Therapeutic Advances and Challenges in the Management of HER2-Positive Gastroesophageal Cancers.

Gastroesophageal cancer is one of the most common cancers in the world, with a high rate of mortality. While there has been significant progress over the past decade, particularly with the addition of anti-HER2 therapies to platinum-based chemotherapy agents in the advanced setting, the prognosis remains poor and the treatment options for this disease entity remain limited. In this review, we discuss the current therapeutic landscape for HER2-positive gastroesphageal cancer and the seminal clinical trials that have shaped our approach to this disease entity. In addition, we highlight some of the challenges to the understanding and management of this disease, specifically discussing the breadth of molecular diversity and intratumoral heterogeneity of HER2 expression that impact the clinical efficacy and prognosis. Furthermore, we discuss the potential role of next-generation sequencing (NGS) and circulating-tumor DNA (ctDNA) as complementary tools to immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) to guiding clinical decision making. Finally, we highlight promising clinical trials of new treatment regimens that will likely reshape the therapeutic approach to this disease entity.

Complete response to neoadjuvant pembrolizumab and capecitabine in microsatellite stable, Epstein-Barr virus-positive, locally advanced gastric adenocarcinoma: case report.

Immunotherapy has been established as a standard in select molecular subgroups of treatment-refractory advanced gastric cancer. However, its role in resectable gastric cancer where perioperative systemic therapy is the standard remains unclear. We present a case of a man who was diagnosed with resectable gastric cancer that was microsatellite stable but programmed death-ligand 1 (PD-L1) and Epstein-Barr Virus (EBV)-positive. Given extenuating circumstances of the SARS-CoV-2 pandemic, preferences to limit exposure to the healthcare setting, and the unique tumor molecular features, neoadjuvant pembrolizumab and capecitabine was pursued after multidisciplinary discussion. He was able to achieve a complete response to this neoadjuvant regimen with no further signs of radiographic or pathologic disease on follow-up. We highlight a dramatic response to this novel approach that represents among the first cases to support a potentially viable neoadjuvant chemoimmunotherapy strategy to resectable gastric cancer. In select patients, perioperative immunotherapy-based therapy may constitute a promising strategy in resectable gastric cancer and warrants further investigation.

Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE-Mutant Uterine Carcinosarcoma.

Gynecologic carcinosarcomas, previously known as malignant mixed Müllerian tumors, are uncommon malignancies that demonstrate an aggressive biology and lack a standard therapeutic approach. Molecular analyses have revealed recurrent alterations in chromatin remodeling genes, but clinical support for therapeutic significance is lacking. We prospectively identified a patient with refractory uterine carcinosarcoma whose tumor was subject to molecular profiling at diagnosis and again at radiographic progression. Initial molecular testing did not assess tumor mutational burden, DNA polymerase ɛ (POLE), or microsatellite status. After the failure of several lines of chemotherapy, comprehensive genomic profiling of a repeat biopsy identified two missense mutations of the exonuclease domain of POLE (P286R and T323A). Tumor mutational burden was elevated (169 mutations per DNA megabase), consistent with an ultramutator phenotype. As seen in previously reported POLE-endometrioid cases, our patient harbored alterations in PIK3CA, ARID1A, and PTEN and was microsatellite stable, with appreciable tumor-infiltrating lymphocytes. She achieved an ongoing durable response with pembrolizumab. This is the first report of programmed cell death protein 1 response in uterine carcinosarcoma. KEY POINTS: Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis.Inactivating DNA polymerase ɛ (POLE) mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition.To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma.This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB-high tumors.

Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature.

Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is a universal event and limits clinical efficacy. The third-generation EGFR inhibitor osimertinib is active in EGFR-mutant/T790M positive non-small-cell lung cancer. Mechanisms of acquired resistance are emerging, and here we describe a cis-oriented solvent-front EGFR G796S mutation as the resistance mechanism observed in a progression biopsy and circulating tumor DNA (ctDNA) from a patient with initial response followed by progression on osimertinib. This is one of the earliest reports of a sole solvent-front tertiary EGFR mutation as a resistance mechanism to osimertinib. Our case suggests a monoclonal resistance mechanism. We review the importance of the solvent-front residues across TKIs and describe known osimertinib resistance mechanisms. We observe that nearly all clinical osimertinib-resistant tertiary EGFR mutations are oriented in cis with EGFR T790M. This case highlights the importance of mutations affecting EGFR kinase domains and supports the feasibility of broad panel ctDNA assays for detection of novel acquired resistance and tumor heterogeneity in routine clinical care.

Prior CT May Improve Diagnostic Confidence in Myocardial Perfusion Imaging.

PURPOSE: Many patients with matching myocardial perfusion imaging defects may have prior CT examinations that include the myocardial region of interest, such as a CT chest or CT abdomen. We correlate these perfusion defects with available prior CT examinations to determine if this will improve diagnostic confidence. METHODS: Myocardial perfusion scans were reviewed to identify cases with myocardial perfusion defects and prior CT imaging that included the myocardium. The CT was reviewed for evidence of myocardial injury that correlated with the perfusion defect. RESULTS: A retrospective review of 732 myocardial perfusion scans was performed, of which 69 cases with perfusion defects were identified that also had prior CT imaging available for review. Of this subset of patients, 19 patients had findings on the CT scan compatible with ischemia or infarction in the expected region of the perfusion defect, which allowed for a more confident diagnosis. CONCLUSIONS: Reviewing a prior CT scan, if available, during the interpretation of a myocardial perfusion scan, can help improve diagnostic confidence in over 25% of cases. This can lead to decreased indeterminate results and can be used to potentially avoid unhelpful further testing.

FDG PET/CT images demonstrating epididymo-orchitis in a patient with HIV, acute kidney injury and known epididymo-orchitis on scrotal ultrasound.

A 52-year-old man with HIV was referred for an F-FDG PET/CT scan for the cause of kidney injury. FDG PET/CT scan revealed increased renal cortical FDG activity, which can be seen in HIV nephropathy or acute interstitial nephritis. Diffuse increased FDG uptake was demonstrated within the right testicle and epididymis, consistent with the patient's known right epididymo-orchitis, as diagnosed on ultrasound 1 week before admission. Multiple enlarged lymph nodes with increased FDG activity were also found within the right inguinal and external iliac nodal chains, which were presumed to be reactive. The patient was treated with ciprofloxacin with symptomatic improvement.

Raccoon roundworm encephalitis.

Raccoon roundworm encephalitis is a rare but devastating infection characterized by progressive neurological decline despite attempted therapy. Patients present with deteriorating neurological function, eosinophilia, and history of pica or geophagia resulting in ingestion of the parasite. Neuroimaging studies demonstrate nonspecific findings of progressive white matter inflammation and cortical atrophy.