Neoplasms of the Appendix.

BACKGROUND: Neoplasms of the vermiform appendix are rare. They comprise a heterogeneous group of entities requiring differentkinds of treatment. METHODS: This review is based on publications retrieved by a selective literature search in the PubMed, Embase, and Cochranedatabases. RESULTS: 0.5% of all tumors of the gastrointestinal tract arise in the appendix. Their treatment depends on their histopathologicalclassification and tumor stage. The mucosal epithelium gives rise to adenomas, sessile serrated lesions, adenocarcinomas,goblet-cell adenocarcinomas, and mucinous neoplasms. Neuroendocrine neoplasms originate in neuroectodermal tissue. Adenomasof the appendix can usually be definitively treated by appendectomy. Mucinous neoplasms, depending on their tumorstage, may require additional cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC). Adeno -carcinomas and goblet-cell adenocarcinomas can metastasize via the lymphatic vessels and the bloodstream and should thereforebe treated by oncological right hemicolectomy. Approximately 80% of neuroendocrine tumors are less than 1 cm in diameterwhen diagnosed and can therefore be adequately treated by appendectomy; right hemicolectomy is recommended if the patienthas risk factors for metastasis via the lymphatic vessels. Systemic chemotherapy has not been shown to be beneficial forappendiceal neoplasms in prospective, randomized trials; it is recommended for adenocarcinomas and goblet-cell adenocarcinomasof stage III or higher, in analogy to the treatment of colorectal carcinoma.

Hypothalamic integrity is necessary for sustained weight loss after bariatric surgery: A prospective, cross-sectional study.

OBJECTIVE: The hypothalamus is the main integrator of peripheral and central signals in the control of energy homeostasis. Its functional relevance for the effectivity of bariatric surgery is not entirely elucidated. Studying the effects of bariatric surgery in patients with hypothalamic damage might provide insight. SUMMARY BACKGROUND DATA: Prospective study to analyze the effects of bariatric surgery in patients with hypothalamic obesity (HO) vs. matched patients with common obesity (CO) with and without bariatric surgery. METHODS: 65 participants were included (HO-surgery: n = 8, HO-control: n = 10, CO-surgery: n = 12, CO-control: n = 12, Lean-control: n = 23). Body weight, levels of anorexic hormones, gut microbiota, as well as subjective well-being/health status, eating behavior, and brain activity (via functional MRI) were evaluated. RESULTS: Patients with HO lost significantly less weight after bariatric surgery than CO-participants (total body weight loss %: 5.5 % vs. 26.2 %, p = 0.0004). After a mixed meal, satiety and abdominal fullness tended to be lowest in HO-surgery and did not correlate with levels of GLP-1 or PYY. Levels of PYY (11,151 ± 1667 pmol/l/h vs. 8099 ± 1235 pmol/l/h, p = 0.028) and GLP-1 (20,975 ± 2893 pmol/l/h vs. 13,060 ± 2357 pmol/l/h, p = 0.009) were significantly higher in the HO-surgery vs. CO-surgery group. Abundance of Enterobacteriaceae and Streptococcus was increased in feces of HO and CO after bariatric surgery. Comparing HO patients with lean-controls revealed an increased activation in insula and cerebellum to viewing high-caloric foods in left insula and cerebellum in fMRI. CONCLUSIONS: Hypothalamic integrity is necessary for the effectiveness of bariatric surgery in humans. Peripheral changes after bariatric surgery are not sufficient to induce satiety and long-term weight loss in patients with hypothalamic damage.

Prognostic impact of additive chemotherapy after curative resection of metachronous colorectal liver metastasis: a single-centre retrospective study.

BACKGROUND: A prognostic benefit of additive chemotherapy in patients following resection of metachronous colorectal liver metastases (CRLM) remains controversial. Therefore, the goal of this retrospective study was to investigate the impact of perioperative chemotherapy on disease-free survival (DFS) and overall survival (OS) of patients after curative resection of metachronous CRLM. METHODS: In a retrospective single-centre study, patients after curative resection of metachronous CRLM were included and analysed for DFS and OS with regard to the administration of additive chemotherapy. The Kaplan-Meier method was applied to compare DFS and OS while Cox regression models were used to identify independent prognostic variables. RESULTS: Thirty-four of 75 patients were treated with additive 5-FU based chemotherapy. OS was significantly prolonged in this patient subgroup (62 vs 57 months; p = 0.032). Additive chemotherapy significantly improved 10-year survival rates (42% vs 0%, p = 0.023), but not 5-year survival (58% vs 42%, p = 0.24). Multivariate analysis identified additive chemotherapy (p = 0.016, HR 0.44, 95% CI 0.23-0.86), more than five CRLM (p = 0.026, HR 2.46, 95% CI 1.16-10.32) and disease recurrence (0.009, HR 2.70, 95% CI 1.29-5.65) as independent risk factors for OS. CONCLUSION: Additive chemotherapy significantly prolonged OS and 10-year survival in patients after curative resection of metachronous CRLM. Randomized clinical trials are needed in the future to identify optimal chemotherapy regimens for those patients.

Discovery of indane propanamides as potent and selective TRPV1 antagonists.

A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase.

Patterns of Lymph Node Recurrence in Adrenocortical Carcinoma: Possible Implications for Primary Surgical Treatment.

BACKGROUND: In the surgical treatment of adrenocortical carcinoma (ACC), lymphadenectomy may improve oncologic outcome. However, patterns of metastatic lymphatic spread in ACC are unknown. METHODS: Clinical data of patients included in the European Network for the Study of Adrenal Tumors (ENSAT) registry were retrospectively reviewed. Inclusion criteria were: nonmetastatic ACC, complete resection of the primary tumor, a disease-free time of > 3 months, and lymph node metastases as the first disease relapse. The retroperitoneal lymphatic drainage area was evaluated by using follow-up imaging. RESULTS: Of 971 patients from the ENSAT registry, 56 patients were included. In left-sided ACC (n = 36), lymphatic recurrence was detected in the left renal hilum (50%), in the perirenal fat tissue cranial to the renal hilum (ventral, 47%; dorsal, 55%), para-aortic (47%), interaorto-caval (22%), and/or in the perirenal fat tissue caudal to the renal hilum (ventral, 20%; dorsal, 17%). In right-sided ACC (n = 20), lymph node metastases were detected in the perirenal fat tissue cranial to the renal hilum (dorsal, 55%; ventral, 45%), interaorto-caval (35%), in the area of the right renal artery (10%), and/or paracaval (15%). Patients with right-sided ACC showed left-paraaortic lymph node recurrences in 10% of cases. CONCLUSION: Metastatic lymphatic spread appears to be more extensive than previously thought. The distribution pattern of lymph node metastases described in our study could be used as a guide for a more extended lymph node dissection.

Antiproliferative and antimetabolic effects behind the anticancer property of fermented wheat germ extract.

BACKGROUND: Fermented wheat germ extract (FWGE) sold under the trade name Avemar exhibits anticancer activity in vitro and in vivo. Its mechanisms of action are divided into antiproliferative and antimetabolic effects. Its influcence on cancer cell metabolism needs further investigation. One objective of this study, therefore, was to further elucidate the antimetabolic action of FWGE. The anticancer compound 2,6-dimethoxy-1,4-benzoquinone (DMBQ) is the major bioactive compound in FWGE and is probably responsible for its anticancer activity. The second objective of this study was to compare the antiproliferative properties in vitro of FWGE and the DMBQ compound. METHODS: The IC50 values of FWGE were determined for nine human cancer cell lines after 24 h of culture. The DMBQ compound was used at a concentration of 24 µmol/l, which is equal to the molar concentration of DMBQ in FWGE. Cell viability, cell cycle, cellular redox state, glucose consumption, lactic acid production, cellular ATP levels, and the NADH/NAD(+) ratio were measured. RESULTS: The mean IC50 value of FWGE for the nine human cancer cell lines tested was 10 mg/ml. Both FWGE (10 mg/ml) and the DMBQ compound (24 µmol/l) induced massive cell damage within 24 h after starting treatment, with changes in the cellular redox state secondary to formation of intracellular reactive oxygen species. Unlike the DMBQ compound, which was only cytotoxic, FWGE exhibited cytostatic and growth delay effects in addition to cytotoxicity. Both cytostatic and growth delay effects were linked to impaired glucose utilization which influenced the cell cycle, cellular ATP levels, and the NADH/NAD(+) ratio. The growth delay effect in response to FWGE treatment led to induction of autophagy. CONCLUSIONS: FWGE and the DMBQ compound both induced oxidative stress-promoted cytotoxicity. In addition, FWGE exhibited cytostatic and growth delay effects associated with impaired glucose utilization which led to autophagy, a possible previously unknown mechanism behind the influence of FWGE on cancer cell metabolism.

Sphincter-sparing intersphincteric rectal resection as an alternative to proctectomy in long-standing fistulizing and stenotic Crohn's proctitis?

PURPOSE: Long-standing fistulizing and stenotic proctitis (LFSP) in Crohn's disease (CD) indicates the end stage of the disease. Definitive diversion such as proctectomy is considered to be the only surgical option. The impact of intersphincteric sphincter-sparing anterior rectal resection (IAR) as an alternative to proctectomy is unclear. The aim of this study was to evaluate feasibility, morbidity, outcome, and quality of life (QL) in patients with LFSP undergoing intended IAR. PATIENTS AND METHODS: Out of a single institution database, 15 patients with LFSP intended for surgery from 856 patients with CD were selected for follow-up analyses. RESULTS: In 12/15 cases, IAR was carried out while 3/15 patients underwent primary proctectomy due to malignancy (n = 2) or due to patient's wish (n = 1). In one case, IAR revealed unexpected malignancy, which led to secondary proctectomy. In patients with IAR, complete healing of fistulas and stenosis was observed in 46% (n = 5) while 36% (n = 4) of patients showed relapse of fistula and 18% (n = 2) developed restenosis. Ileostomy closure was performed in seven patients from which six patients remained stoma free. QL and fecal incontinence measured by standardized scoring systems were unchanged while stool frequency was reduced after IAR in patients with ileostomy closure. The rate of malignancy in this cohort was 20% (n = 3). CONCLUSION: LFSP in CD was associated with 20% of malignant transformation. Although IAR fails to improve QL, it is a suitable procedure for the treatment of fistulas and stenosis associated with acceptable healing rates and can avoid a permanent stoma.

Neurostimulated levator augmentation--a new approach in restoring continence.

PURPOSE: Restoration of continence remains a major challenge in patients after abdominoperineal rectal excision (APE) or with end-stage fecal incontinence. A new surgical technique, the neurostimulated levator augmentation, was introduced for pelvic floor augmentation using dynamic graciloplasty in order to restore anorectal angulation. The aim of this study was to assess feasibility and efficiency. METHODS: From November 2009 to March 2014, n = 17 patients underwent neurostimulated levator augmentation (n = 10 after APE, n = 5 intractable idiopathic fecal incontinence, n = 2 traumatic anal amputation). Gracilis muscle was transposed through the obturator foramen into the pelvic cavity, positioned in a U-shaped sling behind the rectum, fixed to the contralateral os pubis to restore anorectal angulation, and then conditioned by neurostimulation. Questionnaires analyzing function and quality of life were administered. RESULTS: For neurostimulated levator augmentation, four patients suffered from complications that needed operative intervention (n = 3 wound infection, n = 1 colon perforation); three pharmacological treatment and two complications needed no further invasive intervention. One patient died due to causes unrelated to the operation, and no complication required intensive care management. Fecal incontinence in patients with idiopathic incontinence improved significantly after surgery as well as incontinence episodes, urgency, and disease-specific quality of life through all dimensions. Generic quality of life was significantly better after surgery in all patients. After median follow-up of 17 months (2-45), all but one patient would undergo the procedure again. CONCLUSIONS: Neurostimulated levator augmentation was feasible in all patients with acceptable morbidity. It may represent a new therapeutic option in selected patients with intractable fecal incontinence.

Complete pathological remission of locally advanced, unresectable pancreatic cancer (LAPC) after intensified neoadjuvant chemotherapy.

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) has an extremely poor prognosis. Results of neoadjuvant (radio-)chemotherapy approaches aiming at achieving resectability are currently not satisfactory. CASE REPORT: We report the case of a 67-year-old woman with histologically confirmed pancreas carcinoma that was not resectable on first surgical exploration who achieved a well-documented complete pathological remission (pCR). The carcinoma became resectable after consecutive neoadjuvant treatment with nanoparticle albumin-bound (nab)-paclitaxel/gemcitabine and FOLFIRINOX chemotherapy regimens. CONCLUSION: This is the first reported LAPC case in which neoadjuvant chemotherapy alone has been shown to lead to demonstrated pCR. CA19-9 levels, but not imaging criteria, were useful for response prediction and timing of the Whipple's procedure. The findings in this case suggest possible conceptual changes in the treatment approach for LAPC, and indicate that the new effective chemotherapy regimens should be integrated into clinical trials for LAPC.

Hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis: role of heat shock proteins and dissecting effects of hyperthermia.

BACKGROUND: In patients with isolated peritoneal carcinomatosis (PC) of gastrointestinal cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. Heat shock proteins (HSP) seem to play a major role in cellular stress during HIPEC therapy. We analyzed differentially hyperthermic conditions and HSPs responsible for cell stress-mediated repair mechanisms in tumor tissues from patients who underwent HIPEC therapy and in an in vitro hyperthermic model. METHODS: Tumor tissues from our patient cohort with isolated PC were selected for further analysis when representative material was available before and after HIPEC therapy. To further dissect the role of HSPs under conditions of hyperthermia, gene and protein expression was additionally determined, together with cellular apoptosis and proliferation in human HT-29 colon cancer cells. RESULTS: Differently up-regulated HSP70/72 and HSP90 gene and protein expression was found in all investigated patient tumors. In vitro studies confirmed observations from clinical tumor analysis as underlying HSP-mediated cell stress mechanisms. Moreover, results from proliferation and apoptosis assays combined with differentiated HSP expression analysis demonstrated the relevance of preselecting specific target temperatures to achieve optimal toxic effects on remaining tumor cells in vivo. CONCLUSIONS: Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis-inducing cellular effects in patients with PC are negatively influenced by highly conserved HSP mechanisms in tumor cells. This study shows for the first time that specific hyperthermic conditions are necessary to be established to achieve optimal toxic effects on tumor cells during HIPEC therapy, a finding that opens potentially new therapeutic strategies.

Natural resistance to ascorbic acid induced oxidative stress is mainly mediated by catalase activity in human cancer cells and catalase-silencing sensitizes to oxidative stress.

BACKGROUND: Ascorbic acid demonstrates a cytotoxic effect by generating hydrogen peroxide, a reactive oxygen species (ROS) involved in oxidative cell stress. A panel of eleven human cancer cell lines, glioblastoma and carcinoma, were exposed to serial dilutions of ascorbic acid (5-100 mmol/L). The purpose of this study was to analyse the impact of catalase, an important hydrogen peroxide-detoxifying enzyme, on the resistance of cancer cells to ascorbic acid mediated oxidative stress. METHODS: Effective concentration (EC(50)) values, which indicate the concentration of ascorbic acid that reduced the number of viable cells by 50%, were detected with the crystal violet assay. The level of intracellular catalase protein and enzyme activity was determined. Expression of catalase was silenced by catalase-specific short hairpin RNA (sh-RNA) in BT-20 breast carcinoma cells. Oxidative cell stress induced apoptosis was measured by a caspase luminescent assay. RESULTS: The tested human cancer cell lines demonstrated obvious differences in their resistance to ascorbic acid mediated oxidative cell stress. Forty-five percent of the cell lines had an EC(50) > 20 mmol/L and fifty-five percent had an EC(50) < 20 mmol/L. With an EC(50) of 2.6-5.5 mmol/L, glioblastoma cells were the most susceptible cancer cell lines analysed in this study. A correlation between catalase activity and the susceptibility to ascorbic acid was observed. To study the possible protective role of catalase on the resistance of cancer cells to oxidative cell stress, the expression of catalase in the breast carcinoma cell line BT-20, which cells were highly resistant to the exposure to ascorbic acid (EC(50): 94,9 mmol/L), was silenced with specific sh-RNA. The effect was that catalase-silenced BT-20 cells (BT-20 KD-CAT) became more susceptible to high concentrations of ascorbic acid (50 and 100 mmol/L). CONCLUSIONS: Fifty-five percent of the human cancer cell lines tested were unable to protect themselves against oxidative stress mediated by ascorbic acid induced hydrogen peroxide production. The antioxidative enzyme catalase is important to protect cancer cells against cytotoxic hydrogen peroxide. Silenced catalase expression increased the susceptibility of the formerly resistant cancer cell line BT-20 to oxidative stress.

Evaluation of best supportive care and systemic chemotherapy as treatment stratified according to the retrospective peritoneal surface disease severity score (PSDSS) for peritoneal carcinomatosis of colorectal origin.

BACKGROUND: We evaluate the long-term survival of patients with peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective peritoneal disease severity score (PSDSS) on outcomes. METHODS: One hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987-2006 were identified from a prospective institutional database. These patients either received no chemotherapy, 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy. Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinically relevant factors. Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test. RESULTS: Median survival was 5 months (95% CI, 3-7 months) for patients who had no chemotherapy, 11 months (95% CI, 6-9 months) for patients treated with 5 FU/LV, and 12 months (95% CI, 4-20 months) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy. Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy (p = 0.026). PSDSS staging was identified as an independent predictor for survival on multivariate analysis [RR 2.8 (95%CI 1.5-5.4); p < 0.001]. CONCLUSION: A trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy. The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin.

Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule.

Tapentadol exerts its analgesic effects through micro opioid receptor agonism and noradrenaline reuptake inhibition in the central nervous system. Preclinical studies demonstrated that tapentadol is effective in a broad range of pain models, including nociceptive, inflammatory, visceral, mono- and polyneuropathic models. Moreover, clinical studies showed that tapentadol effectively relieves moderate to severe pain in various pain care settings. In addition, it was reported to be associated with significantly fewer treatment discontinuations due to a significantly lower incidence of gastrointestinal-related adverse events compared with equivalent doses of oxycodone. The combination of these reduced treatment discontinuation rates and tapentadol efficacy for the relief of moderate to severe nociceptive and neuropathic pain may offer an improvement in pain therapy by increasing patient compliance with their treatment regimen.

Laser-induced thermotherapy (LITT) elevates mRNA expression of connective tissue growth factor (CTGF) associated with reduced tumor growth of liver metastases compared to hepatic resection.

BACKGROUND AND OBJECTIVES: Proliferation and synthesis of hepatocellular tissue after tissue damage are promoted by specific growth factors such as hepatic tissue growth factor (HGF) and connective growth factor (CTGF). Laser-induced thermotherapy (LITT) for the treatment of liver metastases is deemed to be a parenchyma-saving procedure compared to hepatic resection. The aim of this study was to compare the impact of LITT and hepatic resection on intrahepatic residual tumor tissue and expression levels of mRNA HGF/CTGF within liver and tumor tissue. STUDY DESIGN/MATERIALS AND METHODS: Two independent adenocarcinomas (CC531) were implanted into 75 WAG rats, one in the right (untreated tumor) and one in the left liver lobe (treated tumor). The left lobe tumor was treated either by LITT or partial hepatectomy. The control tumor was submitted to in-situ hybridization of HGF and CTGF 24-96 hours and 14 days after intervention. RESULTS: Volumes of the untreated tumors prior to intervention were 38+/-8 mm(3) in group I (laser), 39 +/- 7 mm(3) in group II (resection), and 42 +/- 12 mm(3) in group III (control) and did not differ significantly (P > 0.05). Fourteen days after the intervention the mean tumor+/-SEM volume of untreated tumor in group I (laser) [223 +/- 36] was smaller than in group II (resection) [1233.28 +/- 181.52; P < 0.001], and in group III (control) [978.92 +/- 87.57; P < 0.003]. Forty-eight hours after the intervention intrahepatic mRNA expression level of HGF in group II (resection) was almost twofold higher than in group I (laser) [7.2 +/- 1.0 c/mf vs. 3.9 +/- 0.4 c/mf; P<0.01]. Fourteen days after the intervention intrahepatic mRNA expression level of CTGF in group I (laser) was higher than in group II (resection) [13.89 +/- 0.77 c/mf vs. 9.09 +/- 0.78 c/mf; P < 0.003]. CONCLUSIONS: LITT leads to a decrease of residual tumor growth in comparison to hepatic resection. Accelerated tumor growth after hepatic resection is associated with higher mRNA level of HGF and reduced tumor growth after LITT with higher mRNA level of CTGF. The increased CTGF-mediated regulation of ECM may cause reduced residual tumor growth after LITT.

Colorectal tumors and hepatic metastases differ in their optical properties-relevance for dosimetry in laser-induced interstitial thermotherapy.

BACKGROUND AND OBJECTIVES: The therapeutic application of laser light is a promising alternative to surgical resection of colorectal liver metastases. The extent of tumor destruction achieved by this strategy depends primarily on light distribution in the target tissue. Knowledge about optical properties is necessary to predict light distribution in the tissue for careful irradiation planning. The aim of this study was to compare the optical behavior of healthy colon tissue with that of colorectal carcinomas and their hepatic metastases in the native and coagulated state in order to test the effect of malignant degeneration, metastasis, and thermal coagulation on optical parameters. MATERIALS AND METHODS: Ninety tissue samples were taken from patients with a colorectal carcinoma and concomitant liver metastases: healthy colon tissue (n = 30); colon carcinoma (n = 30); liver metastases (n = 30). Optical properties were measured according to the single integrating sphere principle in the native state and after thermal coagulation in the wavelength range of 800-1,100 nm and analyzed by inverse Monte Carlo simulation. RESULTS: The highest optical penetration depth for all tissue types was obtained at the end of the spectral range investigated. The highest penetration depths of 4.13 mm (healthy colon), 7.47 mm (colon carcinoma tissue), and 4.08 (liver metastases) were at 1,060 nm, although the values decreased significantly after thermal coagulation. Comparing healthy colon-to-colon carcinoma always revealed a significantly lower absorption and scattering coefficient in the tumor tissue. This resulted in a higher optical penetration depth of the laser light in the colon carcinoma tissue (P < 0.05). A direct comparison disclosed no agreement between the optical properties of the primary tumor and the liver metastases. In the native state, colon carcinoma tissue had a lower scattering coefficient (P < 0.05), higher anisotropy factor, and optical penetration depth than liver metastases (P < 0.05). The absorption coefficient did not differ significantly. The differences in the native state were equalized by tissue coagulation. CONCLUSIONS: Colon carcinoma tissue has a higher optical penetration depth than healthy colon tissue, which speaks in favor of tumor selectivity for interstitial laser application, since large treatment volumes can be obtained in the tumor. The lack of agreement between primary tumors and their concomitant liver metastases indicates a modification of optical behavior through metastasis. Thermal coagulation of tissue leads to changes in the optical properties, which are clearly less pronounced in carcinoma tissue. The data obtained in this study clearly show that an individual irradiation schedule is necessary for effective and safe dosimetry in laser-induced thermotherapy (LITT).