Long-term outcomes of elderly patients with peritoneal metastases of colorectal origin after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) were reportedly safe for the elderly. However, long-term survival data in this subgroup of patients are scarce. Our aim was to evaluate the peri-operative and long-term outcomes of CRS + HIPEC in colorectal peritoneal metastases (CRC-PM) in patients ≥70 years of age. MATERIAL AND METHODS: We retrospectively analyzed our combined institutional databases for patients who underwent CRS + HIPEC for CRC-PM. Clinical and pathological characteristics, as well as overall survival (OS) and progression-free survival (PFS) were compared between the groups. Tumor extent was measured by the peritoneal carcinomatosis index (PCI) and completeness of cytoreduction by the CCR score. Major morbidity was defined according to Clavien-Dindo classification. RESULTS: The dataset of 159 patients included 33 elderly and 126 non-elderly patients. Clinical characteristics between the groups differed only in medical comorbidities (Charlson comorbidity index 10 vs. 7, P < 0.001) and delivery of post-HIPEC adjuvant treatment (12.5% vs. 43.8%, P = 0.004). Overall PCI and CCR0 rates were similar between the groups, as were length of stay and major morbidity and mortality rates. Long-term outcomes in the elderly group were lower than those of the non-elderly (median OS: 21.8 vs. 40.5 months, P < 0.001; median PFS: 6 vs. 8 months, P = 0.02, respectively). CONCLUSIONS: CRS + HIPEC in selected elderly patients can be safe in terms of postoperative morbidity and mortality. However, despite the same surgical extents and radicality, their long-term outcomes are inferior, possibly due to under-usage of systemic chemotherapy.

The efficiency of MarginProbe in detecting positive resection margins in epithelial breast cancer following breast conserving surgery.

INTRODUCTION: Up to 30% of patients undergoing lumpectomy for breast cancer are in need for re-excision due to either close or involved margins. We evaluated the yield of Margin Probe© (MP; Dilon Technologies, USA) in a cohort of patients undergoing lumpectomy for both palpable and non-palpable tumors. METHODS: Following lumpectomy, margins were evaluated with MP and readings were compared to the lumpectomies' pathological evaluation irrespective of whether additional margins were removed during surgery. Involved margins or the presence of DCIS within 1 mm of the resection margins were considered as positive margins. RESULTS: 48 patients with 51 tumors underwent lumpectomy. Thirteen of the 51 lumpectomies had pathological close or involved margins. MP identified 3 out of the 13 positive margins. False-positive readings were recorded in 97 out of 287 margins. The sensitivity, specificity, positive predictive value and negative predictive value were 23.1% (95%CI 5.0% 53.8%), 66.4% (95%CI 60.7%-71.9%), 3% (95%CI 0.6%-8.5%), and 95.1% (95%CI 91.1%-97.6%) respectively. CONCLUSIONS: MP cancer detection rate is relatively low while high false-positive rate leads to unnecessary shavings in almost all patients. Evaluation of MP performance should be based on comparing MP read to pathology report.

Lymph Node Metastases from Visceral Peritoneal Colorectal Metastases are Associated with Systemic Recurrence.

BACKGROUND: Visceral peritoneal colorectal metastases (VPCMs) may further metastasize to lymph nodes that drain those organs. The rate of lymph node metastases (LNMs) from VPCMs and their clinical and prognostic significance are unknown. METHODS: This study retrospectively analyzed the authors' institutional databases of 160 patients with peritoneal colorectal metastases who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Patients with LNM-VPCM (n = 12) were identified by pathologic reports, and both their short- and long-term outcomes were compared with those of patients without LNM-VPCM. RESULTS: The clinical presentation and primary tumor pathologic characteristics did not differ between the two groups. The patients with LNM-VPCM had a higher tumor burden (measured by the peritoneal carcinomatosis index [PCI]) and visible remnant disease compared with those who had no LNM-VPI (10 vs 5.5 [p = 0.03] vs 33.3% vs 6.8% [p = 0.007], respectively). The postoperative outcomes also were comparable. The patients with LNM-VPCM had a shorter overall survival (OS) than those without LNM-VPCM (median OS, 22.5 months; 95% confidence interval [CI], 15.1-29.9 months vs 40.1 months; 95% CI, 38.1-42 months; p = 0.02). However, only tumor grade and PCI were predictors of OS in the multivariate analysis (hazard ratio [HR], 2.33 [p = 0.001]; 1.77 [p = 0.03], respectively). The study showed that LNM-VPCM was associated with systemic but not peritoneal recurrence compared with non-LNM-VPCM (81.8% vs 51.6% for systemic recurrence, respectively; p = 0.05). CONCLUSION: The small distinct group of patients defined by LNM-VPCM were prone to systemic recurrence. Given its correlation with systemic recurrence, LNM-VPCM may indicate the need for adjuvant treatment.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from colorectal cancer: The prognostic impact of baseline neutrophil-lymphocyte, platelet-lymphocyte and lymphocyte-monocyte ratios.

PURPOSE: In this retrospective analysis we sought to determine if the preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR) were predictive of both operability and survival in those patients presenting with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) who underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: Analysis included all patients admitted between 2009 and 2017 with PC from CRC who were treated with curative intent by CRS-Mitomycin C-HIPEC. Patients were assessed pre- and intra-operatively by the PC index (PCI) and by a completeness of cytoreduction (CC) score with calculation of Kaplan-Meier survival curves and multivariate analysis of prognostic factors. Discrimination was made for NLR >3.5, PLR >168.8 and LMR >4.4. RESULTS: We identified 98 CRC patients undergoing 105 CRS-HIPEC procedures. There were no associations detected between NLR/PLR/LMR and the rates of incomplete or abandoned CRS cases. Overall survival (OS) after CRS-HIPEC was worse with high versus low NLR (19.9 mths vs. 45.7 mths, respectively; P = 0.009) and also with low versus high LMR (27.1 mths vs. 53.2 mths, respectively; P = 0.01). On multivariate analysis, a low LMR (P = 0.008), the preoperative CT PCI value (P = 0.004), poor tumor differentiation (P = 0.023) and the preoperative CEA level (P < 0.001) were all independent variables associated with a worse OS after surgery. CONCLUSIONS: The baseline LMR value may have potential value as a selection tool for CRS-HIPEC in patients with CRC-related PC.

Breast Cancer in Men: A Single Center Experience Over a Period of 22 years.

BACKGROUND: Male breast cancer (MBC) is a rare disease that is poorly understood. Treatment protocols are widely extrapolated from breast cancer in women. OBJECTIVES: To review the experience with MBC of a single center in Israel over a period of 22 years. METHODS: This single center retrospective study evaluated all patients diagnosed with MBC over a period of 22 years (1993-2015). Data were extracted from patient medical charts and included demographics, clinical, surgical, and oncological outcomes. RESULTS: The study comprised 49 patients. Mean age at diagnosis was 64.1 ± 13.5 years. The majority were diagnosed at early stages (1A-2A) (54.4%), 30.6% were stage 3B mostly due to direct skin and nipple involvement, and 59.2% of the patients had node negative disease. All of the patients were diagnosed with invasive ductal carcinoma and 30.6% had concomitant ductal carcinoma in situ. Estrogen receptor (ER) status was predominantly positive and luminal B (HER2-) was the most common subtype. Of the patients, 18.4% were BRCA carriers. The majority of patients underwent mastectomy. Radiotherapy was delivered to 46.9% and hormonal therapy to 89.8%. Chemotherapy was administered to 42.9%. Overall survival was 79.6% with a median survival of 60.1 (2-178) months; 5- and 10-year survival was 93.9% and 79.6%, respectively. Progesterone receptor (PR)-negative patients had a significantly improved overall survival. CONCLUSIONS: MBC has increasing incidence. PR-negative status was associated with better overall survival and disease-free interval. Indications to radiotherapy and hormonal therapy need standardization and will benefit from prospective randomized control trials.

Value of Routine Colonic Evaluation Prior To Ileostomy Closure.

BACKGROUND: Evaluation of low rectal anastomosis is often recommended prior to ostomy closure, but the efficacy of such evaluations is uncertain. OBJECTIVES: To assess whether routine colonic preoperative evaluation has an effect on postoperative ileostomy closure results. METHODS: We performed a retrospective study evaluating all patients who underwent ileostomy closure over 9 years. Patient demographics, clinical, surgical details, and surgical outcomes were recorded and analyzed. RESULTS: The study comprised 116 patients who underwent ileostomy closure, of them 65 were male (56%) with a mean age of 61 years (range 20-91). Overall, 98 patients (84.4%) underwent colonic preoperative evaluation prior to ileostomy closure. A contrast enema was performed on 61 patients (62.2%). Abnormal preoperative results were observed in 12 patients (12.2%). The overall complication rate was 35.3% (41 patients). No differences in postoperative outcome was observed in patient gender (P = 1), age (P = 0.96), body mass index (P = 0.24), American Society of Anesthesiologists score (P = 0.21), and the Charlson Comorbidity Index score (P = 0.93). Among patients who had postoperative complications, we did not observe a difference between patients who underwent preoperative evaluation compared to those who did not (P = 0.42). No differences were observed among patients with preoperative findings interpreted as normal or abnormal (P = 1). The time difference between ileostomy creation and closure had no effect on the ileostomy closure outcome (P = 0.34). CONCLUSIONS: Abnormal findings in preoperative colonic evaluation prior to ileostomy closure were not associated with worse postoperative outcome.

[CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY FOR PERITONEAL CARCINOMATOSIS OF COLORECTAL ORIGIN - FIRST 100 CASES].

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an effective treatment for selected patients with peritoneal carcinomatosis of colorectal origin. We present our experience with the first 100 consecutive cases of this combined treatment. METHODS: CRS/HIPEC procedures were performed between 4/2009-8/2016. HIPEC was initially delivered using the "Open" abdomen technique; beginning in January 2014, HIPEC was delivered using the "Closed" technique. As a chemotherapeutic agent we used Mitomycin-C, perfused for duration of 90 minutes at 41 degrees Celsius. RESULTS: A total of 100 procedures were performed in 94 patients (64% females, median age 62 (22-83) years) with colon (n=89) or rectal (n=5) cancer. Complete cytoreduction (CC score≤1) was achieved in 91 procedures. The average duration of surgery was 7.5±2.3 hours, the median number of organs resected was 2 (0-6) and the median length of hospital stay was 9 (5-101) days. Postoperative complications occurred in 54% of procedures and the incidence of major complications (Clavien-Dindo 3-4) was 12%. Three patients (3%) died within 90 days postoperatively. Higher peritoneal cancer index (PCI) score, higher number of organs resected/anastomoses created and longer duration of surgery were associated with perioperative morbidity (all p≤0.05). The median follow-up period was 2.1 years during which 50 patients died. The median overall survival (OS) and disease free survival were 3.1 years and 10.7 months, respectively; 7 patients survived ≥5 years after surgery. Higher PCI score and occurrence of major postoperative complications were associated with poorer OS. CONCLUSIONS: CRS/HIPEC for peritoneal carcinomatosis of colorectal cancer origin is feasible and safe. This treatment may benefit selected patients in terms of OS.

Treatment of Peritoneal Surface Malignancies with Cytoreductive Surgery and Hyperthermic Intra-peritoneal Chemotherapy (HIPEC): Experience in Israel.

The treatment of peritoneal surface malignancies, either primary or secondary (peritoneal metastasis), has evolved over the past two decades. A nihilistic approach of incurable "carcinomatosis" is changing into treatment of peritoneal metastasis with curative intent. The aim of the present study is to review the current practice, past history, and future of peritoneal surface oncology in Israel. A systematic review of all patients treated in institutions performing cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC) for the treatment of peritoneal surface malignancies. Each center provided the following data: start year, number of total cases, number of cases performed in 2017, and the method used (open vs. closed technique). Between 1990 and 2018, there were 1462 patients treated by CRS/HIPEC in Israel by eight different surgical groups in six medical centers. Currently, there are seven surgical groups in six medical centers routinely performing CRS/HIPEC. The annual rate of CRS/HIPEC was 171 cases in 2017 with a range of (4-69 cases/center). This is the first step of establishing an Israeli Peritoneal Surface Oncology Group that will have joined database and perform clinical trials in this challenging field of surgical oncology.

Perineal Stapled Rectal Prolapse Resection in Elderly Patients: Long-term Follow-up.

BACKGROUND: Full-thickness rectal prolapse has a significant negative impact on quality of life. The therapeutic options, specifically in elderly patients, are imperfect. Perineal stapled rectal prolapse resection is a novel operation for treating external rectal prolapse. Long-term follow-up following this procedure is lacking. In our study, we report a long-term follow-up of 30 patients, analyzing the long-term recurrence rate, morbidity, and functional outcome. OBJECTIVE: This study aimed to examine the long-term results of perineal stapled rectal resection in a population unfit for prolonged general anesthesia. DESIGN: This was a cohort study with a prospective follow-up. SETTINGS: This study was conducted at a single tertiary referral center. PATIENTS: Patients undergoing perineal stapled rectal resection from January 2010 to June 2013 were included. INTERVENTIONS: Perineal stapled rectal prolapse resection was performed. MAIN OUTCOME MEASURES: The primary outcome measured was prolapse recurrence. RESULTS: A total of 30 patients underwent the surgical intervention. The median follow-up period was 61 months (range, 37-65). No intraoperative or postoperative complications occurred. Six patients (20%) had recurrent rectal prolapse, and continence was not achieved in any of the patients. Two patients who had recurrence underwent a redo perineal stapled rectal resection. LIMITATIONS: This study was limited by the small cohort of selected patients. CONCLUSIONS: Frail patients that can only endure a short procedure under regional anesthesia should be considered for perineal stapled rectal prolapse resection. The lack of mortality and morbidity, specifically in this population, along with the low long-term recurrence rates, make this a favorable surgical alternative. See Video Abstract at http://links.lww.com/DCR/A745.

Hospital readmission rates and risk factors for readmission following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal surface malignancies.

BACKGROUND: Cytoreductive surgery and Hyperthermic intra-peritoneal chemotherapy (CRS/HIPEC) for peritoneal surface malignancies is associated with high morbidity. The increased numbers of patients undergoing CRS/HIPEC in recent years mandates risk analysis and quality assurance. However, only scarce data exist regarding causative parameters for readmission. The aim of this study was to assess readmission rates and risk factors associated with readmission. METHODS: A retrospective-cohort study including patients from two high-volume centers who underwent CRS/HIPEC surgery between the years 2007-2016 was performed. Patients' demographics, peri-operative data and readmission rates were recorded. RESULTS: 223 patients were included in the study. The 7 and 30-day readmission rates were 3.5% (n = 8) and 11% (n = 25), respectively. Late readmission rates (up to 90 days) were 11% (n = 25). The most common causes of readmission were surgical related infections (35%), small bowel obstruction (17.5%) and dehydration (14%). Post-operative complications were associated with higher readmission rates (p = 0.0001). PCI score was not associated with higher rates of readmission. CONCLUSION: Readmissions following CRS/HIPEC occur mainly due to infectious complications and dehydrations. Patients following CRS/HIPEC should be discharged after careful investigation to a community based continuing care with access for IV fluid replacement or antibiotics administration when required.

Mammographic Breast Density as a Predictor of Radiological Findings Requiring Further Investigation.

BACKGROUND: High density breast mammography has been associated with a greater risk for breast cancer and an increased likelihood of false negative results. OBJECTIVES: To assess whether the degree of mammographic breast density correlates with increased risk for the presence of radiographic findings requiring further histological investigation. METHODS: Included in the study were 2760 consecutive screening mammograms performed in a large volume, early detection mammography unit. All mammograms were complemented by high resolution ultrasound and interpreted by a single expert radiologist. Breast density (BD) was evaluated using a semi-quantitative 5 grade scale and grouped into low breast density (LBD) and high breast density (HBD) mammograms. Demographic and all relevant obstetric, personal and family history of breast cancer data were recorded. RESULTS: Of the 2760 mammograms 2096 (76%) were LBD and 664 (24%) were HBD. Mean age of the LBD and HBD groups was 59 ± 10.5 and 50.9 ± 9.3 years respectively (P = 0001). Breast density significantly correlated with presence of mammographic findings requiring further histological assessment (8.7% and 12.3% for LBD and HBD respectively, P < 0.01). In women younger than 60 years in whom histological assessment was required due to these findings, malignant pathology was significantly more prevalent in the HBD group (2.3% and 4.1% respectively, P = 0.03). Age, parity, patient history and HBD were identified as independent risk factors for any pathological mammographic finding. CONCLUSIONS: Highly dense mammography, aside from being an indicator of higher risk for breast cancer, appears to be associated with a significantly higher incidence of findings that will prompt further investigation to achieve a definite diagnosis.

Volvulus and bowel obstruction in ATR-X syndrome-clinical report and review of literature.

Alpha thalassemia-mental retardation, X-linked (ATR-X) syndrome is a rare genetic disorder with a variety of clinical manifestations. Gastrointestinal symptoms described in this syndrome include difficulties in feeding, regurgitation and vomiting which may lead to aspiration pneumonia, abdominal pain, distention, and constipation. We present a 19-year-old male diagnosed with ATR-X syndrome, who suffered from recurrent colonic volvulus that ultimately led to bowel necrosis with severe septic shock requiring emergent surgical intervention. During 1 year, the patient was readmitted four times due to poor oral intake, dehydration and abdominal distention. Investigation revealed partial small bowel volvulus which resolved with non-operative treatment. Small and large bowel volvulus are uncommon and life-threatening gastrointestinal manifestations of ATR-X patients, which may contribute to the common phenomenon of prolonged food refusal in these patients.

Locoregional disease patterns in well-differentiated and dedifferentiated retroperitoneal liposarcoma: implications for the extent of resection?

BACKGROUND: Well-differentiated (WD)/dedifferentiated (DD) liposarcoma is the most common soft tissue sarcoma of the retroperitoneum. The frequency of distant metastasis is low and the major burden of disease is locoregional. We sought to define the patterns of locoregional disease to help guide surgical decision making. METHODS: Data were collected from 247 patients with de novo or recurrent tumors treated at our institution from 1993 to early 2012. The number and location of tumors at both initial presentation and subsequent locoregional recurrence were determined by combined analysis of operative dictations and radiologic imaging. RESULTS: Thirty-four percent of patients had multifocal locoregional disease (two or more tumors) at initial presentation to our institution, including 9 % who had tumors at synchronous remote retroperitoneal sites. The impact of multifocal disease on overall survival was dependent on histologic subtype (WD vs. DD) and disease presentation (de novo vs. recurrence) at the time of resection. Among patients with initial unifocal disease, 57 % progressed to multifocal locoregional disease with subsequent recurrence, including 11 % with new tumors outside of the original resection field. No clinicopathologic or treatment-related variable, including the type or extent of resection, was predictive of either multifocal or 'outside field' progression. CONCLUSIONS: Multifocal disease is common in patients with WD/DD retroperitoneal liposarcoma, and tumors can also develop at remote, locoregional sites. Surgical resection remains the primary method of locoregional control in this disease; however, the aggressiveness of resection should be individualized, with consideration of both tumor and patient-related factors.

Impact of surgical extent and sex on the hepatic metastasis of colon cancer.

PURPOSE: Extensive oncological surgeries were previously suggested to increase cancer recurrence rates. We herein studied the impact of different surgical procedures and sex on colorectal cancer liver metastasis, employing several tumor inoculation approaches in BALB/c mice. METHODS: Experimental hepatic metastases of the syngeneic CT26 colorectal cancer line were induced either by intra-portal inoculation or intra-splenic inoculation, employing different tumor loads. Following intra-splenic inoculation, the entire spleen or an injected hemi-spleen was removed. Additionally, the magnitude of the surgical trauma accompanying the injection procedure was manipulated. RESULTS: Increasing the surgical trauma by adding laparotomy or extending the length of the surgery and hypothermia did not significantly affect the number of liver metastases or liver weight for any of the injection methods and tumor loads. The development of metastasis was significantly greater in males than in females under all conditions studied--a difference not explained by the direct effects of sex hormones on in vitro CT26 proliferation or vitality. CONCLUSION: Concurring with less controlled clinical observations, the surgical extensiveness did not significantly affect CT26 hepatic metastasis, potentially due to a ceiling effect of the surgical trauma on the metastatic process. The sexual dimorphism observed for the CT26 metastasis should be investigated in the context of surgical stress and considering anti-CT26 immunoreactivity.

Localized and metastatic myxoid/round cell liposarcoma: clinical and molecular observations.

BACKGROUND: Myxoid liposarcoma (MLPS), a disease especially of young adults with potential for local recurrence and metastasis, currently lacks solid prognostic factors and therapeutic targets. The authors of this report evaluated the natural history and outcome of patients with MLPS and commonly deregulated protein biomarkers. METHODS: Medical records were retrospectively reviewed for patients who presented to the authors' institution with localized (n = 207) or metastatic (n = 61) MLPS (1990 to 2010). A tissue microarray of MLPS patient specimens (n = 169) was constructed for immunohistochemical analysis of molecular markers. RESULTS: The 5-year and 10-year disease-specific survival rates among patients with localized disease were 93% and 87%, respectively; male gender, age >45 years, and recurrent tumor predicted poor outcome. The local recurrence rate was 7.4%, and the risk of local recurrence was associated with recurrent tumors and nonextremity disease location. Male gender was the main risk factor for metastatic disease, which occurred in 13% of patients. Forty percent of patients who had localized disease received chemotherapy, mostly in the neoadjuvant setting. Immunohistochemical analysis revealed significantly higher expression of C-X-C chemokine receptor type 4 (CXCR4) and platelet-derived growth factor beta (PDGFR-ß) in metastatic lesions versus localized lesions. Tumors with a round cell phenotype expressed increased levels of CXCR4, p53, adipophilin, PDGFR-α, PDGFR-ß, and vascular endothelial growth factor relative to myxoid phenotype. Only the receptor tyrosine kinase encoded by the AXL gene (AXL) was identified as a prognosticator of disease-specific survival in univariate analysis. CONCLUSIONS: In this study, the authors identified clinical and molecular outcome prognosticators for patients with MLPS as well as several potential therapeutic targets.

Long-term outcomes in patients with radiation-associated angiosarcomas of the breast following surgery and radiotherapy for breast cancer.

BACKGROUND: Radiation-associated angiosarcoma (RAAS) is a devastating disease occasionally observed in breast cancer patients treated with radiation. Due to its rarity, our knowledge-of disease risk factors, epidemiology, treatment, and outcome-is extremely limited. Therefore, we sought to identify clinicopathologic factors associated with local and distant recurrence and disease-specific survival (DSS). METHODS: Radiation-associated angiosarcoma was defined as pathologically confirmed breast or chest wall angiosarcoma arising within a previously irradiated field. A comprehensive search of our institutional tumor registry (1/1/93 through 2/28/11) was used to identify patients (n = 95 females). Patient, original tumor, RAAS treatment, and outcome variables were retrospectively retrieved and assembled into a database. RESULTS: The median follow-up for all RAAS patients was 10.3 (range, 2.4-31.8) years. The latency period following radiation exposure ranged from 1.4 to 26 (median, 7) years. One-year and 5-year DSS rates were 93.5 and 62.6 %, respectively. Reduced risk of local recurrence was observed in patients who received chemotherapy (P = 0.0003). In multivariable analysis, size was found to be an independent predictor of adverse outcome (P = 0.015). CONCLUSIONS: Our study demonstrates that RAAS exhibits high recurrence rates. It also highlights the need for well-designed, multicenter, clinical trials to inform the true utility of chemotherapy in this disease.

Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors.

There is a critical need for efficacious therapeutic strategies to improve the outcome of patients afflicted by malignant peripheral nerve sheath tumors (MPNST). Multiple lines of evidence suggest a role for deregulated phosphoinositide 3-kinase (PI3K)/mTOR signaling in MPNST, making this axis an attractive target for therapeutic manipulation. On the basis of previous observations obtained from in vitro experimentation, here we aimed to assess the effects of PI3K/mTOR blockade on MPNST growth in vivo. The anti-MPNST impact of XL765, a dual PI3K/mTOR inhibitor currently being evaluated in human cancer clinical trials, was tested in two human MPNST xenograft models (STS26T and MPNST724) and an experimental model of pulmonary metastasis (STS26T). XL765 abrogated human MPNST local and metastatic growth in severe combined immunodeficient mice. Notably, this therapeutic approach failed to induce apoptosis in MPNST cells but rather resulted in marked productive autophagy. Importantly, genetic and pharmacologic autophagy blockade reversed apoptotic resistance and resulted in significant PI3K/mTOR inhibition-induced MPNST cell death. The addition of the autophagy inhibitor, chloroquine, to the therapeutic regimen of MPNST xenografts after pretreatment with XL765 resulted in superior antitumor effects as compared with either agent alone. Together, preclinical studies described here expand our previous findings and suggest that PI3K/mTOR inhibition alone and (most importantly) in combination with autophagy blockade may comprise a novel and efficacious therapy for patients harboring MPNST.

Perioperative polyphenon E, a green tea extract, does not affect the wound complication rate in mice after sham laparotomy yet has an inhibitory effect on wound healing.

INTRODUCTION: Major surgery is associated with physiologic alterations that may promote tumor growth, and catechins in green tea may inhibit tumor growth. This study's aim was to assess the impact of a green tea extract on laparotomy wound healing in mice. METHODS: Mice were randomized to daily oral catechins solution (n = 25) or placebo (n = 20), underwent sham laparotomy after 10 days, and were sacrificed on postoperative day 7 or 21. The peak force and total energy required to rupture the abdominal wall wound, wound collagen content, and histology were assessed. RESULTS: There were no wound complications in either group, and mean peak wound rupture forces and collagen concentration were similar. Mean energy was lower and more fibroblast proliferation was found in the treatment group on postoperative day 21. CONCLUSIONS: These results suggest that catechins has only mild clinically significant adverse effect on wound healing, and its perioperative use warrants further study.

MiR-155 is a liposarcoma oncogene that targets casein kinase-1α and enhances ß-catenin signaling.

Liposarcoma can be an aggressive, debilitating, and fatal malignancy. In this study, we identifed miRNAs associated with the differentiation status of liposarcoma to gain insight into the basis for its progression. miRNA expression profiles determined in human tumors and normal fat specimens identified a dedifferentiated tumor expression signature consisting of 35 miRNAs. Deregulated miRNA expression was confirmed in a second independent sample cohort. The miR-155 was the most overexpressed miRNA and functional investigations assigned an important role in the growth of dedifferentiated liposarcoma cell lines. Transient or stable knockdown of miR-155 retarded tumor cell growth, decreased colony formation, and induced G(1)-S cell-cycle arrest in vitro and blocked tumor growth in murine xenografts in vivo. We identified casein kinase 1α (CK1α) as a direct target of miR-155 control which enhanced ß-catenin signaling and cyclin D1 expression, promoting tumor cell growth. In summary, our results point to important functions for miR-155 and ß-catenin signaling in progression of liposarcoma, revealing mechanistic vulnerabilities that might be exploited for both prognostic and therapeutic purposes.