Integrated single-cell RNA sequencing analysis reveals distinct cellular and transcriptional modules associated with survival in lung cancer

Lung adenocarcinoma (LUAD) and squamous carcinoma (LUSC) are two major subtypes of non-small cell lung cancer with distinct pathologic features and treatment paradigms. The heterogeneity can be attributed to genetic, transcriptional, and epigenetic parameters. Here, we established a multi-omics atlas, integrating 52 single-cell RNA sequencing and 2342 public bulk RNA sequencing. We investigated their differences in genetic amplification, cellular compositions, and expression modules. We revealed that LUAD and LUSC contained amplifications occurring selectively in subclusters of AT2 and basal cells, and had distinct cellular composition modules associated with poor survival of lung cancer. Malignant and stage-specific gene analyses further uncovered critical transcription factors and genes in tumor progression. Moreover, we identified subclusters with proliferating and differentiating properties in AT2 and basal cells. Overexpression assays of ten genes, including sub-cluster markers AQP5 and KPNA2, further indicated their functional roles, providing potential targets for early diagnosis and treatment in lung cancer.

Sinonasal Hamartomas: From Nasal Chondromesenchymal Hamartoma to Respiratory Epithelial Adenomatoid Hamartoma. Report of six Cases and Review of the Literature

Sinonasal hamartomas are uncommon lesions of nasal and sinus cavities. Based on indigenous cellular components and characteristic histologic features, they are further classified into four entities: respiratory epithelial adenomatoid hamartoma (REAH), seromucinous hamartoma (SH), chondro-osseous and respiratory epithelial hamartoma (CORE), and nasal chondromesenchymal hamartoma (NCH). REAH, SH, and CORE are seen in adult patients, while NCH predominantly occurs in newborns and infants. Morphologically REAH and SH are composed of respiratory epithelium and seromucinous glands, CORE is related to REAH but with additional feature of chondroid and/or osseous tissue, and NCH is composed of chondroid and stromal elements but devoid of epithelial component. All four lesions can present as sinonasal mass lesions and with associated obstructive symptoms. Given the rarity of these lesions, diagnosis can be challenging, especially in unusual clinical scenario. In this study, we report six cases of sinonasal hamartoma, including one case of NCH, one case of CORE, two cases of SH, and two cases of REAH. All cases were from adult patients including four men and two women. We also review the literature of the clinical and pathologic features of these rare lesions.

Diet- and Lifestyle‐Based Prediction Models to Estimate Cancer Recurrence and Death in Patients With Stage III Colon Cancer (CALGB 89803/Alliance)

PURPOSE Current tools in predicting survival outcomes for patients with colon cancer predominantly rely on clinical and pathologic characteristics, but increasing evidence suggests that diet and lifestyle habits are associated with patient outcomes and should be considered to enhance model accuracy. METHODS Using an adjuvant chemotherapy trial for stage III colon cancer (CALGB 89803), we developed prediction models of disease-free survival (DFS) and overall survival by additionally incorporating self-reported nine diet and lifestyle factors. Both models were assessed by multivariable Cox proportional hazards regression and externally validated using another trial for stage III colon cancer (CALGB/SWOG 80702), and visual nomograms of prediction models were constructed accordingly. We also proposed three hypothetical scenarios for patients with (1) good-risk, (2) average-risk, and (3) poor-risk clinical and pathologic features, and estimated their predictive survival by considering clinical and pathologic features with or without adding self-reported diet and lifestyle factors. RESULTS Among 1,024 patients (median age 60.0 years, 43.8% female), we observed 394 DFS events and 311 deaths after median follow-up of 7.3 years. Adding self-reported diet and lifestyle factors to clinical and pathologic characteristics meaningfully improved performance of prediction models (c-index from 0.64 [95% CI, 0.62 to 0.67] to 0.69 [95% CI, 0.67 to 0.72] for DFS, and from 0.67 [95% CI, 0.64 to 0.70] to 0.71 [95% CI, 0.69 to 0.75] for overall survival). External validation also indicated good performance of discrimination and calibration. Adding most self-reported favorable diet and lifestyle exposures to multivariate modeling improved 5-year DFS of all patients and by 6.3% for good-risk, 21.4% for average-risk, and 42.6% for poor-risk clinical and pathologic features. CONCLUSION Diet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

Neoadjuvant Therapy with Doxorubicin-Cyclophosphamide Followed by Weekly Paclitaxel in Early Breast Cancer: A Retrospective Analysis of 200 Consecutive Patients Treated in A Single Center with A Median Follow-Up of 9.5 Years.

Purpose We analyzed outcomes of doxorubicin-cyclophosphamide(AC) followed by weekly paclitaxel as neoadjuvant chemotherapy(NAC) for breast cancer(BC), in an everyday practice with long-term follow-up of patients. Methods All patients (n=200) who received the AC-paclitaxel combination as NAC for BC at the Soroka University Medical Center from 2003 to 2012 were included in this retrospective cohort study. AC was administered on an every 3-week schedule (standard dose) until May, 2007(n=99); and subsequently every 2 weeks (dose dense)(dd)(n=101). Clinical pathologic features, treatment course and outcome information were recorded. Complete pathologic response(pCR) was analyzed according to BC subtype, dose regimen and stage. Results Median age was 49 years; 55.5% and 44.5% of patients were clinically stage 2 and 3, respectively. Standard dose patients had more T3 tumors. Subtypes were human-epidermal-growth-factor receptor(HER 2)-positive 32.5% (of whom 82% received trastuzumab), hormone-receptor positive/HER2 negative 53%, triple negative 14.5%. Breast conserving surgery(BCS) was performed in 48.5% of patients; only 9.5% were deemed suitable for BCS prior to NAC. Toxicity was acceptable. The overall pCR rate was 26.0% and was significantly higher in the dd group and HER2-positive patients. With a median follow-up of 9.51 years median event-free survival(EFS), and overall survival(OS) is 10.85 years and 12.61 years, respectively. Patients achieving pCR had significantly longer EFS and OS. Conclusions- NAC for BC with AC-paclitaxel can be safely administered in the “real-world’ setting with high efficacy. Current efforts are aimed at Increasing rates of pCR and identifying patients who may benefit from additional therapy or conversely, de-escalated treatment.

Evaluating the Prognostic Implication of the Collins Histology Scoring System in a Pediatric Eastern Ontario Population With Eosinophilic Esophagitis

Introduction: Collins et al developed a histology scoring system (EoE HSS) to assess multiple pathologic features. The aim of this study is to identify if the EoE HSS can better detect endoscopic and symptom improvement vs the Peak Eosinophilic Count (PEC). Methods: A retrospective chart review was performed for patients during 2014–2016. All patients ≤18 years old with a diagnosis of EoE and whose records included initial and follow-up upper gastrointestinal endoscopies were included. Severity and extent of endoscopic features were scored using 8 parameters, from normal to maximum change for each location of the esophageal biopsy. Results: Forty patients with EoE were included in the study, of which 35 (87.5%) patients demonstrated symptom and 25 (62.5%) endoscopic improvement at the time of follow-up. In the proximal esophagus, the EoE HSS outperformed the change in eosinophil count of the Children’s Hospital of Eastern Ontario (CHEO) practice in predicting endoscopic improvement by 16.8% when examining the change in grade and 17.1% when examining the change in stage scores. Conclusions: At our institution, adoption of the EoE HSS in assessing biopsies of EoE patients might be warranted, compared to the traditional practice. However, a bigger sample size may give a more robust difference in all locations.

Isocitrate Dehydrogenase–Mutated Cholangiocarcinoma: Natural History and Clinical Outcomes

Purpose Clinical-pathologic features and natural history of patients with isocitrate dehydrogenase ( IDH)-mutant intrahepatic cholangiocarcinoma (CCA) are not well characterized. Here, we sought to describe the natural history, clinical phenotype, and prognostic impact of advanced, IDH-mutated CCA. METHODS We conducted a multicentric, retrospective analysis of patients with IDH-mutated (IDH1 or IDH2) CCA between 2010 and 2020. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. Chi-square test was used to analyze disease control rate (DCR) and overall response rate (ORR). Matched controls were used for comparing survival between patients with and without IDH mutations (mIDH). RESULTS Sixty-five patients with IDH-mutated CCA were included. All patients had intrahepatic CCA. On first-line chemotherapy, median OS and median PFS were 21.2 months and 8.3 months, respectively. Notably, median OS (32.4 v 19.5 months, P = .12) and PFS (18.0 v 8.0 months, P = .12) were not significantly affected by disease status at presentation (locally advanced v metastatic, respectively). Median OS was significantly longer in patients with mIDH (21.2 v 10.5 months; P < .01). First-line gemcitabine-containing regimens had a significantly higher DCR and ORR than non–gemcitabine-containing regimens (DCR: 75% v 33%, P = .01; ORR: 39% v 0%, P = .02). In patients receiving IDH inhibitor therapy, median PFS was 4.6 months with a DCR of 29%. CONCLUSION CCA with m IDH confers a unique subtype resulting in a better survival compared with that of counterparts. IDH inhibitors represent a promising therapeutic option in later lines of therapy in this subgroup.

Hepatocellular Carcinoma and Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease: Causing Factors, Molecular Links, and Treatment Options

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which will affect more than a million people by the year 2025. However, current treatment options have limited benefits. Nonalcoholic fatty liver disease (NAFLD) is the fastest growing factor that causes HCC in western countries, including the United States. In addition, NAFLD co-morbidities including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVDs) promote HCC development. Alteration of metabolites and inflammation in the tumor microenvironment plays a pivotal role in HCC progression. However, the underlying molecular mechanisms are still not totally clear. Herein, in this review, we explored the latest molecules that are involved in obesity, T2DM, and CVDs-mediated progression of HCC, as they share some common pathologic features. Meanwhile, several therapeutic options by targeting these key factors and molecules were discussed for HCC treatment. Overall, obesity, T2DM, and CVDs as chronic metabolic disease factors are tightly implicated in the development of HCC and its progression. Molecules and factors involved in these NAFLD comorbidities are potential therapeutic targets for HCC treatment.