Perioperative clinical trials for glioma: Raising the bar.

Gliomas are a heterogeneous group of primary brain cancers with poor survival despite multimodality therapy that includes surgery, radiation and chemotherapy. Numerous clinical trials have investigated systemic therapies in glioma, but have largely been negative. Multiple factors have contributed to the lack of progress including tumour heterogeneity, the tumour micro-environment and presence of the blood-brain barrier, as well as extrinsic factors relating to trial design, such as the lack of a contemporaneous biopsy at the time of treatment. A number of strategies have been proposed to progress new agents into the clinic. Here, we review the progress of perioperative, including phase 0 and 'window of opportunity', studies and provide recommendations for trial design in the development of new agents for glioma. The incorporation of pre- and post-treatment biopsies in glioma early phase trials will provide valuable pharmacokinetic and pharmacodynamic data and also determine the target or biomarker effect, which will guide further development of new agents. Perioperative 'window of opportunity' studies must use drugs with a recommended-phase-2-dose, known safety profile and adequate blood-brain barrier penetration. Drugs shown to have on-target effects in perioperative trials can then be evaluated further in a larger cohort of patients in an adaptive trial to increase the efficiency of drug development.

Cardiac Troponin I and T in Checkpoint Inhibitor-associated Myositis and Myocarditis.

Checkpoint inhibitor-associated myocarditis (ir-myocarditis) and myositis (ir-myositis) may occur concurrently among patients on checkpoint inhibitor immunotherapy. While cardiac-specific troponin I (cTnI) and troponin T (cTnT) are regarded to have similar sensitivities and specificities in conditions such as acute coronary syndrome, the cardiac specificity of cTnT has been challenged following observation that patients with neuromuscular diseases, including myositis, may have elevated cTnT without apparent clinical evidence of myocardial injury. Consequently, in the context of concurrent ir-myositis, cTnI may be a more appropriate biomarker for diagnosing and monitoring ir-myocarditis. To illustrate this point, we report a case of a patient with severe ir-myositis while on adjuvant programmed cell death protein 1 inhibitor immunotherapy for stage III melanoma, with accompanying elevation in cTnT.

Mechanisms of resistance to PARP inhibitors - an evolving challenge in oncology.

Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) lead to synthetic lethality when used in cancers harbouring a BRCA mutation or homologous recombination deficiency. There are now four PARPi approved by the Food and Drug Administration for therapeutic use is ovarian and breast cancer. In addition to this, there is data supporting its use in pancreatic adenocarcinoma and prostate cancer. However, development of resistance to PARPi limits the duration of response. Key mechanisms found to date include: (1) restoration of homologous recombination; (2) changes in PARP1; (3) suppression of non-homologous end joining; (4) replication fork protection; and (5) drug concentration. Gaining a better understanding of resistance mechanisms may guide combination therapies to overcome the resistance and improve the efficacy of PARPi. The purpose of this review is to describe the resistance mechanisms to PARPi and discuss their early detection.

Recurrent Merkel cell carcinoma of the testis with unknown primary site: a case report.

BACKGROUND: Merkel cell carcinoma is a rare and aggressive neuroendocrine tumor that commonly arises in the skin. It is rare for it to occur in the testes. There are only seven cases of testicular Merkel cell carcinoma reported in the literature. CASE PRESENTATION: A 66-year-old Maori man presented to our hospital with left testicular swelling. His alpha-fetoprotein and beta-human chorionic gonadotrophin levels were within normal limits. His lactate dehydrogenase concentration was elevated to 267 U/L. Ultrasound imaging confirmed a large testicular mass, and he underwent left orchiectomy. His histological examination revealed a neuroendocrine tumor with an immunostaining pattern suggesting Merkel cell carcinoma. He presented to our hospital again 3 months later with right testicular swelling that was confirmed on ultrasound sonography to be a tumor. He underwent a right orchiectomy, and his histological examination revealed metastatic Merkel cell carcinoma. A primary lesion was not identified, and computed tomographic imaging did not reveal spread to other organs. He received six cycles of adjuvant carboplatin and etoposide chemotherapy and remained disease-free 18 months after completion of chemotherapy. CONCLUSIONS: Given the paucity of studies, standard adjuvant treatment for testicular Merkel cell carcinoma remains uncertain, although platinum-based chemotherapy seems to be an appropriate option.

A rare neoplasm of the thyroid gland.

Burkitt's lymphoma of the thyroid gland is a rare malignancy. We present a case of a 58-year-old female who developed a rapid enlargement of her thyroid gland. Core biopsy confirmed the diagnosis of Burkitt's lymphoma. The tumour resolved after three cycles of chemotherapy. This case report emphasises the importance of considering lymphoma when dealing with thyroid nodules and goitres, as its management is different from that of other thyroid pathologies and delaying treatment has an impact on prognosis.