Extensive Peritonectomy is an Independent Risk Factor for Cisplatin HIPEC-Induced Acute Kidney Injury.

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.

Influence of hyperthermic intraperitoneal chemotherapy on renal blood perfusion.

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.

HIPEC-Induced Acute Kidney Injury: A Retrospective Clinical Study and Preclinical Model.

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 < 0.001). Besides, angiotensin receptor blockers and increased preoperative creatinine and urea levels were independent risk factors for AKI after HIPEC. In a preclinical mouse model, intraperitoneal perfusion with cisplatin induced AKI, whereas hyperthermia alone, or in combination with cisplatin, did not induce or enhance renal injury. Amifostine failed to confer nephroprotective effects in a miniaturized HIPEC model. 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.

Does Side Really Matter? Survival Analysis among Patients with Right- Versus Left-Sided Colon Cancer: A Propensity Score-Adjusted Analysis.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Self-Expanding Metal Stents for Anastomotic Leaks After Upper Gastrointestinal Cancer Surgery.

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 < 0.05). 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.

Feasibility, effectiveness, and safety of endoscopic vacuum therapy for intrathoracic anastomotic leakage following transthoracic esophageal resection.

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).

Impact of Perfusate Concentration on Hyperthermic Intraperitoneal Chemotherapy Efficacy and Toxicity in a Rodent Model.

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.

Prognostic value of inflammatory markers for detecting anastomotic leakage after esophageal resection.

BACKGROUND: Early diagnosis of anastomotic leakage (AL) after esophageal resection is crucial for the successful management of this complication. Inflammatory serological markers are indicators of complications during the postoperative course. The aim of the present study was to evaluate the prognostic value of routine inflammatory markers to predict anastomotic leakage after transthoracic esophageal resection. METHODS: Data from all consecutive patients undergoing transthoracic esophageal resection between January 2010 and December 2016 were analyzed from a prospective database. Besides clinicodemographic parameters, C-reactive protein, white blood cell count and albumin were analyzed and the Noble/Underwood (NUn) score was calculated to evaluate their predictive value for postoperative anastomotic leakage. Diagnostic accuracy was measured by sensitivity, specificity, and negative and positive predictive values using area under the receiver operator characteristics curve. RESULTS: Overall, 233 patients with transthoracic esophageal resection were analyzed, 30-day mortality in this group was 3.4%. 57 patients (24.5%) suffered from AL, 176 patients were in the AL negative group. We found significant differences in WBCC, CRP and NUn scores between patients with and without AL, but the analyzed markers did not show an independent relevant prognostic value. For CRP levels below 155 mg/dl from POD3 to POD 7 the negative predictive value for absence of AI was > 80%. Highest diagnostic accuracy was detected for CRP levels on 4th POD with a cut-off value of 145 mg/l reaching negative predictive value of 87%. CONCLUSIONS: In contrast to their prognostic value in other surgical procedures, CRP, WBCC and NUn score cannot be recommended as independent markers for the prediction of anastomotic leakage after transthoracic esophageal resection. CRP is an accurate negative predictive marker and discrimination of AL and no-AL may be helpful for postoperative clinical management. Trial registration The study was approved by the local ethical committee (S635-2013).

Spatially correlated phenotyping reveals K5-positive luminal progenitor cells and p63-K5/14-positive stem cell-like cells in human breast epithelium.

Understanding the mechanisms regulating human mammary epithelium requires knowledge of the cellular constituents of this tissue. Different and partially contradictory definitions and concepts describing the cellular hierarchy of mammary epithelium have been proposed, including our studies of keratins K5 and/or K14 as markers of progenitor cells. Furthermore, we and others have suggested that the p53 homolog p63 is a marker of human breast epithelial stem cells. In this investigation, we expand our previous studies by testing whether immunohistochemical staining with monospecific anti-keratin antibodies in combination with an antibody against the stem cell marker p63 might help refine the different morphologic phenotypes in normal breast epithelium. We used in situ multilabel staining for p63, different keratins, the myoepithelial marker smooth muscle actin (SMA), the estrogen receptor (ER), and Ki67 to dissect and quantify the cellular components of 16 normal pre- and postmenopausal human breast epithelial tissue samples at the single-cell level. Importantly, we confirm the existence of K5+ only cells and suggest that they, in contrast to the current view, are key luminal precursor cells from which K8/18+ progeny cells evolve. These cells are further modified by the expression of ER and Ki67. We have also identified a population of p63+K5+ cells that are only found in nipple ducts. Based on our findings, we propose a new concept of the cellular hierarchy of human breast epithelium, including K5 luminal lineage progenitors throughout the ductal-lobular axis and p63+K5+ progenitors confined to the nipple ducts.

Preclinical Evaluation of Cathepsin-Based Fluorescent Imaging System for Cytoreductive Surgery.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a treatment option for peritoneal surface malignancies. The ability to detect microscopic foci of peritoneal metastasis intraoperatively may ensure the completeness of cytoreduction. In this study, we evaluated the suitability of a hand-held cathepsin-based fluorescent imaging system for intraoperative detection of appendiceal and colorectal peritoneal metastasis. METHODS: Peritoneal tumors and normal peritoneal tissues were collected from patients with appendiceal and colorectal peritoneal metastasis. Expression of different cathepsins (CTS-B, -D, -F, -G, -K, -L, -O, and -S) was determined by quantitative RT-PCR and immunohistochemistry. The hand-held cathepsin-based fluorescent imaging system was used to detect peritoneal xenografts derived from human colon cancer cells (HT29, LoVo and HCT116) in nu/nu mice. RESULTS: While the expression levels of CTS-B, -D, -L, and -S could be higher in peritoneal tumors than normal peritoneum with a median (range) of 6.1 (2.9-25.8), 2.0 (1.0-15.8), 1.4 (0.8-7.0), and 2.1 (1.6-13.9) folds by quantitative RT-PCR, respectively, CTS-B was consistently the major contributor of the overall cathepsin expression in appendiceal and colonic peritoneal tumors, including adenocarcinomas and low-grade appendiceal mucinous neoplasms. Using peritoneal xenograft mouse models, small barely visible colonic peritoneal tumors (<2.5 mm in maximum diameter) could be detected by the hand-held cathepsin-based fluorescent imaging system. CONCLUSIONS: Because cathepsin expression is higher in peritoneal tumors than underlying peritoneum, the hand-held cathepsin-based fluorescent imaging system could be useful for intraoperative detection of microscopic peritoneal metastasis during CRS-HIPEC and clinical trial is warranted.

XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer.

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.