Utilization of Neoadjuvant Therapy in Gastrointestinal Stromal Tumors of the Stomach: Analysis of the 2006-2018 National Cancer Database.

BACKGROUND: Neoadjuvant tyrosine kinase inhibitor (TKI) therapy has reduced tumor burden and improved survival in both primary and recurrent gastrointestinal stromal tumors (GISTs). However, no clear guidelines exist on optimal patient selection for neoadjuvant therapy (NAT). Our aim was to analyze factors and outcomes associated with the therapeutic sequence of TKI therapy before and/or after surgery for gastric GISTs. METHODS: We performed a retrospective study of patients surgically treated for a gastric GIST utilizing the 2006-2018 National Cancer Database. We examined demographic, clinical, and pathological characteristics associated with NAT versus adjuvant therapy (AT) using logistic regression. RESULTS: Of the 3732 patients, 20.4% received NAT and 79.6% had AT. Among patients receiving therapy, NAT significantly increased over our study period (12% to 30.7%). A majority of the AT group received a partial gastrectomy (77.9%) compared with the NAT group who received more near-total/total gastrectomy or gastrectomy with en bloc resection (p < 0.001). In a multivariable model, patients were more likely to receive NAT when insured (private, aOR: 2.37, 95% CI: 1.31-4.29), treated at an academic/research program (aOR: 1.83, 95% CI: 1.49-2.56), had tumors located in the proximal stomach (aOR: 1.40, 95% CI: 1.06-1.86), tumor size > 10 cm (aOR: 1.88, 95% CI: 1.41-2.51), and received near-total/total gastrectomy (aOR: 1.81, 95% CI: 1.42-2.29). There were no differences in outcomes. CONCLUSION: NAT for gastric GIST has increased in utilization. NAT was used in patients with larger tumors and who underwent more extensive resection. Despite these factors, outcomes were similar to patients receiving only AT. More studies are required to determine the therapeutic sequence for gastric GISTs.

Do rural patients with operable breast cancer fare worse than urban patients in Louisiana? Results of the Louisiana cancer consortium.

BACKGROUND: It is unknown whether rural patients with operable breast cancer do worse than urban patients in Louisiana. We performed an analysis of breast cancer based on rural versus urban residencies and evaluate factors associated with worse survival. METHODS: Data on women diagnosed with stages I to III breast cancer from 2004 to 2016 were obtained from the Louisiana Tumor Registry. Overall survival and cancer-specific survival were compared between rural and urban residencies by sociodemographic, clinical-pathologic, and treatment variables. Kaplan-Meier method and the log-rank test were used to compare the survival curves. Cox regression model was used to assess independent factors associated with overall survival and cancer-specific survival. RESULTS: Of the 27,780 patients, 2,441 patients (8.7%) resided in rural areas. Compared with urban patients, rural patients tended to be older, underinsured, more impoverished, less likely to be treated at an American College of Surgeons accredited institution, and more likely to be treated at a low-volume center (P < .005 each). For stages I and II diseases, there was a statistically significant difference in overall survival favoring urban regions, but no difference in cancer-specific survival. For stage III disease, there was no difference in either overall survival or cancer-specific survival between the 2 cohorts. Overall survival and cancer-specific survival curves for the entire cohort were not different at the 5-year mark, but become statistically significant with greater time; although rural patients had a lower long-term overall survival (P = .0001) and cancer-specific survival (P = .049) compared with urban patients, the rural-urban differences in overall survival and cancer-specific survival were no longer different after adjusting for other covariates, indicating the observed differences in univariate analysis were attributable to sociodemographic, clinicpathologic, and treatment factors. CONCLUSION: Despite rural patients with operable breast cancer having an overall lesser overall survival and cancer-specific survival than their urban counterpart, rural residence itself was not an independent predictor of outcome. In fact, particular socioeconomic factors increased the risk of death among patients residing in rural areas. Additional analysis at the patient-level is needed to understand the interactions between rurality and breast cancer outcomes in Louisiana.

Increased SOX9 Expression in Premalignant and Malignant Pancreatic Neoplasms.

BACKGROUND: SOX9, a progenitor cell marker, is important for pancreatic ductal development. Our goal was to examine SOX9 expression differences in intraductal papillary mucinous neoplasms (IPMNs) and ductal adenocarcinoma (PDAC) compared with benign pancreatic duct (BP). METHODS: SOX9 expression was evaluated by immunohistochemistry performed on 93 specimens: 37 BP, 24 low grade (LG) IPMN, 12 high grade (HG) IPMN, and 20 PDAC. A linear mixed-effects model was used to compare the percentage of cells expressing SOX9 by specimen type. A separate linear mixed-effects model evaluated differences in SOX9 expression by staining intensity in pancreatic epithelial cells. RESULTS: Nuclear SOX9 expression was detected in the epithelial cells of 98% HG IPMN, 93% LG IPMN, 83% PDAC, and 60% BP. Compared with BP, SOX9 was expressed from a significantly greater percentage of cells in LG IMPN, HG IMPN, and PDAC (p < 0.001 for each). BP and PDAC showed greater variability in SOX9 expression in epithelial cells compared with IPMNs which showed strong, homogenous SOX9 expression in almost all cells. Compared with BP, both LG and HG IPMN showed significantly greater SOX9 expression (p < 0.001 for each), but there was no significant difference in SOX9 expression between LG and HG IPMN (p > 0.05). PDAC had significantly higher expression of SOX9 compared with BP but significantly lower SOX9 expression compared with LG or HG IPMN (p < 0.001 for each). CONCLUSIONS: IPMNs demonstrated the highest expression levels of SOX9. SOX9 expression in BP and PDAC demonstrated much more heterogeneity compared with the strong, uniform expression in IPMN.

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.

Accurate staging with internal mammary chain sentinel node biopsy for breast cancer.

BACKGROUND: Although internal mammary chain (IMC) metastases are an independent predictor of prognosis, collecting IMC sentinel nodes (SN) remains controversial. We sought to determine predictors for IMC nodal positivity and the role positive IMC-SNs have on changing staging and management. METHODS: We reviewed a prospectively collected database (1997-2012) to identify patients who had IMC drainage detected on lymphoscintigraphy and underwent biopsy. Chi square tests and logistic regression models were used to determine trends and factors associated with IMC node positivity. RESULTS: A total of 122 patients with cTis-T2cN0M0 breast cancer underwent IMC-SN biopsy. Mean age of the cohort was 53 years, and mean tumor size was 2.0 cm. Identification of IMC nodes was successful in 100% of the cases. There were no complications. Sentinel nodes mapped to the IMC alone in 14 of 122 (11%) patients. Overall, 26% of patients were node positive, with 12 of 122 (10%) patients having a positive IMC-SN. In patients with a positive axilla, IMC-SN was positive in 33% of patients, whereas in patients with a negative axilla, IMC-SN was positive in 3% of cases (P < 0.001). The number of positive axillary nodes was the only independent predictor of IMC positivity (1-3 positive axillary nodes odds ratio 16.9, 95% CI 3.1-91.1; ≥4 positive axillary nodes odds ratio 45.0, 95% CI 4.0-500.7). IMC-SN positivity led to a more advanced nodal category in all patients and more accurate staging in 4 of 12 (33%) patients. CONCLUSIONS: IMC-SN biopsy is predictable and safe. Identification of IMC metastases though IMC-SN biopsy has the potential to alter the stage and adjuvant therapy of breast cancer patients.

Peritumoral expression of adipokines and fatty acids in breast cancer.

BACKGROUND: Adipokines in the tumor microenvironment may contribute to cancer growth. We hypothesized that peritumoral fat can be a source of lipid-derived energy for tumors by increasing adipose triglyceride lipase (ATGL)-mediated lipolysis and down-regulating a negative regulator of adipogenesis, pigment epithelium-derived factor (PEDF). METHODS: In a pilot study, tissue from mastectomies (n = 19) was collected from sites both adjacent (peritumoral) and distant to the tumor for comparison of ATGL, PEDF, and leptin expression levels using immunohistochemistry. Statistical analysis was performed by Student's t test to determine significance. RESULTS: Mean tumor size was 2.4 cm, and 10 (59 %) patients had tumor-positive nodes. Mean body mass index (BMI) was 28.1 kg/m(2). ATGL expression was significantly increased in obese patients (BMI ≥ 30 kg/m(2)) compared with the nonobese group (P < 0.04). Leptin expression was increased in the peritumoral stroma of obese patients compared with distant sites (P = 0.03). Peritumoral PEDF and the leptin/PEDF ratio were significantly affected by tumor size and node status. Tumors ≥ 2 cm had lower peritumoral stromal expression of PEDF than tumors <2 cm (P = 0.01). In node-positive cases, expression of PEDF was significantly decreased in the peritumoral stroma compared with node-negative cases (1.22 vs. 1.80, P < 0.04). The leptin/PEDF ratio was markedly elevated in the peritumoral region of node-positive cases versus node-negative cases (2.17 vs. 1.18, P < 0.001). CONCLUSIONS: Peritumoral expression of adipokines was altered in both obesity and more advanced breast tumors, suggesting a role for adipokines in enhancing tumor growth. Future studies should focus on the use of adipokines as biomarkers.

Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs.

RATIONALE: Strategies to stage and treat cancer rely on a presumption of either localized or widespread metastatic disease. An intermediate state of metastasis termed oligometastasis(es) characterized by limited progression has been proposed. Oligometastases are amenable to treatment by surgical resection or radiotherapy. METHODS: We analyzed microRNA expression patterns from lung metastasis samples of patients with ≤ 5 initial metastases resected with curative intent. RESULTS: Patients were stratified into subgroups based on their rate of metastatic progression. We prioritized microRNAs between patients with the highest and lowest rates of recurrence. We designated these as high rate of progression (HRP) and low rate of progression (LRP); the latter group included patients with no recurrences. The prioritized microRNAs distinguished HRP from LRP and were associated with rate of metastatic progression and survival in an independent validation dataset. CONCLUSION: Oligo- and poly- metastasis are distinct entities at the clinical and molecular level.

Microscopic margins and patterns of treatment failure in resected pancreatic adenocarcinoma.

OBJECTIVE: To correlate microscopic margin status with survival and local control in a large cohort of patients from a high-volume pancreatic cancer center. DESIGN: Retrospective database review. A uniform procedure for margin analysis was used with 4-color inking (neck, portal vein groove, uncinate, and posterior pancreatic margin) by the surgeon in the operating room. SETTING: A tertiary care hospital. PATIENTS: We reviewed patients who underwent pancreaticoduodenectomy between September 1, 1997, and December 31, 2008, from a prospective, institutional database. MAIN OUTCOME MEASURES: Using Cox regression models, we identified pathologic characteristics associated with local recurrence (LR) after controlling for potential confounding variables. Overall and LR-free survival curves were generated by the Kaplan-Meier method. RESULTS: Of 285 patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma, 97 (34.0%) had 1 or more positive microscopic margins (uncinate, 16.5%; portal vein groove, 8.8%; neck, 7.7%; and posterior, 10.5%). A total of 198 patients (69.5%) recurred, with the first site of failure being LR only in 47 (23.7%), local plus distant recurrence in 42 (21.2%), and distant recurrence only in 109 (55.1%). Patients with LR only were significantly more likely to have lymph node involvement (adjusted hazard ratio, 2.66; 95% CI, 1.25-5.63) or a positive posterior margin (adjusted hazard ratio, 4.27; 95% CI, 2.07-8.81). Patients with a positive posterior margin had significantly poorer LR-free survival with (P < .001) or without (P = .01) lymph node involvement. CONCLUSIONS: When systematically assessed, the incidence of positive microscopic margins is high. Positive posterior margins and lymph node involvement were each independently and significantly associated with LR.

Extrapleural pneumonectomy complicated by acute superior mesenteric artery syndrome.

We present a patient who developed an acute superior mesenteric artery (SMA) syndrome following pneumonectomy. Although rarely described, a majority of cases develop insidiously from a gradual loss of retroperitoneal fat in the setting of malnourishment. A postoperative presentation is atypical, however procedures that narrow the aortomesenteric angle have been associated with the development of SMA syndrome. This case illustrates an important anatomic relationship that thoracic surgeons performing lung resection surgery should be aware of in order to avoid predisposing patients to SMA syndrome.

Simultaneous necrotizing soft tissue infection and colonic necrosis caused by Clostridium septicum.

BACKGROUND: Clostridial myonecrosis is an uncommon, highly lethal necrotizing soft tissue infection. The source may be occult at the time of clinical presentation. In cases caused by Clostridium septicum, there is an association with colorectal malignant disease, suggesting that underlying colonic pathology frequently is the source of the infection. METHODS: Case report and literature review. CASE REPORT: A 37-year old man with acquired immunodeficiency syndrome, end-stage renal disease, and C. difficile colitis presented to the Emergency Department (ED) with a primary complaint of abdominal pain and incidental right forearm pain. While undergoing evaluation in the ED, he developed progressive erythema, edema, and emergence of bullae over his right forearm. After rapid imaging of his abdomen, he underwent guillotine amputation of his right upper extremity because of extensive myonecrosis and total abdominal colectomy secondary to right colonic necrosis and C. difficile colitis. Blood cultures were positive for C. septicum. Microscopic examination of both the necrotic colon and the right forearm musculature demonstrated invasion of gram-positive bacilli throughout. CONCLUSIONS: Myonecrosis caused by C. septicum frequently occurs in the presence of colonic pathology, typically malignant disease. This case report illustrates the development of this pathological process in an immunosuppressed patient who did not have colon cancer, but rather colonic mucosal inflammation produced by C. difficile.

Poorer survival outcomes for male breast cancer compared with female breast cancer may be attributable to in-stage migration.

BACKGROUND: Male breast cancer accounts for less than 1% of all breast cancers, yet males have a worse prognosis than females with breast cancer. METHODS: Using the 1988-2003 Surveillance, Epidemiology, and End Results Program data, we conducted a retrospective, population-based cohort study to investigate stage-specific differences in breast cancer-specific and all-cause mortality between males and females. We calculated adjusted hazard ratios (aHR) and 95% confidence intervals (CI) using Cox regression models to compare breast cancer-specific and all-cause mortality by stage between males and females, controlling for potential confounding variables. RESULTS: There were 246,059 patients with a first, single, primary breast cancer [1,541 (0.6%) male; 244,518 (99.4%) female]. Compared with females, males were more likely to be older, Black, married, diagnosed at more advanced stages, and treated with mastectomy (each P < 0.001). Males also were more likely to have lower grade and estrogen/progesterone receptor-positive tumors (each P < 0.001). After controlling for confounders, males were more likely to die from their breast cancer when compared with females, only if diagnosed with stage I disease (aHR 1.72, CI 1.15-2.61). For all-cause mortality, males were more likely than females to die at each stage of disease except stage IV. CONCLUSIONS: Although all-cause mortality was higher for men than women at all stages of nonmetastatic breast cancer, higher male breast cancer-specific mortality was attributed to poorer survival in stage I disease. However, this statistical difference is unlikely to be clinically relevant and attributable to in-stage migration.

Induction of Th17 cells in the tumor microenvironment improves survival in a murine model of pancreatic cancer.

An important mechanism by which pancreatic cancer avoids antitumor immunity is by recruiting regulatory T cells (Tregs) to the tumor microenvironment. Recent studies suggest that suppressor Tregs and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Because IL-6 in the presence of TGF-ß has been shown to inhibit Treg development and induce Th17 cells, we hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression. Pan02 murine pancreatic tumor cells that secrete TGF-ß were transduced with the gene encoding IL-6. C57BL/6 mice were injected s.c. with wild-type (WT), empty vector (EV), or IL-6-transduced Pan02 cells (IL-6 Pan02) to investigate the impact of IL-6 secretion in the tumor microenvironment. Mice bearing IL-6 Pan02 tumors demonstrated significant delay in tumor growth and better overall median survival compared with mice bearing WT or EV Pan02 tumors. Immunohistochemical analysis demonstrated an increase in Th17 cells (CD4(+)IL-23R(+) cells and CD4(+)IL-17(+) cells) in tumors of the IL-6 Pan02 group compared with WT or EV Pan02 tumors. The upregulation of IL-17-secreting CD4(+) tumor-infiltrating lymphocytes was substantiated at the cellular level by flow cytometry and ELISPOT assay and mRNA level for retinoic acid-related orphan receptor γt and IL-23R by RT-PCR. Thus, the addition of IL-6 to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer. The delayed tumor growth and improved survival suggests that induction of Th17 in the tumor microenvironment produces an antitumor effect.

Saline-linked surface radiofrequency ablation: a safe and effective method of surface ablation of hepatic metastatic colorectal cancer.

OBJECTIVE: To determine the safety and efficacy of saline-linked surface radiofrequency ablation (SLSRFA) in a clinical setting. SUMMARY BACKGROUND DATA: We have previously identified safe and effective parameters for use of SLSRFA in a porcine model. METHODS: An initial study was conducted to determine if parameters defined in the porcine model were safe and effective in human livers. In 16 patients undergoing liver resection, normal areas of liver were treated with SLSRFA using various power/diameter combinations (10 W/1 cm; 15 W/2 cm; 45 W/4 cm) for 9 minutes with and without inflow occlusion. In a second study, superficial hepatic colorectal cancer (CRC) metastases were treated at 45 W/4 cm for 9 minutes without inflow occlusion in 11 patients. Ablation depth was measured and samples were examined for cell viability by nicotine adenine dinucleotide stain. This study was registered in the ClinicalTrials.gov database and has the following ID number, NCT00869843. RESULTS: Ablation depth in normal liver varied from 3 to 20 mm. Depth was significantly dependent on power, lesion size, and inflow occlusion. Nicotine adenine dinucleotide stains showed total cell necrosis to the full depth of ablation. In the second study, large hepatic CRC metastases showed total cell necrosis to a mean depth of 12 mm. Two tumors less than 7 mm in depth showed complete necrosis. Metastases were more susceptible to SLSRFA than normal liver. CONCLUSION: SLSRFA completely and safely ablates normal liver to a depth of at least 4 mm at 45 W/4 cm treatment parameters. Remarkably, it is even more effective in ablating metastatic CRC. SLSRFA is an effective tool for extending resection margins and for ablating superficial small tumors or superficial parts of large tumors.

Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease.

BACKGROUND: We investigated differences in breast cancer mortality between younger (younger than 40 years of age) and older (40 years of age and older) women by stage at diagnosis to identify patient and tumor characteristics accounting for disparities. STUDY DESIGN: We conducted a retrospective study of women diagnosed with breast cancer in the 1988 to 2003 Surveillance, Epidemiology, and End Results Program data. Multivariate Cox regression models calculated adjusted hazard ratios (aHR) and 95% confidence intervals to compare overall and stage-specific breast cancer mortality in women younger than 40 years old and women 40 years and older, controlling for potential confounding variables identified in univariate tests. RESULTS: Of 243,012 breast cancer patients, 6.4% were younger than 40 years old, and 93.6% were 40 years of age or older. Compared with older women, younger women were more likely to be African American, single, diagnosed at later stages, and treated by mastectomy. Younger women had tumors that were more likely to be higher grade, larger size, estrogen receptor/progesterone receptor-negative, and lymph-node positive (p < 0.001). Younger women were more likely to die from breast cancer compared with older women (crude HR = 1.39; CI, 1.34 to 1.45). Controlling for confounders, younger women were more likely to die compared with older women if diagnosed with stage I (aHR = 1.44; CI, 1.27 to 1.64) or stage II (aHR = 1.09; CI, 1.03 to 1.15) disease and less likely to die if diagnosed with stage IV disease (aHR = 0.85; CI, 0.76 to 0.95). CONCLUSIONS: Higher breast cancer mortality in younger women was attributed to poorer outcomes with early-stage disease. Additional studies should focus on specific tumor biology contributing to the increased mortality of younger women with early-stage breast cancer.