Muscarinic receptor agonist-induced ßPix binding to ß-catenin promotes colon neoplasia.

M3 muscarinic receptors (M3R) modulate ß-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, ßPix, binds to ß-catenin in colon cancer cells, augmenting ß-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of ßPix and ß-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of ßPix with ß-catenin. ßPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing ßPix dose-dependently augmented ß-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of ßPix. Expression levels of ß-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from ßPix-deficient conditional knockout mice. Targeting the M3R/ßPix/ß-catenin axis may have therapeutic potential.

Outcomes after endoscopic local excision of early-stage gastric adenocarcinoma in the United States.

BACKGROUND AND OBJECTIVES: Local excision (LE) for early-stage gastric cancer has expanded in the United States over recent years, however, national outcomes are unknown. The objective of the study was to evaluate national survival outcomes following LE for early-stage gastric cancer. METHODS: Patients with resectable gastric adenocarcinoma between 2010 and 2016 were identified from the National Cancer Database then classified by LE curability into eCuraA (high) and eCuraC (low) according to Japanese Gastric Cancer Association guidelines. Demographics, clinical/provider descriptors, and perioperative/survival outcomes were extracted. Propensity-weighted cox proportional hazards regression assessed factors associated with overall survival. RESULTS: Patients were stratified into eCuraA (N = 1167) and eCuraC (N = 13,905) subgroups. Postoperative 30-day mortality (0% vs 2.8%, p < 0.001) and readmission (2.3% vs 7.8%, p = 0.005) favored LE. Local excision was not associated with survival on propensity-weighted analyses. However, among eCuraC patients, LE was associated with higher likelihood of positive margins (27.1% vs 7.0%, p < 0.001), which was the strongest predictor of poor survival (HR 2.0, p < 0.001). CONCLUSIONS: Although early morbidity is low, oncologic outcomes following LE are compromised for eCuraC patients. These findings support careful patient selection and treatment centralization in the early adoption phase of LE for gastric cancer.

Increasing utilization of endoscopic local excision for early-stage gastric cancers in the United States.

BACKGROUND: The Japanese Gastric Cancer Association provided updated criteria for endoscopic local excision of early-stage gastric cancer in 2018. The purpose of this study was to evaluate utilization patterns for endoscopic local excision in the United States for resectable gastric adenocarcinoma. METHODS: Patients with resectable gastric adenocarcinoma were identified from the National Cancer Database between 2010 and 2017. Patients were classified into strict appropriate criteria, expanded criteria, and inappropriate based on the Japanese Gastric Cancer Association guidelines. Factors associated with endoscopic local excision were identified using univariate and logistic multivariate regression. RESULTS: Within the National Cancer Database, 46,334 patients were stratified into strict appropriate criteria (n = 1,405), expanded criteria (n = 727), and inappropriate (n = 43,675). Annual cases of local excision increased by 76.9% over the study period, from 273 in 2010 to 483 in 2017. Among patients who underwent local excision, 10.1% were classified as strict appropriate criteria, 1.6% were classified as expanded criteria, and 84.5% were classified as inappropriate. Among inappropriate patients, factors associated with endoscopic local excision were: more recent year of diagnosis, increasing age, female sex, tumor located in the cardia, smaller size, low-grade, absence of lymphovascular invasion, and treatment at an academic facility. CONCLUSION: The use of endoscopic local excision for gastric cancer has nearly doubled since 2010. However, most patients do not satisfy consensus criteria for endoscopic therapy.

Pancreaticoduodenectomy and metastasectomy for metastatic pancreatic neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Various treatment options exist for patients with metastatic pancreatic neuroendocrine tumors (PNETs). Surgical resection with pancreaticoduodenectomy (PD) typically reserved for patients with limited disease. Definitive data are lacking to support either the resection of primary PNET in the metastatic setting or for surgical debulking of metastatic lesions. METHODS: We conducted an analysis of the National Cancer Database (NCDB) using the pancreatic cancer Participant User File. Thirty- and 90-day mortality rates and survival rates were determined for patients undergoing PD for primary tumor resection and compared with patients who had no surgery or metastasectomy. The Kaplan-Meier method was used to compare survival time. Cox regression models were used to assess factors independently associated with overall survival time. RESULTS: Resection of the primary tumor or metastatic disease each significantly improved overall survival time compared with no resection. Adding metastasectomy to PD resulted in an incremental increase in overall survival time. Both PD and metastasectomy are independently associated with overall survival time. CONCLUSIONS: Our report highlights the potential for survival time benefit in appropriately selected patients who undergo PD in the setting of metastatic PNET.

Utilization of radiotherapy for malignant phyllodes tumors: analysis of the National Cancer Data Base, 1998-2009.

BACKGROUND: Malignant phyllodes tumors of the breast have traditionally been treated with surgical excision. Recently, the use of adjuvant radiotherapy has been advocated to reduce the risk of local recurrence; however, this recommendation is controversial in the absence of consistent outcome data. We hypothesize that there has been a trend toward increased utilization of adjuvant radiotherapy for malignant phyllodes tumors despite its uncertain effect on outcomes. METHODS: Using the National Cancer Data Base, predictors of radiotherapy utilization were examined for women with malignant phyllodes from 1998 to 2009. Kaplan-Meier and Cox regression models were generated to determine the effect of radiotherapy on local recurrence (LR), disease-free survival (DFS), and overall survival (OS). RESULTS: Of the 3,120 patients with malignant phyllodes, 57 % underwent breast conservation surgery and 42 % underwent mastectomy. Overall, 14.3 % of women received adjuvant radiotherapy. Utilization of radiotherapy doubled over the study period (9.5 % in 1998-1999 vs. 19.5 % in 2008-2009, p < 0.001). Women were significantly more likely to receive radiotherapy if they were diagnosed later in the study, were age 50-59 years old, had tumors >10 cm, or had lymph nodes removed. For the 1,774 patients with available recurrence data, overall recurrence was 14.1 %, and LR was 5.9 %. In adjusted models, adjuvant radiotherapy reduced LR (aHR 0.43, 95 % CI 0.19-0.95) but did not impact DFS or OS after 53 months' median follow-up. CONCLUSIONS: Utilization of adjuvant radiotherapy for malignant phyllodes doubled from 1998 to 2009. Radiotherapy significantly reduced LR but had no effect on DFS or OS.

Who should have or not have an axillary node dissection with breast cancer?

There have been dramatic changes in the approach to the axilla in women with breast cancer over the last 100 years, reflecting the evolution in our understanding of the underlying tumor biology, reduced disease burden because of early detection, and advances in all breast cancer treatment modalities. The approach to the axilla needs to be individualized, much like the extent of surgery for the primary tumor. Axillary dissection remains an important intervention for patients with more locally advanced disease. However, in patients with early-stage breast cancer, in whom regional recurrence is extremely low, the added benefit of an ALND has yet to be confirmed.

Monitoring the delivery of cancer care: Commission on Cancer and National Cancer Data Base.

The primary objective of the Commission on Cancer (CoC) is to ensure the delivery of comprehensive, high-quality care that improves survival while maintaining quality of life for patients with cancer. This article examines the initiatives of the CoC toward achieving this goal, utilizing data from the National Cancer Data Base (NCDB) to monitor treatment patterns and outcomes, to develop quality measures, and to benchmark hospital performance. The article also highlights how these initiatives align with the Institute of Medicine's recommendations for improving the quality of cancer care and briefly explores future projects of the CoC and NCDB.

Needle versus excisional biopsy for noninvasive and invasive breast cancer: report from the National Cancer Data Base, 2003-2008.

BACKGROUND: Needle biopsy to diagnose breast cancer may soon become a quality measure for which hospitals are held accountable. This study examines the utilization of needle versus excisional biopsy in a contemporary cohort of patients and identifies factors associated with biopsy type. METHODS: Women with nonmetastatic, clinical Tis-T3 breast cancers diagnosed between 2003 and 2008 were selected from the National Cancer Data Base, which captures information from ~79% of breast cancers in the United States. Patients whose cancer was diagnosed by needle biopsy (fine-needle aspiration or core) were compared with patients diagnosed via excision, analyzing patient, hospital, and tumor characteristics. Logistic regression was used to identify important predictors of biopsy type. RESULTS: Of 373,837 patients, 303,677 (81.2%) underwent needle biopsy while 70,160 (18.8%) had excisional biopsy to diagnose their cancer. The needle biopsy rate increased from 73.8 to 86.7% whereas excisional biopsy declined from 26.2 to 13.3% over the study period (P < 0.001). In 2008, patients were statistically significantly more likely to undergo excisional biopsy if they had stage 0 disease; were treated at low-volume (<25 cases/year), community, or Atlantic census region hospitals; were <40 years old at diagnosis; were less educated; or were Asian/Pacific Islander (P < 0.001). The median rate of needle biopsy at high-volume hospitals (≥140 cases/year) was 89.6%. CONCLUSION: The use of needle biopsy is increasing. Tumor stage, hospital volume, and hospital location were the most statistically significant predictors of biopsy type. Rates of needle biopsy at high-volume hospitals suggest that appropriate utilization of this preferred diagnostic method should approach 90%.