Gerard J. Abood

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.

The Surgical and Systemic Management of Neuroendocrine Tumors of the Pancreas

Neuroendocrine tumors of the pancreas comprise a class of rare tumors that can be associated with symptoms of hormone overproduction. Five distinct clinical endocrinopathies are associated with neuroendocrine tumors; however, most of these tumors remain asymptomatic and follow an indolent course. Complete surgical resection offers the only hope for cure, but understanding the basic biology of the tumors has advanced the medical management in metastatic disease. Surgical resection of hepatic metastases offers survival advantage and should be performed when feasible. Although hepatic artery embolization is currently the preferred mode of nonsurgical palliation for pain and hormonal symptoms, other modalities may play a role in metastatic disease.

Treatment strategies in toxic epidermal necrolysis syndrome: where are we at?

Toxic epidermal necrolysis syndrome (TENS) is a rare, life-threatening medical emergency typically associated with recent drug exposure. Although several theories exist, recent insight has implicated the innate immune system as a significant contributor to the initiation and propagation of this devastating reaction. Standard therapies including transfer to specialized burn units, nutritional support, and protection from infection, remain the mainstay in the treatment of TENS. While alternative treatment strategies have been pursued and reported, there remains no published data that convincingly supports these further interventions. Given the rare nature of this syndrome, multi-institutional studies will be necessary and essential in improving the understanding and treatment of TENS.

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.

Robot-assisted surgery: improved tool for major liver resections?

Minimally invasive liver surgery has recently undergone an explosion in reported worldwide experience. Given its comparable outcomes to its open counterpart, high-volume centers are utilizing minimal access liver surgery more frequently under well-defined criteria. The recent introduction of robot-assisted surgery has further revolutionized the field of minimally invasive surgery and has expanded the reach of feasibility. Robot-assisted surgery was developed to help overcome the disadvantages of conventional laparoscopic surgery. As a result, there has been an increase in the reporting of advanced robot-assisted liver resections. A literature review was performed to identify the current manuscripts describing robot-assisted liver surgery. Nine case series were identified, yielding 144 unique patient characteristics. Outcomes indicate that robot-assisted liver resection is feasible and safe for both minor and major liver resections with regard to estimated blood loss, length of stay, and complications. Early data also suggest that robot-assisted liver surgery is efficacious with regard to short-term oncologic outcomes. Future studies will be needed to better evaluate advantages and disadvantages compared to laparoscopic liver resections.

Hepatic resection for recurrent metastatic ovarian cancer

BACKGROUND The role for liver resection in metastatic ovarian cancer has not been defined. The aim of the current study was to investigate the validity of hepatic resection as a treatment option in metastatic ovarian cancer. METHODS Retrospective review of a single institutions experience of patients undergoing hepatic resection for metastatic ovarian cancer from 1998-2006. RESULTS Ten patients underwent resection for metastatic ovarian cancer. Primary tumor type included serous cystadenocarcinoma (n = 8), granulosa cell (n = 1), and yolk sac (n = 1). Median disease-free interval was 48 months. Liver resections included trisegmentectomy (n = 4), lobectomy (n = 4), and bisegmentectomy(n = 1). Additional surgeries included diaphragm resection (n = 60), bowel resection, (n = 30), and adrenalectomy (n = 10). The median overall survival following liver resection was 33 months. CONCLUSION Liver resection for metastatic ovarian cancer is safe and is associated with long-term survival in some patients. Larger analysis may lead to the identification of prognostic factors associated with improved outcomes.

The influence of 18flourodeoxyglucose positron emission tomography on the management of gastroesophageal junction carcinoma

BACKGROUND The influence of positron emission tomography (PET) scanning with flourodeoxyglucose (FDG) on decision making for the treatment of patients with esophagogastric junction (EGJ) carcinoma is unclear as is the utility of the maximum standardized uptake value (SUV) as a prognostic indicator. METHODS This study was a retrospective review of EGJ carcinoma cases at a single institution during a 5-year period. RESULTS FDG-PET altered treatment in 13 of 64 patients (20%). Of these, 21 patients had PET scans before and after undergoing neoadjuvant chemoradiation (CRT) as well as surgery. Patients who had a decrease in SUV >50% had a 12-month disease-free survival advantage over patients a decrease in SUV <50% (93% vs 43%, P = .025). CONCLUSIONS FDG-PET alters treatment in a significant number of patients with EGJ carcinoma. A >50% decrease in SUV after CRT is associated with an improved prognosis.

The Changing Spectrum of Surgically Treated Cystic Neoplasms of the Pancreas

Introduction. While the incidence of pancreatic cystic lesions has steadily increased, we sought to evaluate the changes in their surgical management. Methods. Patients with pancreatic cystic lesions who underwent surgical resection from 2003 to 2013 were identified. Clinicopathologic factors were analyzed and compared to a similar cohort from 1992 to 2002. Results. There were 134 patients with pancreatic cystic lesions who underwent surgical resection from 2003 to 2013, compared to 73 from 1992 to 2002. The most common preoperative imaging was a CT scan, although 66% underwent EUS and 63% underwent biopsy. Pathology included 18 serous, 47 mucinous, 11 pseudopapillary, and 58 intraductal papillary mucinous neoplasms (IPMN). In comparing cohorts, there were significantly fewer serous lesions and more IPMN. Postoperative complication rates were similar, and perioperative mortality rates were comparable. Conclusion. There has been a dramatic change in surgically treated pancreatic cystic tumors over the past two decades. Our data suggests that the incorporation of new imaging and diagnostic tests has led to greater detection of cystic tumors and a decreased rate of potentially unnecessary resections. Therefore, all patients with cystic pancreatic lesions should undergo a focused CT-pancreas, and an EUS biopsy should be considered, in order to best select those that would benefit from surgical resection.

Peri‐operative epidural may not be the preferred form of analgesia in select patients undergoing pancreaticoduodenectomy

Epidural analgesia has become the preferred method of pain management for major abdominal surgery. However, the superior form of analgesia for pancreaticoduodenecomy (PD), with regard to non‐analgesic outcomes, has been debated. In this study, we compare outcomes of epidural and intravenous analgesia for PD and identify pre‐operative factors leading to early epidural discontinuation.

Take the Volume Pledge may result in disparity in access to care.

Background. “Take the Volume Pledge” proposes restricting pancreatectomies to hospitals that perform ≥20 per year. Our purpose was to identify those factors that characterize patients at risk for loss of access to pancreatic cancer care with enforcement of volume standards. Methods. Using the Healthcare Cost and Utilization Project State Inpatient Database from Florida, we identified patients who underwent pancreatectomy for pancreatic malignancy from 2007–2011. American Hospital Association and United States Census Bureau data were linked to patient‐level data. High‐volume hospitals were defined as performing ≥20 pancreatic resections per year. Univariable and multivariable statistics compared patient characteristics and utilization of high‐volume hospitals. Classification and Regression Tree modeling was used to predict patients at risk for losing access to care. Results. Our study included 1,663 patients. Five high‐volume hospitals were identified, and they treated 1,056 (63.5%) patients. Patients residing far from high‐volume hospitals, in areas with the highest population density, non‐Caucasian ethnicity, and greater income had decreased odds of obtaining care at high‐volume hospitals. Using these factors, we developed a Classification and Regression Tree–based predictive tool to identify these patients. Conclusion. Implementation of “Take the Volume Pledge” is an important step toward improving pancreatectomy outcomes; however, policymakers must consider the potential impact on limiting access and possible health disparities that may arise.