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List of 40 genes in next-generation sequencing (NGS) panel

PCR-based assays to detect human circulating DNA in mice demonstrate that human PTEGR2 assays are specific (A) and sensitive (B). Human-derived DNA could be detected in plasma of PDX (C).

Pathologists diagnose prostate cancer by core needle biopsy. For low-grade and low-volume cases, the pathologists look for the few malignant glands out of hundreds within a core. They may miss the few malignant glands, resulting in repeat biopsies or missed therapeutic opportunities. This study developed a multi-resolution deep learning pipeline detecting malignant glands in core needle biopsies to help pathologists effectively and accurately diagnose prostate cancer in low-grade and low-volume cases. The pipeline consisted of two stages: the gland segmentation model detected the glands within the sections and the multi-resolution model classified each detected gland into benign vs. malignant. Analyzing a gland at multiple resolutions provided the classification model to exploit both morphology information (of nuclei and glands) and neighborhood information (for architectural patterns), important in prostate gland classification. We developed and tested our pipeline on the slides of a local cohort of 99 patients in Singapore. The images were made publicly available, becoming the first digital histopathology dataset of prostatic carcinoma patients of Asian ancestry. Our pipeline successfully classified the core needle biopsy parts (81 parts: 50 benign and 31 malignant) into benign vs. malignant. It achieved an AUROC value of 0.997 (95% CI: 0.987 - 1.000). Moreover, it produced heatmaps highlighting the malignancy of each gland in core needle biopsies. Hence, our pipeline can effectively assist pathologists in core needle biopsy analysis.

There is increasing preclinical evidence suggesting that metformin, an antidiabetic drug, has anticancer properties against various malignancies, including colorectal cancer. However, the majority of evidence, which was derived from cancer cell lines and xenografts, was likely to overestimate the benefit of metformin because these models are inadequate and require supraphysiologic levels of metformin. Here, we generated patient-derived xenograft (PDX) lines from 2 colorectal cancer patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for colorectal cancer. Metformin (150 mg/kg) as a single agent inhibits the growth of both PDX tumors by at least 50% (P < 0.05) when administered orally for 24 days. In one of the PDX models, metformin given concurrently with 5-FU (25 mg/kg) leads to an 85% (P = 0.054) growth inhibition. Ex vivo culture of organoids generated from PDX demonstrates that metformin inhibits growth by executing metabolic changes to decrease oxygen consumption and activating AMPK-mediated pathways. In addition, we also performed genetic characterizations of serial PDX samples with corresponding parental tissues from patients using next-generation sequencing (NGS). Our pilot NGS study demonstrates that PDX represents a useful platform for analysis in cancer research because it demonstrates high fidelity with parental tumor. Furthermore, NGS analysis of PDX may be useful to determine genetic identifiers of drug response. This is the first preclinical study using PDX and PDX-derived organoids to investigate the efficacy of metformin in colorectal cancer. Mol Cancer Ther; 16(9); 2035–44. ©2017 AACR.

We report a case of a woman who was admitted with a suspicion of metastatic malignancy of unknown primary origin. A few months prior to her admission, she presented to a rheumatologist with acute anterior uveitis, psoriasiform rashes and polyarthritis. A diagnosis of psoriatic arthropathy was made and she was treated accordingly. Soon after she presented with persistent back and right upper quadrant abdominal pain for which she had a CT scan done with evidence of hilar lymphadenopathy, liver hypodensities and lytic-sclerotic bone lesions. She was referred to our hospital for further investigations and management. After re-exploring her clinical presentation and further investigations (including a liver biopsy), a diagnosis of multisystemic sarcoidosis with ocular, reticuloendothelial, hepatic and skeletal involvement was made. The patient was started on systemic glucocorticoids and second line immunosuppressants and demonstrated significant clinical improvement with resolution of her liver granulomata on imaging and improvement in her back pain. The case illustrates the importance of a thorough clinical assessment, review of investigations and an open mind in the evaluation of a patient.

Primary malignant mixed Mullerian tumour (MMMT) of the vagina is a rare entity. We report a case of a 62-year-old woman who presented with a fixed and hard anterior vaginal wall mass with contact bleeding. She proceeded to have an anterior infralevator pelvic exenteration with urethrectomy and anterior vaginectomy, creation of an ileal conduit and bilateral lymph node dissection. Histopathological examination and immunohistochemistry confirmed the diagnosis of primary MMMT of the vagina. The patient was stage IVA at diagnosis. Despite chemotherapy and radiotherapy, she had progressive disease and eventually passed away at the age of 65 years.

in our case, biopsies do not always yield the expected results. We should not forget that this test may also sometimes give false positive results, especially in low-grade AS that cannot be readily distinguished from radiotherapy-induced changes [3]. Standard therapy entails surgery with complete tumour resection. However, as in our case, chemotherapy becomes the first treatment of choice when surgery is not possible. Results are far from alone promising for the most widely used drugs. Anthracyclines alone or with iphosphamide have led to disease control after several months (between 7 and 24 months) [8], always in combination with previous surgery. Over the past few years, paclitaxel has been used for used in advanced stage and/or metastatic AS [9,10]. In our case, the weekly taxane kept the disease under control for five months. Our case reveals the sound profile of paclitaxel as a single agent in the initial treatment of unresectable, radiotherapyinduced AS in an anthracycline-naive patient.

Background: Glioblastomas (GBM) are highly infiltrative, cellular and mitotically active tumors with large histologic variations within and between tumours. Several subtypes have been described including the GBM with oligodendroglial differentiation (GBM-O) and primitive neuroectodermal tumour components (GBM-PNET). We report the first described case of a patient with synchronous multi-centric GBM-O and GBM-PNET components. Case Description: A patient, who presented with a short history of progressive headache and difficulty with memory recall, was found on MRI imaging to have two intracranial lesions. These showed heterogeneous enhancement and were found in the left frontal and left temporal regions. The patient underwent gross total resection of these two lesions which were found to show GBM-O and GBM-PNET differentiations. Conclusion: Although tumour cell migration in the context of GBM is a well-recognized phenomenon, the traditional hypothesis is not able to satisfactorily explain this case of multicentric GBM whereby the two lesions demonstrate different cell origins. More current understanding of the migratory pathways from the subventricular zone provide an alternate and plausible pathway that fits our patient's unusual diagnosis.

Background Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are two distinct but closely related entities with strong morphologic and genetic similarities. While chRCC is a malignant tumor, oncocytoma is usually regarded as a benign entity. The overlapping characteristics are best explained by a common cellular origin, and the biologic differences between chRCC and oncocytoma are therefore of considerable interest in terms of carcinogenesis, diagnosis and clinical management. Previous studies have been relatively limited in terms of examining the differences between oncocytoma and chromophobe RCC. Methods Gene expression profiling using the Affymetrix HGU133Plus2 platform was applied on chRCC (n = 15) and oncocytoma specimens (n = 15). Supervised analysis was applied to identify a discriminatory gene signature, as well as differentially expressed genes. High throughput single-nucleotide polymorphism (SNP) genotyping was performed on independent samples (n = 14) using Affymetrix GeneChip Mapping 100 K arrays to assess correlation between expression and gene copy number. Immunohistochemical validation was performed in an independent set of tumors. Results A novel 14 probe-set signature was developed to classify the tumors internally with 93% accuracy, and this was successfully validated on an external data-set with 94% accuracy. Pathway analysis highlighted clinically relevant dysregulated pathways of c-erbB2 and mammalian target of rapamycin (mTOR) signaling in chRCC, but no significant differences in p-AKT or extracellular HER2 expression was identified on immunohistochemistry. Loss of chromosome 1p, reflected in both cytogenetic and expression analysis, is common to both entities, implying this may be an early event in histogenesis. Multiple regional areas of cytogenetic alterations and corresponding expression biases differentiating the two entities were identified. Parafibromin, aquaporin 6, and synaptogyrin 3 were novel immunohistochemical markers effectively discriminating the two pathologic entities. Conclusions Gene expression profiles, high-throughput SNP genotyping, and pathway analysis effectively distinguish chRCC from oncocytoma. We have generated a novel transcript predictor that is able to discriminate between the two entities accurately, and which has been validated both in an internal and an independent data-set, implying generalizability. A cytogenetic alteration, loss of chromosome 1p, common to renal oncocytoma and chRCC has been identified, providing the opportunities for identifying novel tumor suppressor genes and we have identified a series of immunohistochemical markers that are clinically useful in discriminating chRCC and oncocytoma.