Brian D. Badgwell

The antitumor effects of IFN-α are abrogated in a STAT1-deficient mouse

IFN-alpha activates the signal transducer and activator of transcription (STAT) family of proteins; however, it is unknown whether IFN-alpha exerts its antitumor actions primarily through a direct effect on malignant cells or by stimulating the immune system. To investigate the contribution of STAT1 signaling within the tumor, we generated a STAT1-deficient melanoma cell line, AGS-1. We reconstituted STAT1 into AGS-1 cells by retroviral gene transfer. The resulting cell line (AGS-1STAT1) showed normal regulation of IFN-alpha-stimulated genes (e.g., H2k, ISG-54) as compared with AGS-1 cells infected with the empty vector (AGS-1MSCV). However, mice challenged with the AGS-1, AGS-1STAT1, and AGS-1MSCV cell lines exhibited nearly identical survival in response to IFN-alpha treatment, indicating that restored STAT1 signaling within the tumor did not augment the antitumor activity of IFN-alpha. In contrast, STAT1-/- mice could not utilize exogenous IFN-alpha to inhibit the growth of STAT1+/+ melanoma cells in either an intraperitoneal tumor model or in the adjuvant setting. The survival of tumor-bearing STAT1-/- mice was identical regardless of treatment (IFN-alpha or PBS). Additional cell depletion studies demonstrated that NK cells mediated the antitumor effects of IFN-alpha. Thus, STAT1-mediated gene regulation within immune effectors was necessary for mediating the antitumor effects of IFN-alpha in this experimental system.

Mammography Before Diagnosis Among Women Age 80 Years and Older With Breast Cancer

PURPOSE Screening mammography guidelines for patients age 80 years and older are variable. We determined the effect of mammography use on stage at breast cancer diagnosis and survival among women of this age range. PATIENTS AND METHODS We used the linked Surveillance, Epidemiology, and End Results-Medicare database to evaluate 12,358 women >or= 80 years of age diagnosed with breast cancer between 1996 and 2002. Patients were grouped according to number of mammograms during the 60 months before diagnosis: nonusers (0 mammograms), irregular users (one to two mammograms), and regular users (three or more mammograms). Effects of mammography on disease stage (I to IIa v IIb to IV) and survival were determined by logistic regression and Cox proportional hazards analyses. RESULTS Percentages of women with nonuse, irregular use, and regular use of mammography during the 5 years preceding diagnosis were 49%, 29%, and 22%, respectively. On multivariate analysis, patients were 0.37 times less likely to present with late-stage cancer for each mammogram obtained (odds ratio, 0.63; 95% CI, 0.63 to 0.67). Breast cancer-specific 5-year survival among nonusers was 82%, that among irregular users was 88%, and that among regular users was 94%. However, survival from causes other than breast cancer was also associated with mammography use, suggesting a bias for healthier patients to undergo mammography. CONCLUSION Regular mammography among women >or= 80 years of age was associated with earlier disease stage, although improved survival remains difficult to demonstrate. Health care providers should consider discussing the potential benefits of screening mammography with their older patients, particularly for those without significant comorbidity.

Patterns of recurrence after sentinel lymph node biopsy for breast cancer.

AbstractBackground: Sentinel lymph node biopsy (SLNB) is gaining acceptance as an alternative to axillary lymph node dissection. The purpose of this study was to determine the frequency and pattern of disease recurrence after SLNB. Methods: Two-hundred twenty-two consecutive patients undergoing SLNB from April 6, 1998, to October 27, 1999, and who were ≥24 months out from their procedure were identified from a prospectively maintained database. Retrospective chart review and data analysis were performed to identify variables predictive of recurrence. Results: The median patient follow-up was 32 months (range, 24–43 months). A total of 159 patients (72%) were sentinel lymph node (SLN) negative and had no further axillary treatment. Five of these patients (3.1%) developed a recurrence (one local and four distant), with no isolated regional (axillary) recurrences. Sixty-three patients (28%) were SLN positive and underwent a subsequent axillary lymph node dissection. Six of these patients (9.5%) developed a recurrence (three local, one regional, and two distant). Pathologic tumor size (P < .001), lymphovascular invasion (P = .018), and a positive SLN (P = .048) were all statistically significantly associated with disease recurrence. Conclusions:With a minimum follow-up of 24 months, patients with a negative SLN and no subsequent axillary treatment demonstrate a low frequency of disease recurrence. This supports the use of SLNB as the sole axillary staging procedure in SLN-negative patients.

Lymph Node Ratio Predicts Disease-Specific Survival in Melanoma Patients

The objectives of this analysis were to compare various measures associated with lymph node (LN) dissection and to identify threshold values associated with disease‐specific survival (DSS) outcomes in patients with melanoma.

Comprehensive geriatric assessment of risk factors associated with adverse outcomes and resource utilization in cancer patients undergoing abdominal surgery

The purpose of this prospective study was to identify risk factors for adverse outcomes or increased resource utilization after abdominal cancer surgery in geriatric patients.

Challenges in Surgical Management of Abdominal Pain in the Neutropenic Cancer Patient

Background:Abdominal pain in neutropenic cancer patients presents a unique clinical challenge for surgeons. The purposes of this retrospective study were to characterize the clinicopathologic factors associated with the presentation of neutropenia and abdominal pain, examine the treatment strategies used, and define associated outcomes for these patients. Methods:We identified patients with concomitant neutropenia (absolute neutrophil count <1000 cells/&mgr;L) and abdominal pain who had been evaluated by surgical oncologists over a period of more than 6 years. A Cox proportional hazards regression model was used to analyze the association between clinicopathologic factors and overall survival time. Results:Sixty patients were included in this analysis. After our clinical and radiographic evaluations, we determined that the most frequent causes of the abdominal pain were neutropenic enterocolitis (28%) and small bowel obstruction (12%); the cause remained uncertain in 35%. Surgical interventions had been performed in 9 patients. The 30- and 90-day mortality rates for all patients were 30% and 52%, respectively. Multivariate analysis revealed that severe sepsis, a relatively long duration of neutropenia, and the lack of surgical intervention were significant adverse prognostic factors for overall survival. Conclusions:Abdominal pain as a symptom in neutropenic patients continues to be a diagnostic and therapeutic challenge and is associated with a high mortality rate. Based on our results, we conclude that efforts should focus on improving neutrophil counts and on treating the frequent and serious comorbidities found in these patients. Surgery should be delayed, when possible, to allow for neutrophil recovery.

Medical management of gastric cancer: A 2014 update

Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10% realized by adjunctive treatments to surgery is unacceptable as > 50% patients with localized gastric cancer succumb to their disease. Either postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the localized gastric cancer management. In metastatic disease the addition of trastuzumab to chemotherapy is standard of care in Her2 positive disease. In the HER2 negative population, the treatments remain limited. In the first line setting, the standard of care is a combination of fluoropyrimidine and platinum containing chemotherapy, with or without epirubicin or docetaxel. The results of targeted therapy trials have by and large been disappointing, but none of these trials looked at an appropriately enriched population. Finally there is a meager overall survival benefit in treating patients with metastatic disease in the second line setting, with either irinotecan, docetaxel or ramucirumab however none of these drugs have been compared head to head in a well-powered randomized controlled trial.

IL-12 Pretreatments Enhance IFN-α-Induced Janus Kinase-STAT Signaling and Potentiate the Antitumor Effects of IFN-α in a Murine Model of Malignant Melanoma

IFN-α 2b (IFN-α) has been used to treat patients with metastatic malignant melanoma and patients rendered disease-free via surgery but at high risk for recurrence. We hypothesized that IL-12 pretreatments would result in endogenous IFN-γ production, and that this, in turn, would up-regulate levels of Janus kinase-STAT signaling intermediates and lead to increased expression of genes regulated by IFN-α. Treatment of PBMCs with IL-12 stimulated a significant and dose-dependent production of IFN-γ. Pretreatment of PBMCs and tumor cells with IFN-γ-containing supernatants from IL-12-stimulated PBMCs led to up-regulation of STAT1, STAT2, and IFN regulatory factor 9 (IRF9) and potentiated IFN-α-induced STAT signaling within PBMCs and tumor cells. These effects were abrogated by neutralization of IFN-γ in the PBMC supernatants with an anti-IFN-γ Ab. Pretreatment of HT144 melanoma cells and PBMCs with IFN-γ or IFN-γ-containing supernatants enhanced the actions of IFN-α at the transcriptional level, as measured by real-time RT PCR analysis of the IFN-stimulated gene 15. Experiments in wild-type C57BL/6 and IFN-γ receptor knockout (B6.129S7-Ifngrtm1Agt) mice demonstrated that a regimen of IL-12 pretreatment, followed by IFN-α, could cure mice of i.p. B16F1 melanoma tumors (p < 0.007), whereas mice treated with either agent alone or PBS succumbed to fatal tumor burden. However, this treatment regimen did not significantly prolong the survival of IFN-γ-deficient (B6.129S7-Ifngtm1Ts) mice compared with mice treated with IFN-α alone. These results suggest that the response to IFN-α immunotherapy can be significantly enhanced by IL-12 pretreatment, and this effect is dependent upon endogenous IFN-γ production and its actions on melanoma cells.

Axillary reverse mapping: Five-year experience

BACKGROUND We hypothesize that mapping the lymphatic drainage of the arm with blue dye (axillary reverse mapping, ARM) during axillary lymphadenectomy decreases the likelihood of disruption of lymphatics and subsequent lymphedema. METHODS This institutional review board-approved study from May 2006 to October 2011 involved 360 patients undergoing SLNB and/or ALND. Technetium sulfur colloid (4 mL) was injected subareolarly and 5 mL of blue dye was injected subcutaneously in the volar surface ipsilateral upper extremity (ARM). Data were collected on variations in lymphatic drainage, successful identification and protection of arm lymphatics, crossover, and occurrence of lymphedema. RESULTS A group of 360 patients underwent SLNB and/or ALND. A total of 348 patients underwent a SLNB. Of those, 237/348(68.1%) had a SLNB only and 111/348(31.9%) went on to an ALND due to a positive axilla. An additional 12/360(3.3%) axilla had ALND due to a clinically positive axilla/preoperative core needle biopsy. In 96%(334/348) of patients with SLNB, breast SLNs were hot but not blue; crossover (SLN hot and blue) was seen in 14/348(4%). Blue lymphatics were identified in 80/237(33.7%) of SLN incisions and in 93/123(75.4%) ALND. Average follow-up was 12 months (range 3 to 48 months) and resulted in a SLNB lymphedema rate of 1.7%(4/237) and ALND of 2.4%(3/123). CONCLUSIONS ARM identified significant lymphatic variations draining the upper extremities and facilitated preservation. Metastases in ARM-identified lymph nodes were acceptably low indicating that ARM is safe. ARM added to present-day ALND and SLNB may be useful to lower lymphedema rates.

Predictors of Survival in Patients with Resectable Gastric Cancer Treated with Preoperative Chemoradiation Therapy and Gastrectomy

BACKGROUND The purpose of this study was to determine the overall survival (OS) of patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. STUDY DESIGN The medical records of patients with gastric adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. RESULTS Of 192 patients who met inclusion criteria, 103 (54%) required total gastrectomy. One hundred sixty-eight patients (88%) had an extended lymph node dissection, 26 (14%) had resection of adjacent organs, and 178 (93%) had an R0 resection. Median follow-up time for surviving patients was 4.2 years. Median OS for all patients was 5.8 years, and 5-year OS rate was 56%. Multivariable Cox regression model results identified variables associated with diminished OS including age ≥ 65 years (hazard ratio [HR] 1.62; 95% CI 1.05 to 2.51), male sex (HR 1.76; 95% CI 1.13 to 2.74), adjacent organ resection (HR 1.97; 95% CI 1.16 to 3.35), R1 status (HR 2.29; 95% CI 1.17 to 4.48), pathologic N1 stage (HR 1.92; 95% CI 1.24 to 2.98), N2 stage (HR 2.58; 95% CI 1.01 to 6.58), and N3 stage (HR 6.54; 95% CI 2.69 to 15.93). Five-year OS rates for patients with pathologic N0, N1, N2, and N3 disease were 67%, 42%, 43%, and 0%, respectively. CONCLUSIONS Patients with gastric cancer who undergo diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy have a high frequency of obtaining an R0 resection and excellent OS rates. Nodal status after surgery remains an important determinant of OS.