Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients.

BackgroundGender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied.MethodsForty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974-2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients.ResultsOur murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations.ConclusionsAlthough our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance

Novel Dedifferentiated Liposarcoma Xenograft Models Reveal PTEN Down-Regulation as a Malignant Signature and Response to PI3K Pathway Inhibition

Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care

Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients.

BackgroundGender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied.MethodsForty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974-2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients.ResultsOur murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations.ConclusionsAlthough our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance

Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors

PURPOSE: The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic human papillomavirus 16-transformed murine tumors. EXPERIMENTAL DESIGN: Animals bearing E7-expressing tumors were coimmunized by lymph node injection with E7 49-57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and antitumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease. RESULTS: In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen-specific T lymphocytes in the range of 1/10 CD8(+) T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with antitumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T-cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization. CONCLUSIONS: This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system. Results A total of 3288 patients were included in the analysis, of whom 301 (9 center dot 2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P < 0 center dot 001). There were no significant differences in rates of readmission between these groups (6 center dot 6 versus 8 center dot 0 per cent; P = 0 center dot 499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0 center dot 90, 95 per cent c.i. 0 center dot 55 to 1 center dot 46; P = 0 center dot 659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34 center dot 7 versus 39 center dot 5 per cent; major 3 center dot 3 versus 3 center dot 4 per cent; P = 0 center dot 110). Conclusion Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien–Dindo classification system. Results: A total of 3288 patients were included in the analysis, of whom 301 (9·2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4–7) and 7 (6–8) days respectively (P < 0·001). There were no significant differences in rates of readmission between these groups (6·6 versus 8·0 per cent; P = 0·499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0·90, 95 per cent c.i. 0·55 to 1·46; P = 0·659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34·7 versus 39·5 per cent; major 3·3 versus 3·4 per cent; P = 0·110). Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery

Background: Ileus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery. Methods: A prospective multicentre cohort study was delivered by an international, student- and trainee-led collaborative group. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The primary outcome was time to gastrointestinal recovery, measured using a composite measure of bowel function and tolerance to oral intake. The impact of NSAIDs was explored using Cox regression analyses, including the results of a centre-specific survey of compliance to enhanced recovery principles. Secondary safety outcomes included anastomotic leak rate and acute kidney injury. Results: A total of 4164 patients were included, with a median age of 68 (i.q.r. 57\u201375) years (54\ub79 per cent men). Some 1153 (27\ub77 per cent) received NSAIDs on postoperative days 1\u20133, of whom 1061 (92\ub70 per cent) received non-selective cyclo-oxygenase inhibitors. After adjustment for baseline differences, the mean time to gastrointestinal recovery did not differ significantly between patients who received NSAIDs and those who did not (4\ub76 versus 4\ub78 days; hazard ratio 1\ub704, 95 per cent c.i. 0\ub796 to 1\ub712; P = 0\ub7360). There were no significant differences in anastomotic leak rate (5\ub74 versus 4\ub76 per cent; P = 0\ub7349) or acute kidney injury (14\ub73 versus 13\ub78 per cent; P = 0\ub7666) between the groups. Significantly fewer patients receiving NSAIDs required strong opioid analgesia (35\ub73 versus 56\ub77 per cent; P < 0\ub7001). Conclusion: NSAIDs did not reduce the time for gastrointestinal recovery after colorectal surgery, but they were safe and associated with reduced postoperative opioid requirement

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function.Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system.Results: A total of 3288 patients were included in the analysis, of whom 301 (9.2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P < 0.001). There were no significant differences in rates of readmission between these groups (6.6 versus 8.0 per cent; P = 0.499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0.90, 95 per cent c.i. 0.55 to 1.46; P = 0.659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34.7 versus 39.5 per cent; major 3.3 versus 3.4 per cent; P = 0.110).Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients