The Nail in the Coffin?: Examining the KEYNOTE-789 Clinical Trial's Impact.

Targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), have revolutionized the treatment landscape for EGFR-mutant non-small cell lung cancer (NSCLC). However, the emergence of resistance to EGFR TKIs especially the third generation TKIs such as osimertinib remains a major clinical challenge. As a broader strategy for combating resistance, several clinical trials have explored the efficacy of immune checkpoint inhibitors (ICIs)+chemotherapy in EGFR-mutated NSCLC. Until now, the ORIENT-31 and IMpower150 trials suggested that ICIs+ chemotherapy may be more effective than chemotherapy alone after failure of EGFR-TKIs (although ORIENT-31 was negative for overall survival [OS] and IMpower150 was a subset analysis, so the study was not powered to detect a difference); however, the CheckMate-722 trial yielded disappointing results. Thus, the results of this global trial KEYNOTE-789 were highly anticipated.

Epithelial ovarian cancer survival by race and ethnicity in an equal-access healthcare population.

BACKGROUND: Previous studies in the general population observed that compared with non-Hispanic White women, Pacific Islander and Black women have higher age-adjusted mortality rates from epithelial ovarian cancer (EOC), while Asian American patients have lower mortality. We investigated whether race and ethnicity is associated with differences in EOC survival in a United States Military population where patients have equal access to healthcare. METHODS: This retrospective study included women diagnosed with EOC between 2001 and 2018 among Department of Defense beneficiaries. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models adjusting for age and year of diagnosis, histology and stage. RESULTS: In our study population of 1230 invasive EOC cases (558 non-Hispanic White, 74 non-Hispanic Black, 73 Asian, 30 Pacific Islander and 36 Hispanic cases), 63% of the women died (all-cause death) after a mean = 4.8 years (SD = 4.1) of follow-up following diagnosis. Compared with non-Hispanic White cases, Asian cases had better overall survival, HR = 0.76 (95% CI = 0.58-0.98), whereas there were no differences in survival for other racial and ethnic groups. CONCLUSIONS: These findings highlight the need to investigate how differences in access to healthcare may influence observed racial and ethnic disparities for EOC.

Case Report: A complete pathologic response in pancreatic cancer with squamous cell differentiation.

Primary pancreatic malignancies are mostly composed of the adenocarcinoma histological subtype. However, squamous cell carcinoma (SCC) accounts for approximately 0.5%-1% of all malignant pancreatic cancers. Because of the rarity of SCC of the pancreas, guideline-directed treatment is lacking, treatment response is difficult to access, and treatment options are poorly defined. Here, we report a case of a 65-year-old man diagnosed with pancreatic carcinoma with dominant squamous cell differentiation, who achieved complete pathologic response (CPR) after treatment with gemcitabine, cisplatin, and nab-paclitaxel every 14 days for six cycles and who continues to lead a high quality of life 7 months later. To our knowledge, this is the first case of CPR in a case of SCC of the pancreas. To highlight the ambiguity and the need for further studies, we also performed a narrative review analyzing recent cases and compared them to our case.

Strategies to Mitigate the Drug-Drug Interaction between Nirmatrelvir/Ritonavir and Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Azole Antifungals: Results of a Case Series.

INTRODUCTION: Nirmatrelvir/ritonavir (NIM/r) inhibits tacrolimus metabolism resulting in a profound drug-drug interaction that is further complicated by the use of azole antifungals. CASE PRESENTATIONS: We describe three strategies, in 4 patient cases, for the initiation of NIM/r in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients on tacrolimus at the time of diagnosis. Patients 1 and 2 (strategy 1) experienced prolonged, elevated tacrolimus concentrations after an empiric 33% reduction in tacrolimus dose and adjustment of azole antifungal at NIM/r initiation (strategy 1) and with complete discontinuation of tacrolimus and azole antifungal at NIM/r initiation (strategy 2). Patients 3 and 4 (strategy 3) did not experience elevated tacrolimus concentrations on NIM/r treatment with complete discontinuation of tacrolimus and azole antifungal and a 12-24-h delay in NIM/r initiation. Reinitiation of tacrolimus after NIM/r completion resulted in variable tacrolimus concentrations. CONCLUSION: NIM/r-tacrolimus is a serious drug-drug interaction which can be mitigated by early discontinuation of tacrolimus and azole antifungals, close monitoring, and reinitiation of tacrolimus and antifungal 48-72 h after completion of therapy.

Racial and ethnic differences in tumor characteristics among endometrial cancer patients in an equal-access healthcare population.

PURPOSE: There are racial and ethnic differences in endometrial cancer incidence and mortality rates; compared with Non-Hispanic White women, Black women have a similar incidence rate for endometrial cancer, but their mortality is higher. Pacific Islander women may also have worse outcomes compared to their White counterparts. We assessed tumor characteristics and adjuvant therapy by racial and ethnic group among endometrial cancer patients treated within the Military Health System, an equal access healthcare organization. METHODS: We retrospectively identified women diagnosed with invasive endometrial cancer among US Department of Defense beneficiaries reported in the Automated Central Tumor Registry database (year of diagnosis: 2001-2018). We compared tumor characteristics and receipt of adjuvant therapy across racial and ethnic groups using Chi-square or Fisher tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of all cause mortality were calculated using Cox proportional hazards regression models adjusting for age at diagnosis, adjuvant therapy, histology and stage. RESULTS: The study included 2574 endometrial cancer patients [1729 Non-Hispanic White, 318 Asian, 286 Black, 140 Pacific Islander and 101 Hispanic women]. Among all cases, a higher proportion of Black patients had non-endometrioid histology (46.5% versus ≤ 29.3% in other groups, P < 0.01) and grade 3-4 tumors (40.1% versus ≤ 29.3% in other groups, P < 0.01). In multivariable Cox models, compared with Non-Hispanic White cases, Black endometrial cancer patients had a higher mortality risk (HR 1.43, 95% CI, 1.13-1.83). There was no difference in mortality risk for other racial and ethnic groups. CONCLUSION: Black patients with endometrial cancer presented with more aggressive tumor features and they had worse overall survival compared with patients in other racial and ethnic groups. Further study is needed to better direct preventive and therapeutic efforts in order to correct endometrial cancer disparities in the future.

Endometrial Adenocarcinoma with Discordant Microsatellite Stability Status Treated with First-Line Pembrolizumab: A Case Report and Narrative Review.

BACKGROUND Microsatellite instability (MSI) is a hallmark of specific cancers and can be diagnosed using both tissue- and liquid-based approaches. When these tissue- and liquid-based approaches give differing results, they are known as discordant or being at variance. MSI-H tumors are well-researched candidates for treatment with programmed cell death protein 1 (PD-1) inhibitor-based immunotherapy, but the efficacy of immunotherapy in MSI-H discordant endometrial cancer, especially as first-line therapy, is not yet well documented in the literature. CASE REPORT A 67-year-old woman presented with a retroperitoneal mass positive for recurrent adenocarcinoma of endometrial origin. Her stage I endometrial adenocarcinoma 7 years ago demonstrated microsatellite stable (MSS) by immunohistochemical (IHC) stain and indeterminant due to insufficient tissue by Caris Next-Generation Sequencing (NGS). She then presented with a retroperitoneal mass that was MSI-H on IHC stain and Caris NGS, as well as MSI high on liquid biopsy @Guardant360 (@G360). The patient proceeded with pembrolizumab treatment 1 year ago and has sustained a complete clinical response at the time of writing. CONCLUSIONS Our case provides further evidence for the need to retest the microsatellite stability of metastatic sites, especially after a long disease-free survival. Here, we providing a literature review of case reports and a review of studies outlining discordance of testing modalities. Our case also highlights the importance of considering the use of immunotherapy as a first-line agent in patients who may have a poor ECOG performance status, as it can significantly improve their quality of life and reduce the number of adverse effects compared to chemotherapy.

Improving Self-Confidence of Military Medical Providers With Joint Procedure Simulation: A Pilot Study.

INTRODUCTION: Military medical providers are a unique population that encounter different environments across the world. From hospital clinics to war zones, these providers must perform procedures and rely on their training and skill to help their patients. This pilot study aimed to assess the self-confidence of military medical providers performing joint aspiration and injection before and after a simulation workshop in both clinical and austere settings. METHODS: In 2016, 25 military physicians from various military facilities participated in a 1-hour knee arthrocentesis and injection and shoulder injection workshop. Education was provided on the knee and shoulder anatomy and various approaches to performing the procedures before the hands-on portion of the workshop. Surveys assessing self-reported confidence levels by performing the procedures in the clinic and austere settings were completed before and after simulation training. RESULTS: The results were analyzed and grouped based on the provider experience level, simulation environment, and specific procedure performed. There was a statistical significance seen in the shoulder arthrocentesis group, which included all participating providers, with a P-value of <.01 in the clinic setting and a P-value of <.001 in the austere setting. In the knee aspiration simulation, there were also improvements in the provider confidence, but it was not statistically significant with P-values of .36 and .14 in the clinical and austere settings, respectively. CONCLUSION: Simulation training can lead to increased medical provider self-confidence in performing musculoskeletal joint aspirations and injections in both clinic and austere settings. The military medicine demographics have had little research in joint injections and provider confidence to date. This pilot study was one of the first to evaluate this unique population. The methods used in this study, and the positive data collected on provider confidence, can be used in larger studies, encompassing other medical providers to increase the confidence of providers throughout various fields of medicine.

A Long Overdue Targeted Treatment for KRAS Mutations in NSCLC: Spotlight on Adagrasib.

KRASG12C is one of the most common oncogenes in non-small cell lung cancer (NSCLC) and is associated with a poor prognosis. Historically, KRAS mutations have been difficult to target due to lack of binding sites and exceptionally high affinity for guanosine triphosphate/guanosine diphosphate (GTP/GDP). Recently, KRASG12C selective inhibitors have shown promising results in Phase I/II studies. Here we discuss the mechanism of action, pharmacokinetic and pharmacodynamic properties, efficacy, and tolerability of adagrasib (MRTX849).

A Rare Coexistence of Seminoma and Hodgkin's Lymphoma in Hawai'i.

Both Hodgkin's lymphoma and testicular cancers can present in young men; however, concurrent Hodgkin's lymphoma with seminoma is very rare. When they do coexist, careful consideration must be made to avoid missing new cancer by assuming the presence of primary metastatic disease when lymphadenopathy presents. Here we present a rare case of coexistence of seminoma and Hodgkin's lymphoma and the staging and treatment challenges associated with a 2-cancer diagnosis.

Chronic Cough as a Presenting Symptom of a Giant Thoracic Aortic Aneurysm: A Case Report.

Chronic cough has a broad differential, and thoracic aortic aneurysm (TAA) is a rare but potentially life-threatening etiology. We present a giant arch TAA in a non-dyspneic, Pacific Islander man with significant tobacco-use history who presented with chronic cough with no acute pulmonary process noted on imaging. Given the high mortality rates associated with thoracic aortic aneurysms, the purpose of this report is to highlight the importance of keeping TAA as a rare differential for chronic cough, particularly when caring for patients with elevated risk. Recognition of patients with thoracic aortic disease who have a class I indication for surgical intervention (meaning there is evidence or general agreement that surgery will be beneficial, useful, and effective) as well as prompt evaluation of their anatomical landmarks in the perioperative period is critical. Imaging and, in particular, computed tomography remain the optimal modalities to screen for thoracic aortic disease.

The Three P's: Parotid, PD-L1, and Pembrolizumab.

We present a case of recurrent, platinum-refractory undifferentiated carcinoma of the parotid which was treated with checkpoint inhibitor, Pembrolizumab, and achieved a complete response to therapy. We review the literature of checkpoint inhibitor use in undifferentiated carcinoma of the parotid.

Acute eosinophilic pneumonia following electronic cigarette use.

Electronic cigarette (e-cigarette) use, or vaping, is gaining widespread popularity among adults aged 18-35. Vaping is commercially promoted as a safer alternative to traditional cigarette smoking. Previous studies have reported a close relationship between conventional cigarette smoking and acute eosinophilic pneumonia (AEP), but only one case report to date associates vaping with AEP in a male patient. We present the first case of AEP involving a young female after use of e-cigarettes. Clinicians should consider AEP when evaluating young patients with hypoxic respiratory failure and a recent history of e-cigarette use. This case highlights the need for more research into the relationship between e-cigarettes and AEP.

GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 Signaling and Down-regulating Expression of GNAI2.

BACKGROUND & AIMS: Interleukin 6 (IL6) and tumor necrosis factor contribute to the development of colitis-associated cancer (CAC). We investigated these signaling pathways and the involvement of G protein subunit alpha i1 (GNAI1), GNAI2, and GNAI3 in the development of CAC in mice and humans. METHODS: B6;129 wild-type (control) or mice with disruption of Gnai1, Gnai2, and/or Gnai3 or conditional disruption of Gnai2 in CD11c+ or epithelial cells were given dextran sulfate sodium (DSS) to induce colitis followed by azoxymethane (AOM) to induce carcinogenesis; some mice were given an antibody against IL6. Feces were collected from mice, and the compositions of microbiomes were analyzed by polymerase chain reactions. Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) isolated from spleen and colon tissues were analyzed by flow cytometry. We performed immunoprecipitation and immunoblot analyses of colon tumor tissues, MDSCs, and mouse embryonic fibroblasts to study the expression levels of GNAI1, GNAI2, and GNAI3 and the interactions of GNAI1 and GNAI3 with proteins in the IL6 signaling pathway. We analyzed the expression of Gnai2 messenger RNA by CD11c+ cells in the colonic lamina propria by PrimeFlow, expression of IL6 in DCs by flow cytometry, and secretion of cytokines in sera and colon tissues by enzyme-linked immunosorbent assay. We obtained colon tumor and matched nontumor tissues from 83 patients with colorectal cancer having surgery in China and 35 patients with CAC in the United States. Mouse and human colon tissues were analyzed by histology, immunoblot, immunohistochemistry, and/or RNA-sequencing analyses. RESULTS: GNAI1 and GNAI3 (GNAI1;3) double-knockout (DKO) mice developed more severe colitis after administration of DSS and significantly more colonic tumors than control mice after administration of AOM plus DSS. Development of increased tumors in DKO mice was not associated with changes in fecal microbiomes but was associated with activation of nuclear factor (NF) κB and signal transducer and activator of transcription (STAT) 3; increased levels of GNAI2, nitric oxide synthase 2, and IL6; increased numbers of CD4+ DCs and MDSCs; and decreased numbers of CD8+ DCs. IL6 was mainly produced by CD4+/CD11b+, but not CD8+, DCs in DKO mice. Injection of DKO mice with a blocking antibody against IL6 reduced the expansion of MDSCs and the number of tumors that developed after CAC induction. Incubation of MDSCs or mouse embryonic fibroblasts with IL6 induced activation of either NF-κB by a JAK2-TRAF6-TAK1-CHUK/IKKB signaling pathway or STAT3 by JAK2. This activation resulted in expression of GNAI2, IL6 signal transducer (IL6ST, also called GP130) and nitric oxide synthase 2, and expansion of MDSCs; the expression levels of these proteins and expansion of MDSCs were further increased by the absence of GNAI1;3 in cells and mice. Conditional disruption of Gnai2 in CD11c+ cells of DKO mice prevented activation of NF-κB and STAT3 and changes in numbers of DCs and MDSCs. Colon tumor tissues from patients with CAC had reduced levels of GNAI1 and GNAI3 and increased levels of GNAI2 compared with normal tissues. Further analysis of a public human colorectal tumor DNA microarray database (GSE39582) showed that low Gani1 and Gnai3 messenger RNA expression and high Gnai2 messenger RNA expression were significantly associated with decreased relapse-free survival. CONCLUSIONS: GNAI1;3 suppresses DSS-plus-AOM-induced colon tumor development in mice, whereas expression of GNAI2 in CD11c+ cells and IL6 in CD4+/CD11b+ DCs appears to promote these effects. Strategies to induce GNAI1;3, or block GNAI2 and IL6, might be developed for the prevention or therapy of CAC in patients.