. typhimurium A1-R combined with o-rMETase group was significantly more effective than S. typhimurium A1-R or o-rMETase monotherapy (p = 0.032, p = 0.032)., Conclusions: The present results suggest that the combination of S. typhimurium A1-R and o-rMETase has promise to be a transformative therapy for ES., (© 2019 S. Karger AG, Basel.)

Objective: To estimate the incidence of serious infections in patients with HIV infection and autoimmune disease who were treated with tumor necrosis factor (TNF) inhibitors, and to compare these rates by stratified viral load levels., Methods: Using a unified search strategy, 4 centers identified HIV-infected patients exposed to TNF inhibitors. Patient characteristics and infection data were assessed via chart review in all patients who were ≥18 years old and who received TNF inhibitor therapy after HIV diagnosis, between January 1999 and March 2015., Results: We studied 23 patients with 26 uses of TNF inhibitor therapy (86.7 person-years of followup). Two (8.7%) experienced at least 1 serious infection episode, for an overall incidence rate of 2.55 per 100 patient-years (95% confidence interval [95% CI] 0.28-9.23). The incidence rate per 100 patient-years was 3.28 (95% CI 0.04-18.26) among patients with a viral load >500 copies/ml at therapy initiation and 2.09 (0.03-11.65) among patients with a viral load ≤500 copies/ml., Conclusion: This study suggests that the rate of serious infections in patients with HIV infection under active care who have received treatment with TNF inhibitors may be comparable to the rates observed in registry databases., (© 2016, American College of Rheumatology.)

Isolated distal deep-vein thrombosis (DDVT) of the lower extremities can be associated with subsequent proximal deep-vein thrombosis (PDVT) and/or acute pulmonary embolism (PE). We aimed to develop a model predicting the probability of developing PDVT and/or PE within three months after an isolated episode of DDVT. We conducted a retrospective cohort study of patients with symptomatic DDVT confirmed by lower extremity vein ultrasounds between 2001-2012 in the Cleveland Clinic Health System. We reviewed all the ultrasounds, chest ventilation/perfusion and computed tomography scans ordered within three months after the initial DDVT to determine the incidence of PDVT and/or PE. A multiple logistic regression model was built to predict the rate of developing these complications. The final model included 450 patients with isolated DDVT. Within three months, 30 (7 %) patients developed an episode of PDVT and/or PE. Only two factors predicted subsequent thromboembolic complications: inpatient status (OR, 6.38; 95 % CI, 2.17 to 18.78) and age (OR, 1.02 per year; 95 % CI, 0.99 to 1.05). The final model had a bootstrap bias-corrected c-statistic of 0.72 with a 95 % CI (0.64 to 0.79). Outpatients were at low risk (< 4 %) of developing PDVT/PE. Inpatients aged ≥ 60 years were at high risk (> 10 %). Inpatients aged < 60 were at intermediate risk. We created a simple model that can be used to risk stratify patients with isolated DDVT based on inpatient status and age. The model might be used to choose between anticoagulation and monitoring with serial ultrasounds.