Jennifer L. Gnerlich

Surgical Removal of the Primary Tumor Increases Overall Survival in Patients With Metastatic Breast Cancer: Analysis of the 1988–2003 SEER Data

BackgroundPrimary treatments for stage IV breast cancer are chemotherapy and radiation, with surgery usually reserved for tumor-related complications. We sought to determine whether surgical removal of the primary tumor provides a survival advantage for women with metastatic breast cancer.MethodsWe conducted a retrospective, population-based cohort study by using the 1988–2003 Surveillance, Epidemiology, and End Results (SEER) program data. By use of multivariate Cox regression models, overall survival in women with stage IV disease was compared between women who underwent surgical excision of their breast tumor with women who did not, controlling for potential confounding demographic, tumor- and treatment-related variables, and propensity scores (accounting for variables associated with the likelihood of having surgery).ResultsOf 9734 SEER patients with stage IV breast cancer, 47% underwent breast cancer surgery and 53% did not. Median survival was longer for women who had surgery than for women who did not, both among women who were alive at the end of the study period (36.00 vs. 21.00 months; P < .001) and among women who had died during follow-up (18.00 vs. 7.00 months; P < .001). After controlling for potential confounding variables and propensity scores, patients who underwent surgery were less likely to die during the study period compared with women who did not undergo surgery (adjusted hazard ratio, .63, 95% confidence interval, .60–.66).ConclusionsAnalysis of the 1988–2003 SEER data indicated that extirpation of the primary breast tumor in patients with stage IV disease was associated with a marked reduction in risk of dying after controlling for variables associated with survival.

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.

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-β 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-β 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.

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.

Racial disparities in breast cancer survival: an analysis by age and stage.

BACKGROUND Black women often present with advanced-stage breast cancer compared with White women, which may result in the observed higher mortality among Black women. Age-related factors (e.g., comorbidity) also affect mortality. Whether racial disparities in mortality are evident within age and/or stage groups has not been reported, and risk factors for greater mortality among Black women are not well defined. METHODS Using the 1988-2003 Surveillance, Epidemiology, and End Results Program data, we conducted a retrospective, population-based cohort study to compare overall and stage-specific breast-cancer mortality between Black and White women within each age (<40, 40-49, 50-64, and 65+) and stage (stage 0-IV and unstaged) group at diagnosis. Cox regression models calculated unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI), the latter controlling for potential confounders of the relationship between race and survival. RESULTS In the 1988-2003 Surveillance, Epidemiology, and End Results data, 20,424 Black and 204,506 White women were diagnosed with first primary breast cancer. In unadjusted models, Black women were more likely than White women to die from breast cancer (HR: 1.90; 95% CI: 1.83-1.96) and from all causes (HR: 1.52; 95% CI: 1.48-1.55) during follow-up. In models stratified by age and stage, Black women were at increased risk of breast-cancer-specific mortality within each stage group among women <65 y. CONCLUSION Racial disparities in breast-cancer-specific mortality were predominantly observed within each stage at diagnosis among women <65 y old. This greater mortality risk for Black women was largely not observed among women >or=65 y of age.

Neuroendocrine Responses to a Cold Pressor Stimulus in Polydipsic Hyponatremic and in Matched Schizophrenic Patients

Schizophrenia, many believe, reflects an enhanced vulnerability to psychological stress. Controlled exposure to stressors, however, has produced inconclusive results, particularly with regards to neurohormones. Some of the variability may be attributable to the nature and psychological significance of the stimulus and failure to control physiologic confounds. In addition, it is possible that the heterogeneity of schizophrenia is an important factor. In a carefully designed study and in a controlled setting, we measured the neuroendocrine response of eight polydipsic hyponatremic (PHS), seven polydipsic normonatremic (PNS), and nine nonpolydipsic normonatremic (NNS) (ie normal water balance) schizophrenic in-patients as well as 12 healthy controls (HC) to two different stressors: one of which appears to influence neuroendocrine secretion through its psychological (cold pressor) and the other (upright posture) through its systemic actions. Subjects in the three psychiatric groups were stabilized and acclimated to the research setting, and all received saline to normalize plasma osmolality. Following the cold pressor, plasma adrenocorticotropin and cortisol levels showed a more prolonged rise in PHS patients relative to PNS patients. NNS patients, in contrast, exhibited blunted responses relative to both of the polydipsic groups and the HC. Peak vasopressin responses were also greater in PHS and blunted in NNS patients. Responses to the postural stimulus were similar across patient groups. These findings provide a mechanism for life threatening water intoxication in schizophrenia; help to reconcile conflicting findings of stress responsiveness in schizophrenia; and potentially identify a discrete patient subset with enhanced vulnerability to psychological stress.

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.

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.

Patient and Tumor Characteristics Associated with Primary Tumor Resection in Women with Stage IV Breast Cancer: Analysis of 1988–2003 SEER Data

Abstract:  Surgery is the cornerstone of treatment for women with nonmetastatic breast cancer. In contrast, standard treatment for patients with Stage IV disease includes chemotherapy and radiation, with surgery usually reserved for local tumor‐related complications. Little is known about the predictive factors associated with primary tumor resection for Stage IV breast cancer. We conducted a retrospective, population‐based, case–control study using the 1988–2003 Surveillance Epidemiology and End Results (SEER) data. Using multiple logistic regression, we identified patient and tumor characteristics from among SEER region, age at diagnosis, year of diagnosis, marital status, race, Hispanic ethnicity, tumor grade, and size that were associated with surgical resection of the primary breast tumor (compared with no surgical resection) among women with stage IV breast cancer. Adjusted odds ratios and 95% confidence intervals are reported. Of 10,017 patients, 4,836 (48%) underwent surgical resection of the primary breast tumor. Patients in the Northeast and Midwest and patients presenting with two or more primary breast tumors were more likely to have surgical resection. Patients who were older, diagnosed after 1992, unmarried, black, and whose tumors were >5 cm, inflammatory, of unknown size, indeterminate grade, or unknown progesterone status were less likely to have had surgical resection of the primary tumor. Several patient and tumor characteristics were significantly associated with surgical resection of the primary breast tumor in Stage IV disease. Further study of the surgery decision‐making process is recommended.