Enhancing prognostic power in multiple myeloma using a plasma cell signature derived from single-cell RNA sequencing.

Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum of plasma cell dyscrasias (all p < 0.05) and a shorter overall survival in MM (hazard ratio, HR = 1.72; p < 0.001). Notably, the prognostic effect of the PBM score was independent of the International Staging System (ISS) and Revised ISS (R-ISS). The downstream analysis further linked higher PBM scores with the presence of cytogenetic abnormalities, TP53 mutations, and compositional changes in the myeloma tumor immune microenvironment. Our integrated analyses suggest the PBM score may provide an opportunity for refining risk stratification and guide decisions on therapeutic approaches to MM.

Timely delivery of PORT for head and neck squamous cell carcinoma in a county hospital.

Objectives: The objective of this study was to compare the rate of post-operative radiation therapy (PORT) initiation within 6 weeks for head and neck squamous cell carcinoma patients treated at a safety net, academic institutio between 2019 and 2021 versus those treated in 2022 after implementation of a new clinical pathway. Methods: A retrospective case-control study was performed at a single tertiary care, safety-net, academic institution. Patient demographics, tumor characteristics, dates of surgery, and other treatment dates were collected from the electronic medical record. The time from surgery to PORT was calculated. Patients who started radiation treatment within 42 days of surgery were regarded as having started PORT on time. The demographics, tumor characteristics, and rate of timely PORT for the two cohorts of patients were compared. Results: From 2018 to 2021, our rate of PORT initiation within 6 weeks of surgery was 12% (n = 57). In 2022, our rate of timely PORT was 88% (n = 16), p < 0.5. Patient demographics and characteristics were similar with the exception of marital status and use of free-flap reconstruction. The 2022 cohort was more likely to be single (p < 0.5), and all patients underwent free-flap reconstruction in 2022 (p < 0.05). Conclusion: Early referrals, frequent communication, and use of a secure registry were the key to the success found by our group despite the socioeconomic challenges of our underserved, safety-net hospital patient population. The changes made at our institution should serve as a template for other institutions seeking to improve the quality of care for their HNSCC patients.

Incidental detection of FGFR3 fusion via liquid biopsy leading to earlier diagnosis of urothelial carcinoma.

The rising utilization of circulating tumor DNA (ctDNA) assays in Precision Oncology may incidentally detect genetic material from secondary sources. It is important that such findings are recognized and properly leveraged for both diagnosis and monitoring of response to treatment. Here, we report a patient in whom serial cell-free DNA (cfDNA) monitoring for his known prostate adenocarcinoma uncovered the emergence of an unexpected FGFR3-TACC3 gene fusion, a BRCA1 frameshift mutation, and other molecular abnormalities. Due to the rarity of FGFR3 fusions in prostate cancer, a workup for a second primary cancer was performed, leading to the diagnosis of an otherwise-asymptomatic urothelial carcinoma (UC). Once UC-directed treatment was initiated, the presence of these genetic abnormalities in cfDNA allowed for disease monitoring and early detection of resistance, well before radiographic progression. These findings also uncovered opportunities for targeted therapies against FGFR and BRCA1. Overall, this report highlights the multifaceted utility of longitudinal ctDNA monitoring in early cancer diagnosis, disease prognostication, therapeutic target identification, monitoring of treatment response, and early detection of emergence of resistance.

High risk lung nodule: A multidisciplinary approach to diagnosis and management.

Pulmonary nodules are often discovered incidentally during CT scans performed for other reasons. While the vast majority of nodules are benign, a small percentage may represent early-stage lung cancer with the potential for curative treatments. With the growing use of CT for both clinical purposes and lung cancer screening, the number of pulmonary nodules detected is expected to increase substantially. Despite well-established guidelines, many nodules do not receive proper evaluation due to a variety of factors, including inadequate coordination of care and financial and social barriers. To address this quality gap, novel approaches such as multidisciplinary nodule clinics and multidisciplinary boards may be necessary. As pulmonary nodules may indicate early-stage lung cancer, it is crucial to adopt a risk-stratified approach to identify potential lung cancers at an early stage, while minimizing the risk of harm and expense associated with over investigation of low-risk nodules. This article, authored by multiple specialists involved in nodule management, delves into the diagnostic approach to lung nodules. It covers the process of determining whether a patient requires tissue sampling or continued surveillance. Additionally, the article provides an in-depth examination of the various biopsy and therapeutic options available for malignant lung nodules. The article also emphasizes the significance of early detection in reducing lung cancer mortality, especially among high-risk populations. Furthermore, it addresses the creation of a comprehensive lung nodule program, which involves smoking cessation, lung cancer screening, and systematic evaluation and follow-up of both incidental and screen-detected nodules.

Disparities in mortality among acute myeloid leukemia-related hospitalizations.

Racial and socioeconomic disparities have become apparent in acute myeloid leukemia (AML) outcomes. We conducted a retrospective cohort study of hospitalizations for adults with a diagnosis of AML from 2009 to 2018 in the Nationwide Inpatient Sample (NIS). We categorized patients' ages in groups of <60 years and ≥60 years and stratified them by reported race/ethnicity. Exposures of interest were patient sociodemographics, hospital characteristics, and Elixhauser-comorbidity Index. Outcome of interest was in-hospital death. Statistical analyses included survey logistic regression to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) to quantify the independent associations between patient characteristics and mortality. Of 622,417 AML-related hospitalizations, 57.6% were in patients ≥60 years. The overall rate of in-hospital death was 9.4%. Compared to patients <60, older patients experienced a higher rate of in-hospital death. In both age groups and in all ethnicities, mortality decreased over time. Differences in mortality were observed based on gender, payer, hospital location, and teaching status. For hospitalizations in patients ≥60, NH-Black race was associated with inferior in-hospital death outcomes (OR 1.17; CI 1.08-1.28). Urban teaching hospitals were associated with a 38% increase (OR 1.38; CI 1.06-1.80) in inpatient mortality in patients <60 and a 15% decrease (OR 0.85; CI 0.77-0.95) in inpatient mortality in patients ≥60. Our results highlight the increased need to recognize the role of race/ethnicity and socioeconomic factors and their contribution to disparate outcomes in AML.

Persistent ethnicity-associated disparity in anti-tumor effectiveness of immune checkpoint inhibitors despite equal access.

We reviewed response to immune checkpoint inhibitors (ICI) of 207 patients with diagnoses of lung or head and neck cancer treated with chemotherapy/ICI combination therapy and ICI monotherapy between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine. Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority populations and provide equal access to care regardless of means. 174 patients had a diagnosis of lung cancer (non-small cell or small cell) and 33 had a diagnosis of head and neck squamous cell carcinoma (HNSCC). 38% self-identified as Black, 45% as non-Hispanic White, and 18% as Hispanic. The objective response rate (ORR) was similar for lung cancer (35.057%) and HNSCC patients (30.3%) (p=0.894). The ORR for Hispanic and Black patients was lower compared to non-Hispanic White patients (H 27.0%, B 32.5%, W 38.7%; H vs. W p=0.209; B vs. W p=0.398). When considering only patients treated with ICI monotherapy, the ORR for Hispanic patients dropped further to 20.7% while the ORR of Black and non-Hispanic White patients remained about the same (B 29.3% and W 35.9%, H vs. W p=0.133; B vs. W p=0.419). Immune related adverse events were the lowest in the Hispanic population occurring in only 30% of patients compared to 40% of patients in the Black cohort and 50% of the non-Hispanic White cohorts.

Non-small cell lung cancer in the era of immunotherapy.

Immunotherapy for non-small cell lung cancer (NSCLC) has revolutionized treatment for those with advanced disease, and recent data have emerged providing evidence for its benefits in earlier stages of the disease. Several pivotal clinical trials provide compelling data that adaptive immune cells may be highly effective and possibly even curative for NSCLC. Immune checkpoint inhibitors (ICIs) can unleash highly reactive memory immune responses to tumor antigens with durable effects against advanced or recurrent disease. Despite these encouraging results, many critical questions remain in the field including, for example, how to identify the subsets of NSCLC patients who most benefit from ICI treatment, and how ICI efficacy might be enhanced by utilizing combinations or sequencing of agents. A deeper understanding of biological mechanisms involved in lung cancer offers a unique opportunity to further explore the interaction between the adaptive immune landscape and NSCLC. Given the high incidence of lung cancer in Veterans and many Veterans being treated with immunotherapy for this disease, it is timely to have their adequate representation in future clinical trials. New clinical trials focused on Veterans can assist in exploring ways to mitigate resistant mechanisms as well as to investigate predictive and prognostic biomarkers for response to ICIs and other treatments. This paper will review current data and indications for immunotherapy in NSCLC, introduce new areas of research within immunotherapy, and discuss its applicability to the Veteran population.

An eye-catching atypical illustration of the evaluation and management of AL amyloidosis secondary to myeloma.

We present a case of a 58-year-old male patient who presented to his primary care clinic with complaints of eye swelling and fatigue. Workup ultimately led to a diagnosis of AL amyloidosis secondary to myeloma based on SLiM-CRAB criteria. We discuss his diagnostic workup, treatment, and subsequent relapse.

Primary bone lymphoma of the ilium successfully treated without radiation.

The addition of radiation therapy to chemotherapy and impact on outcomes in primary bone lymphoma is not clear. Nonetheless, tumor location must be considered as radiation to marrow-rich bone areas can lead to myelosuppression and myelotoxicity.

Inhibition of protein kinase Cß reverses increased blood-brain barrier permeability during hyperglycemic stroke and prevents edema formation in vivo.

BACKGROUND AND PURPOSE: We investigated the effect of circulating factors and protein kinase Cß on blood-brain barrier permeability and edema during hyperglycemic stroke. METHODS: Male Wistar rats that were hyperglycemic by streptozotocin (50 mg/kg) for 5 to 6 days underwent middle cerebral artery occlusion (MCAO) for 2 hours with 2 hours of reperfusion. Blood-brain barrier permeability was measured in middle cerebral arteries that were ischemic (MCAO) or nonischemic (CTL) and perfused with plasma (20% in buffer) from MCAO or CTL animals. A separate set of MCAO vessels was perfused with the protein kinase Cß inhibitor CGP53353 (0.5 µmol/L) and permeability measured. Lastly, hyperglycemic rats were treated intravenously with CGP53353 (10 or 100 µg/kg or vehicle 15 minutes before reperfusion and edema formation measured by wet:dry weights (n=6/group). RESULTS: MCAO vessels had increased permeability compared with controls regardless of the plasma perfusate. Permeability (water flux, µm(3)×10(8)) of CTL vessel/CTL plasma (n=8), CTL vessel/MCAO plasma (n=7), MCAO vessel/CTL plasma (n=6), and MCAO vessel/MCAO plasma (n=6) was 0.98±0.11, 1.13±0.07, 1.36±0.02, and 1.34±0.06; P<0.01). Inhibition of protein kinase Cß in MCAO vessels (n=6) reversed the increase in permeability (0.92±0.1; P<0.01). In vivo, hyperglycemia increased edema versus normoglycemia after MCAO (water content=78.84%±0.11% versus 81.38%±0.21%; P<0.01). Inhibition of protein kinase Cß with 10 or 100 µg/kg CGP53353 during reperfusion prevented the increased edema in hyperglycemic animals (water content=79.54%±0.56% and 79.99%±0.43%; P<0.01 versus vehicle). CONCLUSIONS: These results suggest that the pronounced vasogenic edema that occurs during hyperglycemic stroke is mediated in large part by activation of protein kinase Cß.