Comparison of Stage and Lymph Node Ratio in Young and Older Patients with Colorectal Cancer Operated in a Tertiary Hospital in Nepal.

BACKGROUND: Colorectal cancer is being diagnosed more frequently in the young and it presents in an advanced stage. In TNM staging, stage depends on tumor size and number of positive nodes, which depend on location of tumor as well as the extent of dissection.The lymph node ratio is regarded as a more reliable marker for prognosis. In this study, we compare epidemiology of colorectal cancer in the young (<40 years) and older patients as well as the LNR. METHODS: Patients with colorectal cancer operated at the Tribhuvan University Teaching Hospital, Kathmandu, Nepal for a period of 4 years (2012 - 2016) were included in the study. Patients were grouped into young (? 40 years) and older (> 40 years) and clinic-pathological data such as site of lesion, clinical stage, and lymph node ratio were compared. RESULTS: Of the 95 patients of colorectal cancer, 25 patients were of age ? 40 years (26%) and they had a higher median stage at diagnosis. In patients above 40 years, it was diagnosed at a relatively earlier stage. The mean number of positive nodes was 11.64 in younger patients whereas it was 18.34in those more than 40 years of age,but younger patients had higher lymph node ratio than elderly (0.31 vs 0.13) (P-value ? 0.005). CONCLUSIONS: Young patients with colorectal cancer tend to have more advanced disease. The lymph node metastasis and lymph node ratio tend to be higher in young patients.

Reduced folate and serum vitamin metabolites in patients with rectal carcinoma: an open-label feasibility study of pemetrexed with folic acid and vitamin B12 supplementation.

The objectives of this single-center, open-label, phase II study were to evaluate (a) the feasibility and safety of neoadjuvant administration of pemetrexed with oral folic acid and vitamin B12 (FA/B12) in newly diagnosed patients with resectable rectal cancer and (b) intracellular and systemic vitamin metabolism. Patients were treated with three cycles of pemetrexed (500 mg/m, every 3 weeks) and FA/B12 before surgery. The reduced folates tetrahydrofolate, 5-methyltetrahydrofolate, and 5,10-methylenetetrahydrofolate were evaluated from biopsies in tumor tissue and in adjacent mucosa. Serum levels of homocysteine, cystathionine, and methylmalonic acid were also measured. All 37 patients received three cycles of pemetrexed; 89.2% completed their planned dosage within a 9-week feasibility time frame. Neither dose reductions nor study drug-related serious adverse events were reported. Reduced folate levels were significantly higher in tumor tissue compared with adjacent mucosa at baseline. After FA/B12 administration, tissue levels of reduced folates increased significantly and remained high during treatment in both tumor and mucosa until surgery. Serum levels of cystathionine increased significantly compared with baseline after FA/B12 administration, but then decreased, fluctuating cyclically during pemetrexed therapy. Homocysteine and methylmalonic acid levels decreased significantly after FA/B12 administration, and remained below baseline levels during the study. These results indicate that administration of three neoadjuvant cycles of single-agent pemetrexed, every 3 weeks, with FA/B12 in patients with resectable rectal cancer is feasible and tolerable. Tissue and serum vitamin metabolism results demonstrate the influence of pemetrexed and FA/B12 on vitamin metabolism and warrant further study.

Aspects of the non-pharmacological treatment of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is one of the most commonly diagnosed gastrointestinal conditions. It represents a significant healthcare burden and remains a clinical challenge. Over the years IBS has been described from a variety of different perspectives; from a strict illness of the gastrointestinal tract (medical model) to a more complex multi-symptomatic disorder of the brain-gut axis (biopsychosocial/psychosomatic model). In this article we present aspects of the pathophysiology and the non-pharmacological treatment of IBS based on current knowledge. Effects of conditioned stress and/or traumatic influences on the emotional system (top-down) as well as effects on the intestine through stressors, infection, inflammation, food and dysbiosis (bottom-up) can affect brain-gut communication and result in dysregulation of the autonomic nervous system (ANS), playing an important role in the pathophysiology of IBS. Conditioned stress together with dysregulation of the autonomic nervous system and the emotional system may involve reactions in which the distress inside the body is not recognized due to low body awareness. This may explain why patients have difficulty identifying their symptoms despite dysfunction in muscle tension, movement patterns, and posture and biochemical functions in addition to gastrointestinal symptoms. IBS shares many features with other idiopathic conditions, such as fibromyalgia, chronic fatigue syndrome and somatoform disorders. The key to effective treatment is a thorough examination, including a gastroenterological examination to exclude other diseases along with an assessment of body awareness by a body-mind therapist. The literature suggests that early interdisciplinary diagnostic co-operation between gastroenterologists and body-mind therapists is necessary. Re-establishing balance in the ANS is an important component of IBS treatment. This article discusses the current knowledge of body-mind treatment, addressing the topic from a practical point of view.

Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer.

BACKGROUND: Modufolin® ([6R]-5,10-methylene tetrahydrofolate; [6R]-MTHF) is an endogenous biomodulator that is being developed as an alternative to leucovorin, a folate prodrug used in the treatment of colorectal cancer. The objective of this phase 1 dose de-escalation trial was to estimate the minimum tolerated dose of [6R]-MTHF to be used in combination with pemetrexed 500 mg/m(2) in the neoadjuvant treatment of patients with rectal cancer. METHODS: Adult patients (≥18 years) with resectable rectal adenocarcinoma were allocated to [6R]-MTHF doses of 500, 100, 50, and 10 mg/m(2) in combination with pemetrexed 500 mg/m(2). [6R]-MTHF was administered as an intravenous (i.v.) bolus injection 1 week prior to the first dose of pemetrexed and then once weekly for 9 weeks; pemetrexed was administered by i.v. infusion once every 21 days for three cycles. RESULTS: Twenty-four patients (mean [SD] age, 63.1 [12.9] years) were enrolled in the study. A total of 72 treatment-related adverse events (AEs) were reported, of which the most common were fatigue (n = 17; 23.6 %), nausea (n = 10; 13.9 %), and diarrhea (n = 5; 6.9 %). The incidence of treatment-related AEs by [6R]-MTHF dose level (500, 100, 50, 10 mg/m(2)) was 11.1 % (n = 8), 13.9 % (n = 10), 45.8 % (n = 33), and 29.2 % (n = 21), respectively. There were no dose-limiting toxicities, and only two (2.8 %) treatment-related AEs were grade 3 in severity. Of the 11 serious AEs reported, none were considered to be related to [6R]-MTHF treatment. CONCLUSIONS: The results of this phase 1 study indicate that the estimated minimum tolerated dose of [6R]-MTHF was 100 mg/m(2) once weekly in combination with pemetrexed 500 mg/m(2). The low toxicity profile of [6R]-MTHF supports its further evaluation as a component of systemic chemotherapy in the management of colon and rectal cancer.

Pro-inflammatory cytokine release in rectal surgery: comparison between laparoscopic and open surgical techniques.

The objective of the present study was to investigate whether laparoscopic rectal surgery causes a less pronounced release of pro-inflammatory cytokines as compared to open surgical technique. Twenty-four consecutive patients undergoing rectal surgery due to cancer disease were included in a prospective and randomized trial. The patients were randomized to laparoscopic (n = 12) or open surgery (n = 12). Blood was sampled at five occasions; after induction of anesthesia before start of surgery, at 180, 360 min and 24 h after start of surgery and the last sample was taken in the late post-operative period 3-5 days after surgery. The levels of interleukin (IL)-1α, IL-6, IL-8, IL-10, tumor necrosis factor-α, C-reactive protein (CRP), white blood cells, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed using multiplex sandwich enzyme-linked immunosorbent assay. There was a release of both pro- and anti-inflammatory cytokines during colorectal surgery. The release of IL-6, IL-10 and CRP was significantly lower in the laparoscopic group. Rectal surgery causes release of both pro- and anti-inflammatory cytokines. The inflammatory response is lower in laparoscopic rectal surgery as compared to conventional open surgery. Less tissue trauma in laparoscopic rectal surgery and/or less peri-operative bleeding in the laparoscopic cases leads to a lower degree of inflammatory response.

Stage and size using magnetic resonance imaging and endosonography in neoadjuvantly-treated rectal cancer.

AIM: To assess the stage and size of rectal tumours using 1.5 Tesla (1.5T) magnetic resonance imaging (MRI) and three-dimensional (3D) endosonography (ERUS). METHODS: In this study, patients were recruited in a phase I/II trial of neoadjuvant chemotherapy for biopsy-proven rectal cancer planned for surgical resection with or without preoperative radiotherapy. The feasibility and accuracy of 1.5T MRI and 3D ERUS were compared with the histopathology of the fixed surgical specimen (pathology) to determine the stage and size of the rectal cancer before and after neoadjuvant chemotherapy. A Philips Intera 1.5T with a cardiac 5-channel synergy surface coil was used for the MRI, and a B-K Medical Falcon 2101 EXL 3D-Probe was used at 13 MHz for the ERUS. Our hypothesis was that the staging accuracy would be the same when using MRI, ERUS and a combination of MRI and ERUS. For the combination, MRI was chosen for the assessment of the lymph nodes, and ERUS was chosen for the assessment of perirectal tissue penetration. The stage was dichotomised into stage I and stage II or greater. The size was measured as the supero-inferior length and the maximal transaxial area of the tumour. RESULTS: The staging feasibility was 37 of 37 for the MRI and 29 of 36 for the ERUS, with stenosis as a limiting factor. Complete sets of investigations were available in 18 patients for size and 23 patients for stage. The stage accuracy by MRI, ERUS and the combination of MRI and ERUS was 0.65, 0.70 and 0.74, respectively, before chemotherapy and 0.65, 0.78 and 0.83, respectively, after chemotherapy. The improvement of the post-chemotherapy staging using the combination of MRI and ERUS compared with the staging using MRI alone was significant (P = 0.046). The post-chemotherapy understaging frequency by MRI, ERUS and the combination of MRI and ERUS was 0.18, 0.14 and 0.045, respectively, and these differences were non-significant. The measurements of the supero-inferior length by ERUS compared with MRI were within 1.96 standard deviations of the difference between the methods (18 mm) for tumours smaller than 50 mm. The agreement with pathology was within 1.96 standard deviations of the difference between imaging and pathology for all tumours with MRI (15 mm) and for tumours that did not exceed 50 mm with ERUS (22 mm). Tumours exceeding 50 mm in length could not be reliably measured by ERUS due to the limit in the length of each recording. CONCLUSION: MRI is preferable to use when assessing the size of large or stenotic rectal tumours. However, staging accuracy is improved by combining MRI with ERUS.

Uterus transplantation in the rat: model development, surgical learning and morphological evaluation of healing.

OBJECTIVE: Experimental uterus transplantation is a growing research field with the aim to develop a treatment for women with absolute uterus factor infertility. The potential risks of surgery and immunosuppressive treatment involved in uterus transplantation need to be identified and minimized in appropriate animal models before clinical trials commence. The aim of the present study was to develop and evaluate a model for uterus transplantation in the rat that can be reproduced and used in future studies concerning critical aspects of uterine function after transplantation. DESIGN: Animal study. SETTING: University Hospital. SAMPLE: Uterine tissue sampled at different post-operative time points after non-rejecting uterus transplantation in rats. METHODS: Adult, virgin female rats of inbred Lewis strain served as donors and recipients of uterine transplants. Two individuals with no previous microsurgical training performed the transplantations and learning curves were recorded. When transplant survival exceeded 70% for both surgeons, 15 animals were transplanted and grafted uteri were evaluated at 1, 7 and 21 days after surgery by assessment of morphology and enumeration of infiltrating neutrophilic granulocytes. MAIN OUTCOME MEASURES: Animal survival, graft survival, surgery times, uterine morphology, enumeration of infiltrating neutrophilic granulocytes. RESULTS: Both surgeons gained the necessary microsurgical skills needed to achieve above 70% transplant survival at a similar rate. The signs of post-operative inflammation on day one after transplantation were minor and further reduced at later time points. CONCLUSION: A reproducible model for uterus transplantation in the rat was developed, which can be used in future studies concerning uterine function after allogenic transplantation.

Irritable bowel syndrome subtypes differ in body awareness, psychological symptoms and biochemical stress markers.

AIM: To elucidate the differences in somatic, psychological and biochemical pattern between the subtypes of irritable bowel syndrome (IBS). METHODS: Eighty IBS patients, 30 diarrhoea predominant (D-IBS), 16 constipation predominant (C-IBS) and 34 alternating IBS (A-IBS) underwent physiotherapeutic examinations for dysfunctions in body movements and awareness and were compared to an apparently healthy control group (AHC). All groups answered questionnaires for gastrointestinal and psychological symptoms. Biochemical variables were analysed in blood. RESULTS: The D-IBS group showed less body awareness, less psychological symptoms, a more normal sense of coherence and psychosocial rating as well as higher C-peptide values. C-IBS had a higher degree of body dysfunction and psychological symptoms, as well as the lowest sense of coherence compared to controls and D-IBS. They also demonstrated the most elevated prolactin levels. A-IBS had the lowest degree of body disturbance, deteriorated quality of life and affected biochemical pattern. All subtypes had higher pain scores compared to controls. In addition they all had significantly increased triglycerides and elevated morning cortisol levels, however, without statistical significance compared with the controls. CONCLUSION: IBS subtypes showed different profiles in body awareness, somatic and psychological symptoms and in biochemical variables. D-IBS differed compared to the other groups by lowered body awareness, less psychological symptoms and a higher sense of coherence and elevated C-peptide values. C-IBS and A-IBS subtypes suffered more from depression and anxiety, associated with a lower quality of life. These differences may be important and will be taken into account in our treatment of these patients.

Successful uterine transplantation in the mouse: pregnancy and post-natal development of offspring.

BACKGROUND: Uterine transplantation could serve as a tool in studies of the physiology of implantation/pregnancy, and is also a possible future treatment for patients with absolute uterine infertility. Here, the first live-born offspring in any uterine transplantation model is reported. METHODS: A syngeneic mouse model with a uterus transplanted, by end-to-side aorta/vena cava vascular anastomoses, alongside the native uterus was used. The cervix was attached to a cutaneous stoma. Pregnancy rate and offspring (birth weight, growth and fertility) was evaluated after blastocyst transfer to the native and the grafted uterus of transplanted mice and to controls. RESULTS: Pregnancy rates were comparable in the grafted uterus (8/12 animals became pregnant) and the native uterus (9/12 pregnant) of transplanted animals and controls (8/13 pregnant). In a separate set of animals, the native uterus was removed at transplantation to exclude influences from the native uterus on the pregnancy potential of the graft; two of four animals became pregnant after blastocyst transfer. The weights/lengths of fetuses (gestational day 18) and gestational lengths were similar in all groups. Offspring were delivered and the growth trajectories (up to 8 weeks) of offspring delivered from grafted or native uteri of transplanted mice were similar as compared with controls, and all were fertile. The second-generation offspring from transplanted animals were all fertile with normal birth weights. CONCLUSIONS: These observations document the capacity of a transplanted uterus to harbour pregnancies to term, and reveal that offspring from a transplanted uterus develop to normal fertile adults.

Laser-Doppler flowmetry is reliable for early diagnosis of small-bowel acute rejection in the mouse.

The purpose of the study was to investigate intestinal mucosal perfusion in mouse small-bowel transplantation (SBT), using laser-Doppler flowmetry. Heterotopic SBT was performed in syngeneic and allogeneic combinations. Mucosal perfusion was measured both in the native and in the grafted intestine at time of surgery and at 1, 3, 6, and 8 days postoperatively. Histology specimens were obtained at the same time and graded for rejection. No rejection was seen in the syngeneic group at any of the time points studied. The allografts displayed significant decreased mucosal perfusion on postoperative days 3, 6, and 8. Rejection was histologically evident on postoperative days 6 and 8. Laser-Doppler perfusion in the rejecting intestinal allograft was decreased before onset of histological features of rejection. Mucosal blood flow measured by laser-Doppler could be used as an early indicator of acute rejection in SBT.