Rectal cancer : aspects on radiotherapy, androgens and body composition

Rectal cancer is diagnosed among 1200 men in Sweden every year. Current treatment for local and regional disease implies surgical resection of the rectum often in combination with preoperative radiotherapy (RT). This treatment results in a cancer-specific survival of approximately 90% after three years and a cumulative incidence of local recurrence of 5% after five years. The oncological benefits frequently come at the price of impaired bowel and sexual function with consequences for quality of life. To design a research project with the aim to investigate the effects of preoperative RT on testicular function and sexual health in men treated for rectal cancer a review of the available literature was performed. The findings of this review (Paper I) showed that the testicular dose (TD) was on average 3% to 17% of the pre- scribed dose for RT. No reports on semen analysis in men treated for rectal cancer were identified. The androgen levels decreased in men treated with RT and the relative risk to have low serum testosterone (T < 8 nmol/l) was 2.7 (95% CI 1.6 to 4.7; p<0.001) after four years. Low serum T was also related to post-treatment erectile dysfunction. Based on the results of Paper I, a cohort study with preoperative RT as exposure was initiated. One hundred and five men with rectal cancer stage I to III were included between April 2010 and May 2014. To increase the sample size of the unexposed group 63 men with prostate cancer planned to robot-assisted prostatectomy were included additionaly. All participants had a baseline and two follow-up visits 12 and 24 months after surgery to collect blood samples, patient-reported outcome measures and semen samples. Men receiving preoperative RT had an additional blood sample the week prior to surgery. The planned TD was calculated with the treatment planning system based on the planning computed tomography (CT) in 101 men (Paper II). The median planned TD for short course RT was 0.57 Gy (range 0.06 to 14.37 Gy) and 0.81 Gy (range 0.36 to 10.80 Gy) for long course RT. In 32 men the delivered TD was assessed for each RT frac- tion with repeated cone beam CT. The comparison between planned and delivered TD show that the planned TD is an accurate estimate of the delivered dose. The within-person variability of the delivered TD is related to the posi- tion of the testes in men with moderate to high TD. The androgen levels at baseline of the entire cohort were similar and independent of the type of preoperative RT or the type of cancer (Paper III). Preoperative RT resulted in a significant decrease of T and increase of luteinising hormone (LH) and LH-T ratio. The risk of low serum T (T < 8 nmol/l) increased from 14.6% at baseline to 35.5% at the time of surgery in men treated with RT corresponding to a relative risk of 2.41 (95% CI 1.57 to 3.71, p<0.001). These findings confirm that preoperative RT leads to primary testicular failure. The preliminary analy- sis indicates a dose-response relationship between the TD and the negative impact on testicular function. The biochemical signs of testicular failure persisted in 40 men analysed 12 months after surgery (Paper IV). The cross-sectional area of the psoas and erector spinae muscle, assessed on routinely acquired planning and follow-up CT, was related to the level of bioavailable T. The area of subcutaneous tissue was not related to androgen levels. The decrease in these muscle groups is an androgen-dependent sign and identified men with testicular failure that had T levels in the grey zone of hypogonadism one year after surgery

Characterization of Structural Features Controlling the Receptiveness of Empty Class II MHC Molecules

MHC class II molecules (MHC II) play a pivotal role in the cell-surface presentation of antigens for surveillance by T cells. Antigen loading takes place inside the cell in endosomal compartments and loss of the peptide ligand rapidly leads to the formation of a non-receptive state of the MHC molecule. Non-receptiveness hinders the efficient loading of new antigens onto the empty MHC II. However, the mechanisms driving the formation of the peptide inaccessible state are not well understood. Here, a combined approach of experimental site-directed mutagenesis and computational modeling is used to reveal structural features underlying “non-receptiveness.” Molecular dynamics simulations of the human MHC II HLA-DR1 suggest a straightening of the α-helix of the β1 domain during the transition from the open to the non-receptive state. The movement is mostly confined to a hinge region conserved in all known MHC molecules. This shift causes a narrowing of the two helices flanking the binding site and results in a closure, which is further stabilized by the formation of a critical hydrogen bond between residues αQ9 and βN82. Mutagenesis experiments confirmed that replacement of either one of the two residues by alanine renders the protein highly susceptible. Notably, loading enhancement was also observed when the mutated MHC II molecules were expressed on the surface of fibroblast cells. Altogether, structural features underlying the non-receptive state of empty HLA-DR1 identified by theoretical means and experiments revealed highly conserved residues critically involved in the receptiveness of MHC II. The atomic details of rearrangements of the peptide-binding groove upon peptide loss provide insight into structure and dynamics of empty MHC II molecules and may foster rational approaches to interfere with non-receptiveness. Manipulation of peptide loading efficiency for improved peptide vaccination strategies could be one of the applications profiting from the structural knowledge provided by this study

External validation of semi-automated surveillance algorithms for deep surgical site infections after colorectal surgery in an independent country

Abstract Background Automated surveillance methods that re-use electronic health record data are considered an attractive alternative to traditional manual surveillance. However, surveillance algorithms need to be thoroughly validated before being implemented in a clinical setting. With semi-automated surveillance patients are classified as low or high probability of having developed infection, and only high probability patients subsequently undergo manual record review. The aim of this study was to externally validate two existing semi-automated surveillance algorithms for deep SSI after colorectal surgery, developed on Spanish and Dutch data, in a Swedish setting. Methods The algorithms were validated in 225 randomly selected surgeries from Karolinska University Hospital from the period January 1, 2015 until August 31, 2020. Both algorithms were based on (re)admission and discharge data, mortality, reoperations, radiology orders, and antibiotic prescriptions, while one additionally used microbiology cultures. SSI was based on ECDC definitions. Sensitivity, specificity, positive predictive value, negative predictive value, and workload reduction were assessed compared to manual surveillance. Results Both algorithms performed well, yet the algorithm not relying on microbiological culture data had highest sensitivity (97.6, 95%CI: 87.4–99.6), which was comparable to previously published results. The latter algorithm aligned best with clinical practice and would lead to 57% records less to review. Conclusions The results highlight the importance of thorough validation before implementation in other clinical settings than in which algorithms were originally developed: the algorithm excluding microbiology cultures had highest sensitivity in this new setting and has the potential to support large-scale semi-automated surveillance of SSI after colorectal surgery

Impact of radiotherapy on bone health in women with rectal cancer- A prospective cohort study

Introduction: Pelvic radiotherapy (RT) increases the risk of pelvic insufficiency fractures. The aim was to investigate if RT is associated with changes in serum bone biomarkers in women with rectal cancer, and to examine the incidence of radiation-induced bone injuries and the association with bone biomarkers.Material and methods: Women diagnosed with rectal cancer stage I-III, planned for abdominal surgery +/- preoperative (chemo) RT, were prospectively included and followed one year. Serum bone biomarkers comprised sclerostin (regulatory of bone formation), CTX (resorption), BALP and PINP (for-mation). A subgroup was investigated with annual pelvic magnetic resonance imaging (MRI). The as-sociation between RT and bone biomarkers was explored in regression models.Results: Of 134 included women, 104 had surgery with preoperative RT. The formation markers BALP and PINP increased from baseline to one year in the RT-exposed group (p &amp;lt; 0.001, longitudinal comparison). In the adjusted regression analysis, the mean increase in PINP was higher in the RT-exposed than the unexposed group (17.6 (3.6-31.5) mg/L, p = 0.013). Sclerostin and CTX did not change within groups nor differed between groups. Radiation-induced injuries were detected in 16 (42%) of 38 women with available MRI. At one year, BALP was higher among women with than without bone injuries (p = 0.018, cross-sectional comparison).Conclusions: Preoperative RT was associated with an increase in the formation marker PINP, which could represent bone recovery following RT-induced injuries, commonly observed in participants evaluated with MRI. These findings should be further explored in larger prospective studies on bone health in rectal cancer patients.(c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Funding Agencies|Swedish Cancer Society; Stockholm Cancer Society; Bengt Ihre Research Fellowship; Bengt Ihre Foundation; Stockholm County Council; Karolinska Institutet; Region Ostergotland</p

Whole-Body Nonlinear Model Predictive Control Through Contacts for Quadrupeds

ISSN:2377-376

A multicenter randomized clinical trial of primary anastomosis or Hartmann's procedure for perforated left colonic diverticulitis with purulent or fecal peritonitis

OBJECTIVES: To evaluate the outcome after Hartmann's procedure (HP) versus primary anastomosis (PA) with diverting ileostomy for perforated left-sided diverticulitis. BACKGROUND: The surgical management of left-sided colonic perforation with purulent or fecal peritonitis remains controversial. PA with ileostomy seems to be superior to HP; however, results in the literature are affected by a significant selection bias. No randomized clinical trial has yet compared the 2 procedures. METHODS: Sixty-two patients with acute left-sided colonic perforation (Hinchey III and IV) from 4 centers were randomized to HP (n = 30) and to PA (with diverting ileostomy, n = 32), with a planned stoma reversal operation after 3 months in both groups. Data were analyzed on an intention-to-treat basis. The primary end point was the overall complication rate. The study was discontinued following an interim analysis that found significant differences of relevant secondary end points as well as a decreasing accrual rate (NCT01233713). RESULTS: Patient demographics were equally distributed in both groups (Hinchey III: 76% vs 75% and Hinchey IV: 24% vs 25%, for HP vs PA, respectively). The overall complication rate for both resection and stoma reversal operations was comparable (80% vs 84%, P = 0.813). Although the outcome after the initial colon resection did not show any significant differences (mortality 13% vs 9% and morbidity 67% vs 75% in HP vs PA), the stoma reversal rate after PA with diverting ileostomy was higher (90% vs 57%, P = 0.005) and serious complications (Grades IIIb-IV: 0% vs 20%, P = 0.046), operating time (73 minutes vs 183 minutes, P < 0.001), hospital stay (6 days vs 9 days, P = 0.016), and lower in-hospital costs (US \$16,717 vs US \$24,014) were significantly reduced in the PA group. CONCLUSIONS: This is the first randomized clinical trial favoring PA with diverting ileostomy over HP in patients with perforated diverticulitis