Malignant peripheral nerve sheath tumour - A long story: Case report.

INTRODUCTION: We present a rare case of Malignant Peripheral Nerve Sheath Tumour (MPNST) of the upper limb, which was excised thirteen times in thirteen years and ultimately ended in above elbow amputation. PRESENTING COMPLAINT AND INVESTIGATIONS: A 48 year old female presented initially with a localised swelling of 2 cms diameter in the front of the left elbow in 2007, which was excised. It recurred repeatedly and was excised. In the earlier presentations, the swellings were firm, mobile and not fixed to bone. In the last stage alone, bone fixity was identified. All the fourteen surgeries were performed by the primary author from 2007 to 2020, as the patient was particular. THE MAIN CLINICAL DIAGNOSES: had been neurofibroma and fibrosarcoma. There was no evidence of distant metastasis all these years. She did not respond to radiation or chemotherapy. Initially it was single, but later multiple. She had no clinical features of Neurofibromatosis 1 (NF1) or any family history. As the history progressed, the swellings became muscle deep and later encircled the radial nerve. The radial nerve was salvaged on three occasions. On the last three occasions, the tumour had to be shaved off from the humerus. The final amputation specimen showed a single tumour infiltrating the humerus and x-ray revealed bone destruction and tumour calcification. Final diagnosis was aided by immunohistochemistry (IHC) and cytogenetic study (FISH). CONCLUSION: The case is presented for the rarity of the presentation and the trust and dependence of the patient on her personal surgeon.

Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo.

The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple TP53 wild-type cell lines, including several hematologic cancer and MYCN-amplified neuroblastoma cell lines, as well as a subset of TP53-mutant cell lines in vitro Our work suggests that USP7 inhibitors upregulate transcription of genes normally silenced by the epigenetic repressor complex, polycomb repressive complex 2 (PRC2), and potentiate the activity of PIM and PI3K inhibitors as well as DNA-damaging agents. Furthermore, oral administration of USP7 inhibitors inhibits MM.1S (multiple myeloma; TP53 wild type) and H526 (small cell lung cancer; TP53 mutant) tumor growth in vivo Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer.

Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.

USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound 41, a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound 41 demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.

Discovery of a Potent and Selective CCR4 Antagonist That Inhibits Treg Trafficking into the Tumor Microenvironment.

Recruitment of suppressive CD4+ FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, Treg accumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of Treg and increasing the population of activated effector T cells (Teff) in the TME can potentiate antitumor immune responses. We developed a novel series of potent, orally bioavailable small molecule antagonists of CCR4. From this series, several compounds exhibited high potency in distinct functional assays in addition to good in vitro and in vivo ADME properties. The design, synthesis, and SAR of this series and confirmation of its in vivo activity are reported.

Cytological Scoring of Breast Lesions and Comparison with Histopathological Findings.

CONTEXT: Cytological assessment using various morphological parameters helps segregate breast lesions in fine-needle aspiration cytology (FNAC) into different categories. The prognosis and the line of management of each category differ accordingly. AIMS: This study aims at assessing the validity of Modified Masood's Scoring Index (MMSI) by the evaluation of cytomorphological features of various breast lesions compared with histopathological findings. SETTINGS AND DESIGN: This is a cross-sectional study done in 65 female patients with palpable or nonpalpable breast lesions, undergoing FNAC and biopsy over a period of 18 months from December 1, 2012, to May 31, 2014. MATERIALS AND METHODS: MMSI categorizes breast lesions, based on six cytological parameters into different categories such as nonproliferative breast disease (NPBD), proliferative breast disease (PBD) without atypia, PBD with atypia, and malignancy. The findings are compared with gold standard histopathological diagnosis. STATISTICAL ANALYSIS USED: Percentage of agreement, Kappa statistics, and Chi-square test. RESULTS: Of the total 65 cases, all cases in MMSI category I and IV showed good histopathological correlation. The agreement between MMSI and histopathology was 93.8% which is more when compared with 72.3% agreement between cytology without scoring and histopathology. MMSI has increased the diagnostic accuracy of FNAC to 93.8% from 80%. CONCLUSION: The scoring system is easily reproducible, simple, and reliable. MMSI proved good histopathological correlation in category I and IV. This scoring technique has clearly demarcated those cases requiring surgical management. It is applicable for palpable and nonpalpable cases.