Göran Kurlberg

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

AIMnTo assess the stage and size of rectal tumours using 1.5 Tesla (1.5T) magnetic resonance imaging (MRI) and three-dimensional (3D) endosonography (ERUS).nnnMETHODSnIn 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.nnnRESULTSnThe 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.nnnCONCLUSIONnMRI is preferable to use when assessing the size of large or stenotic rectal tumours. However, staging accuracy is improved by combining MRI with ERUS.

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 (nxa0=xa012) or open surgery (nxa0=xa012). Blood was sampled at five occasions; after induction of anesthesia before start of surgery, at 180, 360xa0min and 24xa0h after start of surgery and the last sample was taken in the late post-operative period 3–5xa0days 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.

Alternative Pathway Activation of Complement in Laparoscopic and Open Rectal Surgery

The study was designed to investigate whether complement is activated in patients subject to rectal surgery and whether the choice of surgical technique (open or laparoscopic) has any impact on the activation of complement. Our hypothesis is that laparoscopic surgery leads to a lower‐level activation of complement than open surgery. Patients (nu2003=u200324) subject to rectal surgery owing to rectal cancer were included. The study was prospective and randomized. The patients were randomized to either laparoscopic surgery (nu2003=u200312) or open surgery (nu2003=u200312). Blood samples for determination of complement activation (C4d, Bb, C3bc and the terminal C5b‐9 complex TCC) were drawn before start of surgery (T0) and at the following time‐points after start of surgery: 180u2003min (T1), 360u2003min (T2), 24u2003h (T3) and 3–5u2003days (T4). A significant increase in the alternative pathway activation product Bb and in the terminal pathway activation product TCC was seen over time in both groups (Pu2003<u20030.001). Bb peaked early (T1) and returned to baseline levels post‐operatively, whereas TCC increased steadily with maximum values in the late post‐operative period. The plasma concentrations of C4d and C3bc decreased significantly in both groups at T1 and T2 and returned to baseline levels at T4. There was no significant difference between the groups. Rectal surgery causes activation of the complement system. Complement is activated through the alternative pathway. Results mostly showed no significant differences between laparoscopic and open rectal surgery apart from lower levels of factor Bb in the former group in the perioperative period.

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.

Migration of host and donor T cells in small bowel transplantation

Abstract In this study migration of host and donor CD4+ andCD8+ T cells in a fully allogeneic model was described and compared with the migration pattern in a graft‐versus‐host reaction (GVHR) model, where the T‐cell traffic in the graft served as a physiological control. Heterotopic small bowel transplantations were performed in a rat model, with animals being sacrificed on postoperative days (POD) 2, 3, 4, 5, and 7. Graft and host mesenteric lymph nodes were harvested, homogenized, and stained with monoclonal antibodies against MHC class I, CD4 +, and CD8 + antigens. The host and donor T cell migration patterns were studied using a double‐staining flow cytometric technique. We found that during the development of rejection, the normal physiological circulation of graft and host T cells was disrupted. In the graft of the allogeneic model, a shift from host cell to graft cell dominance occurred on POD 3–4. This change in migration pattern coincided in the host with a 6 % peak in graft cell infiltration, which disappeared on POD 7. These patterns of T‐cell migration may be further explored for diagnostic purposes.

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 (500u2009mg/m2, 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.

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

SummaryBackground 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 500xa0mg/m2 in the neoadjuvant treatment of patients with rectal cancer. Methods Adult patients (≥18xa0years) with resectable rectal adenocarcinoma were allocated to [6R]-MTHF doses of 500, 100, 50, and 10xa0mg/m2 in combination with pemetrexed 500xa0mg/m2. [6R]-MTHF was administered as an intravenous (i.v.) bolus injection 1xa0week prior to the first dose of pemetrexed and then once weekly for 9xa0weeks; pemetrexed was administered by i.v. infusion once every 21xa0days 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 (nu2009=u200917; 23.6xa0%), nausea (nu2009=u200910; 13.9xa0%), and diarrhea (nu2009=u20095; 6.9xa0%). The incidence of treatment-related AEs by [6R]-MTHF dose level (500, 100, 50, 10xa0mg/m2) was 11.1xa0% (nu2009=u20098), 13.9xa0% (nu2009=u200910), 45.8xa0% (nu2009=u200933), and 29.2xa0% (nu2009=u200921), respectively. There were no dose-limiting toxicities, and only two (2.8xa0%) 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 100xa0mg/m2 once weekly in combination with pemetrexed 500xa0mg/m2. 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.