Ketogenic diets consumed during radio-chemotherapy have beneficial effects on quality of life and metabolic health in patients with rectal cancer.

PURPOSE: Interest in ketogenic diets (KDs) as complementary nutritional treatments for cancer patients is rising, although some skepticism about their safety exists. We, therefore, studied the effects of KDs on quality of life and blood parameters in rectal cancer patients undergoing radio-chemotherapy. METHODS: EORTC-QLQ30 questionnaire scores and different metabolic and hormonal blood parameters were obtained prior to, in the middle of and at the end of radiotherapy within the KETOCOMP study (ClinicalTrials.gov Identifier: NCT02516501). A total of 18 patients consuming a KD were compared to 23 patients consuming their standard diet (SD). Baseline-end differences were measured using Wilcoxon tests, and repeated measures analysis was performed using linear mixed effects models. RESULTS: Eighty-nine percent of patients on the KD reported subjectively feeling good or very good, but roughly half of them rated the daily routine implementation as difficult. Only the SD group experienced significant declines in physical and role functioning, while the KD group improved in role (p = 0.045), emotional (p = 0.018) and social functioning (p = 0.009).Urinary frequency, buttock pain and fatigue significantly increased in the SD group, but to a much lesser extent in the KD group. Several biomarkers of metabolic health (gamma-glutamyl-transpeptidase, triglyceride-glucose index, HDL cholesterol/triglyceride ratio, and free T3) improved in the KD, but not the SD group. CONCLUSIONS: Despite being perceived as difficult to implement by ≈50% of patients, KDs are feasible as complementary therapies alongside radio-chemotherapy and associated with subjective well-being. The hypothesis that they exert beneficial effects on quality of life and metabolic health in rectal cancer patients is supported by our data. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02516501, registered Aug 6th 2015.

Impact of a ketogenic diet intervention during radiotherapy on body composition: IV. Final results of the KETOCOMP study for rectal cancer patients.

BACKGROUND & AIMS: Obesity and low muscle mass are associated with worse outcomes of colorectal cancer patients. We conducted a controlled trial to study the impact of a ketogenic diet (KD) based on natural foods versus an unspecified standard diet (SD) on body composition in rectal cancer patients undergoing radiotherapy. METHODS: Patients with non-metastasized rectal cancer were allocated to either the KD (N = 24) or the SD (N = 25) group during radiotherapy. Body composition was measured weekly by bioimpedance analysis and analyzed using linear mixed effects models. Pathologic response in patients undergoing neoadjuvant treatment was evaluated at the time of surgery. RESULTS: A total of 18 KD and 23 SD patients completed the study and were eligible for analysis. The SD group experienced no noteworthy changes in any body composition parameter. In contrast, patients in the KD group lost significant amounts of body weight and fat mass, averaging 0.5 and 0.65 kg/week (p < 0.0001). There was a rapid loss of intracellular water consistent with initial intramuscular glycogen and water depletion, but skeletal muscle tissue was conserved. Pathological tumor responses were somewhat greater in the KD group, with a larger mean Dworak regression grade (p = 0.072) and larger percentage of near-complete (yT0N0 or yT1N1) responses (43 versus 15%, p = 0.116) that almost reached statistical significance in intention-to-treat analysis (50% versus 14%, p = 0.018). CONCLUSIONS: In rectal cancer patients undergoing curative radiotherapy, a KD significantly reduced body weight and fat mass while preserving skeletal muscle mass. We could demonstrate a trend for KDs contributing synergistically to pathological tumor response, a finding in line with preclinical data that warrants future confirmation in larger studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02516501, registered on August 06, 2015.

Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases.

BACKGROUND: The local and systemic activation and regulation of the immune system by malignant cells during carcinogenesis is highly complex with involvement of the innate and acquired immune system. Despite the fact that malignant cells do have antigenic properties their immunogenic effects are minor suggesting tumor induced mechanisms to circumvent cancer immunosurveillance. The aim of this study is the analysis of tumor immune escape mechanisms in a colorectal liver metastases mouse model at different points in time during tumor growth. METHODS: CT26.WT murine colon carcinoma cells were injected intraportally in Balb/c mice after median laparotomy using a standardized injection technique. Metastatic tumor growth in the liver was examined by standard histological procedures at defined points in time during metastatic growth. Liver tissue with metastases was additionally analyzed for cytokines, T cell markers and Fas/Fas-L expression using immunohistochemistry, immunofluorescence and RT-PCR. Comparisons were performed by analysis of variance or paired and unpaired t test when appropriate. RESULTS: Intraportal injection of colon carcinoma cells resulted in a gradual and time dependent metastatic growth. T cells of regulatory phenotype (CD4+CD25+Foxp3+) which might play a role in protumoral immune response were found to infiltrate peritumoral tissue increasingly during carcinogenesis. Expression of cytokines IL-10, TGF-beta and TNF-alpha were increased during tumor growth whereas IFN-gamma showed a decrease of the expression from day 10 on following an initial increase. Moreover, liver metastases of murine colon carcinoma show an up-regulation of FAS-L on tumor cell surface with a decreased expression of FAS from day 10 on. CD8+ T cells express FAS and show an increased rate of apoptosis at perimetastatic location. CONCLUSIONS: This study describes cellular and macromolecular changes contributing to immunological escape mechanisms during metastatic growth in a colorectal liver metastases mouse model simulating the situation in human cancer.

Regulatory allospecific T cell clones abrogate chronic allograft rejection.

True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig-treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4+CD25+Foxp3+ cells and strong mononuclear cell staining for IL-10 but negligible IFN-gamma, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.

The intraportal injection model: a practical animal model for hepatic metastases and tumor cell dissemination in human colon cancer.

BACKGROUND: The development of new therapeutic strategies for treatment of metastasized colorectal carcinoma requires biologically relevant and adequate animal models that generate both reproducible metastasis and the dissemination of tumor cells in the form of so-called minimal residual disease (MRD), an expression of the systemic character of neoplastic disease. METHODS: We injected immunoincompetent nude mice intraportally with different numbers (1 x 10(5), 1 x 10(6) and 5 x 10(6) cells) of the human colon carcinoma cell lines HT-29 and SW-620 and investigated by histological studies and CK-20 RT-PCR the occurrence of hematogenous metastases and the dissemination of human tumor cells in bone marrow. RESULTS: Only the injection of 1 x 10(6) cells of each colon carcinoma cell line produced acceptable perioperative mortality with reproducible induction of hepatic metastases in up to 89% of all animals. The injection of 1 x 10(6) cells also generated tumor cell dissemination in the bone marrow in up to 63% of animals with hepatic metastases. CONCLUSION: The present intraportal injection model in immunoincompetent nude mice represents a biologically relevant and adequate animal model for the induction of both reproducible hepatic metastasis and tumor cell dissemination in the bone marrow as a sign of MRD.

Familial gastrointestinal stromal tumors caused by the novel KIT exon 17 germline mutation N822Y.

Gastrointestinal stromal tumors (GISTs) are most often associated with oncogenic mutations of the KIT gene resulting in activation of the tyrosine kinase receptor KIT. Familial GIST syndrome based on a hereditary predisposition to develop GIST owing to a germline mutation is exceedingly rare. We describe a kindred with familial GIST displaying a novel germline mutation in exon 17. Three siblings (2 females, 1 male; 42 to 49 y) underwent surgery for multiple intra-abdominal tumors within a 3-year period. Their father had been operated on for gastric and jejunal tumors 20 years previously. The GIST was confirmed by immunohistochemistry in each sibling. Tumor and blood samples of the family members were analyzed for mutations in KIT and platelet-derived growth factor receptor (PDGFRalpha) genes. All examined lesions were of spindle cell type with expression of CD117. The tumor material exhibited a novel point mutation in codon 822 in exon 17 resulting in the replacement of asparagine by tyrosine (N822Y). The same mutation was detected in the father's blood sample. One healthy brother of the 3 siblings showed a wild-type sequence of the KIT gene. The germline mutation in exon 17 of the KIT gene identified in this kindred is very different from previously reported mutations of the KIT gene in familial GIST. Although the penetrance of KIT mutations is as yet unknown, assessment of the unaffected kindred of GIST patients for the presence of this mutation could help to distinguish individuals at high risk from those at virtually no risk.

Short- and long-term results of laparoscopic gastric banding for morbid obesity.

BACKGROUND: Today, gastric banding has become a common bariatric procedure. Weight loss can be excellent, but is not sufficient in a significant proportion of patients. Few long-term studies have been published. We present our results after up to 9 years of follow-up. MATERIALS AND METHODS: One hundred twenty-seven patients (1997-2004) were analyzed retrospectively after laparoscopic gastric banding (perigastric technique: n = 60; pars flaccida technique: n = 67) in terms of preoperative characteristics, weight loss, comorbidities, short- and long-term complications, and quality of life. RESULTS: Median follow-up was 63 months (range 2-104). Incidence of postoperative complications were: gastric perforation in 3.1%, band erosion in 3.1%, band or port leak in 2.3%, port infection in 5.3%, port dislocation in 6.9%, and pouch dilatation in 16.9%. Total number of patients requiring reoperation was 34 (26.7%) [perigastric technique n = 23 (38.8%) versus pars flaccida technique n = 11 (16%), p = 0.039]. Mean excess body weight loss (%) was 50.6%. Most patients reported an increase in quality of life after surgery. CONCLUSIONS: Gastric banding is effective for achieving weight loss and improving comorbidity in obese patients. Obviously, gastric banding can be performed more safely with the pars flaccida technique, although the complication rate remains relatively high. Nevertheless, based on adequate patient selection, gastric banding should still be considered a valuable therapeutic option in bariatric surgery.

Spontaneous perforation of a nonaneurysmal infrarenal aorta.

Spontaneous perforation of a nonaneurysmal abdominal aorta due to a penetrating atherosclerotic ulcer (PAU) is exceedingly rare. We describe the case of a 57-year-old man with a perforating PAU of the infrarenal aortic wall and discuss the clinical presentation, diagnostic pathways, and therapeutic options based on a comprehensive review of the literature. Since a PAU of the aorta can give rise to chronic mild to moderate abdominal or back pain, a computed tomographic scan of the abdomen should be performed in patients with evidence of vascular disease and persistent abdominal or back discomfort. Surgical resection or stent-graft placement is indicated in symptomatic patients or in asymptomatic patients with radiographic signs of progressive PAU.

Comparative analysis of predictive biomarkers for therapeutical strategies in colorectal cancer.

BACKGROUND: Prognostic information regarding the risk of postoperative tumor recurrence defined by a profile of serological, morphological and/or molecular markers can have potential value, particularly for patients with colorectal carcinoma (CRC) of the International Union Against Cancer (UICC) stage II/III who may benefit from adjuvant chemotherapy after surgery. METHODS: A retrospective study of 783 patients with CRC (UICC I-III) including a subgroup analysis of 116 subjects was conducted to determine preoperative serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and p53 serum levels. In addition, protein and gene expression of p53, CEA, and adenomatous polyposis coli (APC) was assessed in the tumors of those patients. The values of all serological, morphological, and molecular parameters were correlated with clinicopathological characteristics for their predictive value of tumor recurrence over a mean follow-up period of 32 +/- 6.2 months. RESULTS: Serum CEA but not CA 19-9 or p53 was a significant prognostic factor for disease-free survival, along with UICC and T/N stage. When comparing elevated CEA, CA 19-9, and p53 serum levels with expression of the markers in the tumors, their overall expression was found to be 61.3% in the serum versus 93.5% in the tumor in analyzed patients (n = 116). In particular, all patients in UICC stages I-III who demonstrated at least three elevated markers (CEA/CA 19-9/p53) in serum and/or in the tumor presented with tumor recurrence/metastases. CONCLUSION: Overall increased p53, CEA, and CA 19-9 serum levels and their marker expression in the tumor may be used at the time of primary tumor removal for defining patients at risk for tumor recurrence.

Transfusion-related acute lung injury (TRALI)--an important, severe transfusion-related complication.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is an immune-mediated transfusion reaction that can cause severe complications or even death. It is now the leading cause of transfusion-related death in the United States. METHODS: The TRALI syndrome is presented in two cases in a surgical intensive care unit and discussed against the background of the present literature. In both cases, concomitant diseases led to an extremely difficult course of TRALI. CONCLUSIONS: Knowledge of the TRALI syndrome is necessary to enable early diagnosis and treatment. It should be taken into consideration at any time when cardiopulmonary instability occurs after transfusion of blood products, which is a frequent event on surgical Intensive Care Units. TRALI remains a clinical diagnosis supported by serologic studies if these are available. Against the background of this potentially life-threatening complication, every single indication to transfuse blood products needs to be scrutinized carefully.

Morbidity of temporary loop ileostomy in patients with colorectal cancer.

PURPOSE: This study was designed to quantify the temporary loop ileostomy-related morbidity in patients with colorectal cancer and contrast the morbidity rates after ileostomy closure before, during, and after the start of adjuvant therapy. METHODS: Between 1997 and 2004, 120 patients with colorectal carcinoma underwent colorectal resection and creation of a temporary loop ileostomy to protect the low anastomosis. Stoma-related complications and perioperative morbidity after ileostomy closure were assessed retrospectively by reviewing the medical records. RESULTS: Sixteen of the 120 patients (13.3 percent) suffered stoma-related complications, requiring early ileostomy closure in three. After ileostomy closure, anastomotic leakage of the ileoileostomy occurred in 3 of the 120 patients (2.5 percent), 2 of them died postoperatively (1.7 percent). The rate of minor complications (16.7 percent in all patients) was much higher in patients undergoing adjuvant chemotherapy or radiochemotherapy (25.5 percent) than in patients receiving no additional therapy (9.2 percent). In the former patients, there was a trend toward fewer complications when ileostomy closure was performed before (12.5 percent), rather than during (42.9 percent) or after (21.2 percent), the start of adjuvant therapy. CONCLUSIONS: The morbidity following closure of a temporary loop ileostomy in colorectal cancer patients is much higher in patients receiving adjuvant chemotherapy or radiochemotherapy. The morbidity, however, might possibly be lowered to the level of patients receiving no additional therapy if ileostomy closure is performed before the start of adjuvant therapy.

Feasibility and limits of an orthotopic human colon cancer model in nude mice.

We sought to develop an accurate colorectal cancer model in nude mice with stable local growth, tumor cell dissemination, and reproducible metastatic capacity. To this end, we orthotopically transplanted histologically intact human colorectal cancer tissue from 10 human patients into nude mice. After successful local tumor growth, tumor tissues were retransplanted as many as 9 times in serial passage. All specimens were transplanted using microsurgical techniques. Histologic, immunohistochemical, and polymerase chain reaction techniques were used to determine tumor growth rates and kinetics, development of regional lymph node and distant hepatic metastases, and the induction of minimal residual disease (MRD). Stable local tumor growth rates with variable growth kinetics were detected in 73.4% of all mice. The lymph node and hepatic metastasis rates were low, at 18.4% and 4.9%, respectively. MRD, as reflected by CK20 positivity of the bone marrow in animals with lymph node and hepatic metastases, was present in 22.2%. The orthotopic colorectal cancer model described here is feasible for the induction of reproducible local tumor growth but is limited by variable growth kinetics and the low rate of lymph node and hepatic metastases. Cytokeratin-positive cells indicative of MRD could be detected in the bone marrow of approximately 25% of the nude mice with metastases. The observed induction of MRD after orthotopic implantation of intact human colon cancer in animals with lymph node and hepatic metastases might be improved if established colon cancer cell lines were used.

T-cell response to p53 tumor-associated antigen in patients with colorectal carcinoma.

Despite the radical surgical resection performed in patients with colorectal carcinoma, there is a high rate of tumor recurrence. Over an observation period of 3 years, 18% of the patients in our collective suffered a tumor relapse with local or distinct metastases after initial R0-resection. Some evidence suggests that this may be due to suppression of anti-tumor responses, a phenomenon that might be attributed to regulatory T cells. The aim of our study was to investigate the tumor-specific immune response depending on the UICC stage of patients with colorectal cancer. The cellular immune responses against defined antigens that are overexpressed in most of the patients with colorectal cancer were characterized. For this purpose, the tumor suppressor gene, p53, was chosen as the tumor-associated antigen that exhibits mutations and overexpression in up to 60% of colorectal carcinoma. We observed that p53 induced both IFN-gamma and IL-10 secretion. The predominance of IL-10 production indicated that regulatory T cells directly participate in modulating the anti-tumor immune response. IL-10 levels in the blood as well as the expression of regulatory T-cell specific genes at the tumor site correlate with the UICC stage of the disease. These results may provide an explanation for the poor prognosis and increased recurrence rate in patients with advanced carcinoma.

Band erosion and passage, causing small bowel obstruction.

A rare complication of adjustable gastric banding is reported. A 65-year-old man developed recurrent vomiting, epigastric pain, and small-bowel obstruction 13 months after laparoscopic adjustable gastric banding for morbid obesity. Investigation revealed that the band had migrated completely into the gastric lumen and had passed far down the jejunum. The band was still connected by the tubing to the port chamber. By laparoscopy, the band was cut at the stomach, and removed via a jejunotomy. Postoperative course was uneventful. Complete band migration requires early removal of the band.

Mechanisms of tolerance induction after rat liver transplantation: intrahepatic CD4(+) T cells produce different cytokines during rejection and tolerance in response to stimulation.

Increasing evidence supports the existence of regulatory T cells that may inhibit the allogeneic immune response after transplantation by secreting regulatory cytokines. To determine whether rat liver tolerance is associated with intrahepatic regulatory T cells secreting a characteristic cytokine profile, we analyzed the cytokine production of freshly isolated intragraft CD4(+) T cells at different times postoperatively by semiquantitative reverse transcription-polymerase chain reaction and by enzyme-linked immunosorbent assay before and after in vitro stimulation. Orthotopic arterialized liver transplantation was performed in two allogeneic rat strain combinations, one with fatal acute rejection (DA-to-LEW) and one with long-lasting tolerance (LEW-to-DA) without immunosuppression despite a complete major histocompatibility complex mismatch (spontaneous liver tolerance). Liver allografts of both groups showed continuously increasing cellular infiltration between day 3 and day 7 after transplantation. In this inflammatory situation, very low levels of interleukin-13 were detectable directly after cell isolation, as well as after in vitro stimulation. However, after 30 days, intrahepatic CD4(+)T cells in the tolerance group were then able to express elevated messenger RNA levels of the anti-inflammatory cytokine interleukin-13 in response to stimulation. This result indicates the presence of an intragraft Th2-like CD4(+) T cell population, which may have a regulatory function in the induction of liver tolerance.