Growth Dynamics of Ductal Carcinoma in Situ Recapitulate Normal Breast Development.

Ductal carcinoma in situ (DCIS) and invasive breast cancer share many morphologic, proteomic, and genomic alterations. Yet in contrast to invasive cancer, many DCIS tumors do not progress and may remain indolent over decades. To better understand the heterogenous nature of this disease, we reconstructed the growth dynamics of 18 DCIS tumors based on the geo-spatial distribution of their somatic mutations. The somatic mutation topographies revealed that DCIS is multiclonal and consists of spatially discontinuous subclonal lesions. Here we show that this pattern of spread is consistent with a new 'Comet' model of DCIS tumorigenesis, whereby multiple subclones arise early and nucleate the buds of the growing tumor. The discontinuous, multiclonal growth of the Comet model is analogous to the branching morphogenesis of normal breast development that governs the rapid expansion of the mammary epithelium during puberty. The branching morphogenesis-like dynamics of the proposed Comet model diverges from the canonical model of clonal evolution, and better explains observed genomic spatial data. Importantly, the Comet model allows for the clinically relevant scenario of extensive DCIS spread, without being subjected to the selective pressures of subclone competition that promote the emergence of increasingly invasive phenotypes. As such, the normal cell movement inferred during DCIS growth provides a new explanation for the limited risk of progression in DCIS and adds biologic rationale for ongoing clinical efforts to reduce DCIS overtreatment.

Interstitial lung abnormalities after hospitalization for COVID-19 in patients with cancer: A prospective cohort study.

INTRODUCTION: Survivors of SARS-CoV-2 pneumonia often develop persistent respiratory symptom and interstitial lung abnormalities (ILAs) after infection. Risk factors for ILA development and duration of ILA persistence after SARS-CoV-2 infection are not well described in immunocompromised hosts, such as cancer patients. METHODS: We conducted a prospective cohort study of 95 patients at a major cancer center and 45 patients at a tertiary referral center. We collected clinical and radiographic data during the index hospitalization for COVID-19 pneumonia and measured pneumonia severity using a semi-quantitative radiographic score, the Radiologic Severity Index (RSI). Patients were evaluated in post-COVID-19 clinics at 3 and 6 months after discharge and underwent comprehensive pulmonary evaluations (symptom assessment, chest computed tomography, pulmonary function tests, 6-min walk test). The association of clinical and radiological factors with ILAs at 3 and 6 months post-discharge was measured using univariable and multivariable logistic regression. RESULTS: Sixty-six (70%) patients of cancer cohort had ILAs at 3 months, of whom 39 had persistent respiratory symptoms. Twenty-four (26%) patients had persistent ILA at 6 months after hospital discharge. In adjusted models, higher peak RSI at admission was associated with ILAs at 3 (OR 1.5 per 5-point increase, 95% CI 1.1-1.9) and 6 months (OR 1.3 per 5-point increase, 95% CI 1.1-1.6) post-discharge. Fibrotic ILAs (reticulation, traction bronchiectasis, and architectural distortion) were more common at 6 months post-discharge. CONCLUSIONS: Post-COVID-19 ILAs are common in cancer patients 3 months after hospital discharge, and peak RSI and older age are strong predictors of persistent ILAs.

Mitigating Burnout: Transition to a Condensed Workweek for Advanced Practice Providers in Infectious Diseases.

Burnout among health-care workers is highly prevalent and profoundly impacts the quality of patient care. In addition to affecting patient safety, burnout results in higher staff turnover, revenue deficits due to decreased productivity, financial risk, and diminished organization viability because of the impact on quality of care, patient satisfaction, and safety. Culmination of external and internal stressors in health-care worker populations is associated with a higher probability of burnout and workers who reported perceived low workplace flexibility. In addition, workplace flexibility is associated with reduced odds of experiencing burnout. Workplace flexibility plays a critical role in potentially reducing the occurrence of burnout in the health-care worker population. Individually focused solutions are important to mitigate burnout, however, comprehensive organizational change ensures durable and sustainable solutions. There is a correlation between a positive employee outlook and reduced stress when there is a perceived level of control over one's work schedule. The goal of this article is to showcase the process of a successful implementation of a condensed work schedule for an advanced practice provider workforce in infectious diseases in response to burnout and workload shifts. This chronicles the steps of design, rationale, procuring buy-in by stakeholders, and operational implementation of the new schedules. Advanced practice provider satisfaction and burnout were measured by periodic surveys at timepoints along the way.

Phase II trial of bortezomib alone or in combination with irinotecan in patients with adenocarcinoma of the gastroesophageal junction or stomach.

PURPOSE: To determine the effectiveness of bortezomib plus irinotecan and bortezomib alone in patients with advanced gastroesophageal junction (GEJ) and gastric adenocarcinoma. We also sought to explore the effect of these therapeutics on tumor and normal gene expression in vivo. METHODS: Forty-one patients with advanced GEJ (89 %) or gastric (11 %) adenocarcinoma received bortezomib (1.3 mg/m(2) days 1, 4, 8, 11) plus irinotecan (125 mg/m(2) days 1, 8) every 21 days as first line therapy (N = 29), or bortezomib alone as second line therapy (N = 12). The trial was designed to detect a 40 % response rate for the combination, and 20 % response rate for bortezomib alone. Affymetrix HU133A gene chip arrays were used for gene expression studies. RESULTS: Objective response occurred in 3 of 29 patients (10 %, 95 % confidence intervals [CI] 2 %, 27 %) treated with bortezomib plus irinotecan, and in 1 of 12 patients (8 %, 95 % CI 0 %, 39 %) with bortezomib alone. Due to the limited number of responders, there were no significant correlations with response found in the gene expression profiles of 12 patients whose tumors were sampled before and 24 h after therapy with bortezomib alone (N = 2) or the combination (N = 10). CONCLUSIONS: We conclude that bortezomib is not effective for the treatment of advanced adenocarcinoma of the GEJ or stomach, whether used alone or in combination with irinotecan, in an unselected patient population.