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Background Cisplatin (CDDP)-containing hyperthermic intraperitoneal chemotherapy (HIPEC) is frequently applied in selected patients with peritoneal malignancies derived from ovarian cancer, gastric cancer, and primary peritoneal mesothelioma. HIPEC with CDDP increases perioperative morbidity, in particular by inducing acute kidney injury (AKI). Factors contributing to occurrence of AKI after intraperitoneal perfusion with CDDP have not been sufficiently evaluated. Patients and Methods Data from 63 patients treated with a CDDP-containing HIPEC regimen were retrospectively analyzed concerning demographics, underlying disease, surgery, and HIPEC details to evaluate risk factors of AKI. A preclinical rat perfusion model was applied to assess the influence of temperature, concentration, perfusate volume, perfusion flow rate, and extent of peritonectomy on drug absorption upon intraperitoneal CDDP perfusion. Results AKI occurred in 66.1% of patients undergoing CDDP-containing HIPEC, with total intraoperative fluid influx being a negative and the extent of parietal peritonectomy being a positive independent predictor of postoperative AKI. In a preclinical model, bilateral anterior parietal peritonectomy significantly increased systemic CDDP absorption by 1.6 to 2-fold. CDDP plasma levels in animals were significantly higher after both perfusion with increased CDDP perfusate concentrations and bilateral anterior parietal peritonectomy. Conclusion CDDP-containing HIPEC is associated with relevant morbidity owing to its systemic toxicity. Extent of parietal peritonectomy is an independent predictor of AKI. CDDP dose reduction should be considered in case of extensive parietal peritonectomy. Cytostatic drug concentrations in HIPEC perfusate should be paid more attention to than total dose per body surface area. Further clinical studies are needed to confirm the presented preclinical findings.

Purpose Hyperthermic intraperitoneal chemotherapy (HIPEC) is accompanied with an increased risk of acute kidney injury (AKI). Whether AKI is induced by chemotoxicity or hyperthermia-related changes in renal perfusion remains controversial. The influence of HIPEC on renal perfusion has not been evaluated in patients yet. Methods Renal blood perfusion was assessed in ten patients treated with HIPEC by intraoperative renal Doppler pulse-wave ultrasound. Ultrasound (US) examinations were performed pre-, intra-, and postoperative with analyses of time-velocity curves. Patient demographics, surgical details, and data regarding renal function were recorded perioperatively. For evaluation of renal Doppler US to predict AKI, patients were divided in two groups with (AKI +) and without (AKI −) kidney injury. Results Throughout HIPEC perfusion, neither significant nor consistent changes in renal perfusion could be observed. Postoperative AKI occurred in 6 of 10 participating patients. Intraoperative renal resistive index (RRI) values > 0.8 were observed in one patient developing stage 3 AKI according KDIGO criteria. At 30 min in perfusion, RRI values were significantly higher in AKI + patients. Conclusion AKI is a common and frequent complication after HIPEC, but underlying pathophysiology remains elusive. High intraoperative RRI values may indicate an increased risk of postoperative AKI. Present data challenges the relevance of hyperthermia-derived hypothesis of renal hypoperfusion with prerenal injury during HIPEC. More attention should be drawn towards chemotoxic-induced hypothesis of HIPEC-induced AKI and caution applying regimens containing nephrotoxic agents in patients. Further confirmatory and complementary studies on renal perfusion as well as pharmacokinetic HIPEC studies are required.

Purpose: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil–based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects.Experimental Design: To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models.Results: Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects.Conclusions: Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials. Clin Cancer Res; 22(7); 1663–73. ©2015 AACR.

Supplementary Figure 1. Selinexor induces HT29 and LoVo cell apoptosis; Supplementary Figure 2. Combination of radiation and Selinexor reduces tumor cell radiation survival; Supplementary Figure 3. Body weight of female nude mice; Supplementary Figure 4. mRNA Survivin levels in in vivo models of CRC.

Background Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery (CRS) is the treatment of choice for selected patients with peritoneal malignancies. HIPEC is accompanied by moderate-to-high patient morbidity, including acute kidney injury. The significance of nephrotoxic agents such as cisplatin versus hyperthermia in HIPEC-induced nephrotoxicity has not been defined yet. Patients and Methods A total of 153 patients treated with HIPEC were divided into groups with (AKI+) and without (AKI−) kidney injury. Laboratory parameters and data concerning patient demographics, underlying disease, surgery, complications, and HIPEC were gathered to evaluate risk factors for HIPEC-induced AKI. A preclinical mouse model was applied to assess the significance of cisplatin and hyperthermia in HIPEC-induced AKI, as well as protective effects of the cytoprotective agent amifostine. Results AKI occurred in 31.8% of patients undergoing HIPEC. Treatment with cisplatin-containing HIPEC regimens represented a major risk factor for HIPEC-related AKI (p Conclusions AKI is a frequent complication after HIPEC. The risk of renal injury is particularly high in patients treated with cisplatin-containing HIPEC regimens. Hyperthermic perfusion of the abdomen by itself does not seem to induce or aggravate HIPEC-induced renal injury.

Right- and left-sided colon cancer are increasingly regarded as two independent disease entities based on different gene expression profiles as well as underlying genetic mutations. Data regarding prognosis and survival are heterogeneous and more favorable in cases of left-sided colon cancer. The purpose of this study was to evaluate the long-term oncological outcome for patients with left-sided versus right-sided stage I–III colon cancer. Overall, 318 consecutive patients who underwent surgery for right- or left-sided sided colon cancer between 2001 and 2014 were analyzed. Analysis was performed applying a prospectively maintained database with respect to overall, disease-specific, and relative survival, using Cox regression and propensity score analyses. A total of 155 patients (48.7%) presented with right-sided colon cancer and 163 patients (51.3%) presented with left-sided colon cancer. In risk-adjusted Cox regression analysis, tumor location had no significant impact on overall survival (hazard ratio [HR] 1.53, 95% confidence interval [CI] 0.80–2.92; p = 0.197), disease-specific survival (HR 1.36, 95% CI 0.76–2.44; p = 0.301), and relative survival (HR 1.70, 95% CI 0.89–3.27; p = 0.107). After propensity score matching, the results from risk-adjusted Cox regression analysis were confirmed. Stratified by American Joint Committee on Cancer stage, patients with right-sided stage II colon cancer had a statistically significant superior relative survival compared with patents with left-sided colon cancer. No significant negative impact on overall, disease-specific, or relative survival could be observed in patients with right- versus left-sided colon cancer after risk adjustment, using multivariable Cox regression and propensity score analyses.

Background Anastomotic leakage (AL) in the upper gastrointestinal (GI) tract is associated with high morbidity and mortality rates. Especially intrathoracic anastomotic leakage leads to life-threatening complications. Endoscopic vacuum therapy (EVT) for anastomotic leakage after transthoracic esophageal resection represents a novel concept. However, sound clinical data are still scarce. This retrospective, single-center study aimed to evaluate the feasibility, effectiveness, and safety of EVT for intrathoracic anastomotic leakage following abdomino-thoracic esophageal resection. Methods From March 2014 to September 2019 259 consecutive patients underwent elective transthoracic esophageal resection. 72 patients (27.8%) suffered from AL. The overall collective in-hospital mortality rate was 3.9% (n = 10). Data from those who underwent treatment with EVT were included. Results Fifty-five patients were treated with EVT. Successful closure was achieved in 89.1% (n = 49) by EVT only. The EVT-associated complication rate was 5.4% (n = 3): bleeding occurred in one patient, while minor sedation-related complications were observed in two patients. The median number of EVT procedures per patient was 3. The procedures were performed at intervals of 3–5 days, with a 14-day median duration of therapy. The mortality rate of patients with AL was 7.2% (n = 4). Despite successfully terminated EVT, three patients died because of multiple organ failure, acute respiratory distress syndrome, and urosepsis (5.4%). One patient (1.8%) died during EVT due to cardiac arrest. Conclusions EVT is a safe and effective approach for intrathoracic anastomotic leakages following abdomino-thoracic esophageal resections. It offers a high leakage-closure rate and the potential to lower leakage-related mortalities. Trial registration: This trial was registered and approved by the Institutional Ethics Committee of the University of Heidelberg on 16.04.2014 (Registration Number: S-635/2013).

Background Anastomotic leakage (AL) is a common and severe complication after upper gastrointestinal (UGI) surgery. Although evidence is scarce, endoscopic deployed self-expanding metal stents (SEMS) are well-established for the management of AL in UGI surgery. The present study aimed to evaluate the feasibility, effectiveness, and safety of SEMS in terms of success, mortality, and morbidity in patients with AL after UGI cancer surgery. Materials and Methods Patients with AL after primary UGI cancer surgery were retrospectively analyzed with regard to demographics, disease, surgical and endoscopic procedures, and complications. Stent treatment success was divided into technical, primary (within 72 hours of stent deployment), sustained (after 72 hours of stent deployment), and sealing success. Results In a total of 63 patients, 74 stents were used and 11 were deployed in endoscopic reinterventions. Stent deployment was successful in all patients. Primary and sustained success rates were 68.3% (n = 43) and 65.1% (n = 41), respectively. Of the primarily successfully treated patients, 87.8% remained successfully treated. If primary treatment was unsuccessful, it remained unsuccessful in 66.6% of the patients (P = 0.002). Final sealing of the leakage was observed in 65.1% of patients (n = 41). Longer stent shafts and wider stent end widths were correlated with successful stent treatment (P Conclusion SEMS are a safe and sufficient tool in the treatment of AL after UGI cancer surgery. Treatment success is improved with longer stent shafts and wider stent end widths. Switching to alternative treatments is strongly suggested if signs of persistent leakage are present beyond 72 hours after stent placement, as this is highly indicative of sustained stent failure.

Right- and left-sided colon cancer are increasingly regarded as two independent disease entities based on different gene expression profiles as well as underlying genetic mutations. Data regarding prognosis and survival are heterogeneous and more favorable in cases of left-sided colon cancer.The purpose of this study was to evaluate the long-term oncological outcome for patients with left-sided versus right-sided stage I-III colon cancer.Overall, 318 consecutive patients who underwent surgery for right- or left-sided sided colon cancer between 2001 and 2014 were analyzed. Analysis was performed applying a prospectively maintained database with respect to overall, disease-specific, and relative survival, using Cox regression and propensity score analyses.A total of 155 patients (48.7%) presented with right-sided colon cancer and 163 patients (51.3%) presented with left-sided colon cancer. In risk-adjusted Cox regression analysis, tumor location had no significant impact on overall survival (hazard ratio [HR] 1.53, 95% confidence interval [CI] 0.80-2.92; p = 0.197), disease-specific survival (HR 1.36, 95% CI 0.76-2.44; p = 0.301), and relative survival (HR 1.70, 95% CI 0.89-3.27; p = 0.107). After propensity score matching, the results from risk-adjusted Cox regression analysis were confirmed. Stratified by American Joint Committee on Cancer stage, patients with right-sided stage II colon cancer had a statistically significant superior relative survival compared with patents with left-sided colon cancer.No significant negative impact on overall, disease-specific, or relative survival could be observed in patients with right- versus left-sided colon cancer after risk adjustment, using multivariable Cox regression and propensity score analyses.

Background Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be beneficial in treating limited peritoneal carcinomatosis (PC) from colorectal cancer (CRC). Perfusate volume directly affects treatment concentration and therefore is a key parameter defining HIPEC; yet little is known about the impact of perfusate concentration on systemic toxicity and treatment morbidity. Materials and methods PC was induced through intraperitoneal injection of human CRC cell lines. A novel perfusion model was developed to treat athymic nude mice with continuous circulation of adequately miniaturized volumes of heated perfusate. Oxaliplatin HIPEC was performed applying different volumes of perfusate with fixed doses or fixed concentrations. Early postoperative mortality and morbidity were assessed as well as long-term survival. In addition, antiproliferative and proapoptotic effects of HIPEC were determined in vitro and in vivo. Results Perfusate concentration crucially affected the toxicity of fixed-dose oxaliplatin HIPEC as indicated by postoperative weight loss and early postoperative mortality. Applying different perfusate volumes at a fixed concentration did not influence toxicity. Adequately miniaturized HIPEC with oxaliplatin did not exert relevant cytotoxic effects toward PC arising from human CRC cells in vivo. Conclusions We describe a novel murine model that adequately miniaturizes all physical parameters of HIPEC as applied in humans. HIPEC drug concentration is a crucial parameter determining excess toxicity and should be better standardized. HIPEC with oxaliplatin fails to induce relevant antitumor activity or to improve survival in this murine model of PC from CRC.

Purpose: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil–based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects. Experimental Design: To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models. Results: Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects. Conclusions: Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials. Clin Cancer Res; 22(7); 1663–73. ©2015 AACR.