Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15 complexes mediate proliferation of high-avidity central memory CD8+ T cells for adoptive immunotherapy of cancer and infections.

The lack of persistence of infused T cells is a principal limitation of adoptive immunotherapy in man. Interleukin (IL)-15 can sustain memory T cell expansion when presented in complex with IL-15Rα (15Rα/15). We developed a novel in-vitro system for generation of stable 15Rα/15 complexes. Immunologically quantifiable amounts of IL-15 were obtained when both IL-15Rα and IL-15 genes were co-transduced in NIH 3T3 fibroblast-based artificial antigen-presenting cells expressing human leucocyte antigen (HLA) A:0201, ß2 microglobulin, CD80, CD58 and CD54 [A2-artificial antigen presenting cell (AAPC)] and a murine pro-B cell line (Baf-3) (A2-AAPC15Rα/15 and Baf-315Rα/15 ). Transduction of cells with IL-15 alone resulted in only transient expression of IL-15, with minimal amounts of immunologically detectable IL-15. In comparison, cells transduced with IL-15Rα alone (A2-AAPCRα ) demonstrated stable expression of IL-15Rα; however, when loaded with soluble IL-15 (sIL-15), these cells sequestered 15Rα/15 intracellularly and also demonstrated minimal amounts of IL-15. Human T cells stimulated in vitro against a viral antigen (CMVpp65) in the presence of 15Rα/15 generated superior yields of high-avidity CMVpp65 epitope-specific T cells [cytomegalovirus-cytotoxic T lymphocytes (CMV-CTLs)] responding to ≤ 10- 13 M peptide concentrations, and lysing targets cells at lower effector : target ratios (1 : 10 and 1 : 100), where sIL-15, sIL-2 or sIL-7 CMV-CTLs demonstrated minimal or no activity. Both soluble and surface presented 15Rα/15, but not sIL-15, sustained in-vitro expansion of CD62L+ and CCR7+ central memory phenotype CMV-CTLs (TCM ). 15Rα/15 complexes represent a potent adjuvant for augmenting the efficacy of adoptive immunotherapy. Such cell-bound or soluble 15Rα/15 complexes could be developed for use in combination immunotherapy approaches.

Association of a variable number tandem repeat in the NLRP3 gene in women with susceptibility to RVVC.

Vaginal infections with Candida spp. frequently occur in women of childbearing age. A small proportion of these women experience recurrent vulvovaginal candidosis (RVVC), which is characterized by at least three episodes of infection in one year. In addition to known risk factors such as antibiotics, diabetes, or pregnancy, host genetic variation and inflammatory pathways such as the IL-1/Th17 axis have been reported to play a substantial role in the pathogenesis of RVVC. In this study, we assessed a variable number tandem repeat (VNTR) polymorphism in the NLRP3 gene that encodes a component of the inflammasome, processing the proinflammatory cytokines IL-1ß and IL-18. A total of 270 RVVC patients and 583 healthy controls were analyzed, and increased diseases susceptibility was associated with the presence of the 12/9 genotype. Furthermore, functional studies demonstrate that IL-1ß production at the vaginal surface is higher in RVVC patients bearing the 12/9 genotype compared to controls, whereas IL-1Ra levels were decreased and IL-18 levels remained unchanged. These findings suggest that IL-1ß-mediated hyperinflammation conveyed by the NLRP3 gene plays a causal role in the pathogenesis of RVVC and may identify this pathway as a potential therapeutic target in the disease.

Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

[Knowledge of the general population about hypertension and diabetes mellitus in South Kivu, Democratic Republic of Congo]. / Connaissances de la population générale sur l'hypertension artérielle et le diabète sucré au Sud-Kivu, République démocratique du Congo.

BACKGROUND: In the Democratic Republic of Congo (DRC), a country in a post-conflict period, high priority cannot be given to non-communicable diseases other than to emergencies. This certainly involves inadequacy in raising awareness for prevention of these diseases. OBJECTIVE: To evaluate the level of knowledge of the Congolese general population on hypertension and diabetes mellitus. METHODS: Responses to a questionnaire from 3% of the general population aged 15 and older in the city of Bukavu and two rural areas: Hombo and Walungu (South Kivu, eastern DRC), recruited after stratification by ward in the city of Bukavu and a group of prone villages were expected. The questions focused on identification, testing, causes, complications and treatment of hypertension and diabetes mellitus. RESULTS: Of the 7770 respondents, screening for hypertension and diabetes mellitus affected only 14.9% and 7.3% of subjects respectively. Knowledge of these two conditions was generally low in the general population, although better in the subgroups of patients and those with higher socioeconomic level (P<0.05). Use of the medias was also associated with better knowledge (P<0.05). CONCLUSIONS: This study shows that knowledge about hypertension and diabetes mellitus and their testing in South Kivu is low. It is imperative that the Congolese government includes non-communicable diseases in its priorities of the millennium. Similarly, the WHO should actively contribute to screening for them in low-income countries.

DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene. Genetic defects in a growing number of neurodevelopmental genes have been shown to cause genome-wide disruptions in epigenomic profiles referred to as epi-signatures in affected individuals. RESULTS: In this study we assessed genome-wide DNA methylation profiles in a cohort of 22 individuals with Phelan-McDermid syndrome, including 11 individuals with large (2 to 5.8 Mb) 22q13.3 deletions, 10 with small deletions (< 1 Mb) or intragenic variants in SHANK3 and one mosaic case. We describe a novel genome-wide DNA methylation epi-signature in a subset of individuals with Phelan-McDermid syndrome. CONCLUSION: We identified the critical region including the BRD1 gene as responsible for the Phelan-McDermid syndrome epi-signature. Metabolomic profiles of individuals with the DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.

Cloning and functional characterization of primary alloreactive human T lymphocytes.

Human peripheral blood lymphocytes are activated to proliferate and form colonies in semisolid agarose after only brief exposure (24 h) to allogeneic lymphocytes in liquid culture. Colony development is independent of cell contact and exogenously supplied growth factors. The colonies are composed of T cells which form E rosettes with sheep erythrocytes and do not express surface immunoglobulin. Pooled colonies derived from 24-h allogeneic stimulation of HLA-D homozygous typing cells (HTC) express the appropriate HLA-D-associated DR antigens, as measured by complement-mediated cytotoxicity and by the reactivity of anti-DRw alloantisera after absorption with HLA-D homozygous B lymphoid cell lines. Some of the antisera give extra reactions with HTC colony cells that have not been previously detected on B lymphoid cell lines and purified peripheral B and T cell populations, suggesting that these sera may also contain antibodies against antigens expressed only on alloactivated T lymphocytes. Single colonies removed from agarose undergo extensive proliferation (20-30 generations) in liquid culture with the aid of T cell growth factor provided by conditioned medium. The majority of these T lymphocyte "clones" tested display specific cytolytic effector function, indicating that within 24 h of exposure to alloantigen, responder lymphocytes that subsequently form colonies in agarose are committed to antigen-specific cytotoxic activity; memory for the priming alloantigens is retained after months of culture with reexposure to antigen. This is the first demonstration that primary alloreactive clones of human T lymphocytes express HLA-DRw antigens and are capable of antigen-specific cytotoxic function.

The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4+ T cells.

Activation via the T lymphocyte cell surface molecule CD28 provides a potent amplification signal for interleukin 2 (IL-2) production in several in vitro systems. The B lymphocyte activation antigen, B7/BB1, is a natural ligand for CD28. Here we investigate the role of CD28 and B7/BB1 in primary activation of CD4+ T lymphocytes stimulated with allogeneic B lymphoblastoid cell lines. A subset of peripheral CD4+ T cells that is unresponsive to crosslinking of CD3/T cell receptor (TCR) with CD3 monoclonal antibody (mAb) does proliferate in response to allogeneic B lymphoblasts. TCR binding to allogeneic major histocompatibility complex antigens was an absolute requirement for activation of these cells because mAbs to either CD3 or human histocompatibility leukocyte antigen (HLA) class II completely inhibited activation. CD28 and B7/BB1 antibodies inhibited T cell proliferation 90% and 84%, respectively. Similar results were obtained with the total CD4+ T lymphocyte population. Crosslinking of HLA-DR antigens on small, resting B cells induced rapid expression of B7/BB1, which peaked at 6 h and returned to baseline levels within 18 h. These data demonstrate that CD28-B7/BB1 binding provides an important early second signal for alloactivation of CD4+ T lymphocyte by B lymphoblasts. The results also suggest that T cells interacting with allogeneic resting B cells may induce B7/BB1 expression in the alloantigen-presenting cell as a consequence of interaction between the TCR and class II molecules.

A novel activation pathway for mature thymocytes. Costimulation of CD2 (T,p50) and CD28 (T,p44) induces autocrine interleukin 2/interleukin 2 receptor-mediated cell proliferation.

Prior studies have shown that thymocytes, unlike peripheral T cells, do not proliferate in response to mitogenic combinations of anti-CD2 mAbs. The present study demonstrated that stimulation by a mitogenic anti-CD2 combination (9-1 plus 9.6) with anti-CD28 induced vigorous thymocyte proliferation in the absence of exogenous IL-2. This thymocyte proliferation was IL-2 dependent as shown by the complete inhibition using anti-IL-2-R mAbs. Induction of IL-2-R transcripts was detected in thymocytes stimulated by the anti-CD2 antibody combination alone or the anti-CD2 combination plus anti-CD28 antibody. However, induction of IL-2 transcripts was observed only in thymocytes triggered jointly by the anti-CD2 combination plus anti-CD28 antibodies. The double-negative (CD4-8-) or CD1+ thymocytes isolated by sorting or by panning were unresponsive to CD2/CD28 triggering. The same mitogenic signal could induce vigorous proliferation of thymocytes with a mature phenotype, i.e., CD3+CD4+ or CD3+CD8+ thymocytes. Immunofluorescence studies demonstrated that the majority of CD3+ thymocytes were CD28+, and most of the CD28+ cells were located in the medullary compartment of thymus. These results indicated that the T cell lineage surface molecules CD28 and CD2 are involved in the regulation of expansion and further differentiation of mature thymocytes.

Recognition by pregnancy serums of non-HL-A alloantigens selectively expressed on B lymphocytes.

A group of alloantibodies are found in pregnancy sera which react with antigens present on B lymphocytes and monocytes but are not detectable on the vast majority of unstimulated T cells. This specificity distinguishes them from HL-A antibodies which react with both cell types. They were readily recognized through indirect fluorescent antibody analysis by employing the combination of B-cell lymphoid lines and normal peripheral blood T cells. Different sera gave a variety of patterns of reactivity with a panel of 11 lymphoid lines. Similar differential patterns were also observed with normal B cells from different individuals particularly after concentrating the B cells. The antibodies were also cytotoxic to B cells and this procedure gave parallel results to the fluorescence method. The pattern of reactions obtained indicated a very heterogeneous system similar to that for HL-A. Special study of certain of the sera provided evidence that the lymphocyte-defined determinants of the mixed lymphocyte reaction system were involved. For convenience the term HL-B has been employed for these antigens.

Hereditary C2 deficiency: Genetic studies and association with the HL-A system.

Herediatary C2-deficiency has been shown to be transmitted asn an autosomal recessive characteristic. Recent evidence indicates that some genetic factors involved in the control of the complement (C) system in both man and mice are governed by genes localized within the major histocompatibility regionmthis study describes a large pedigree of the paternal family of a C2-deficient patient with systemic lupus erythematosusl It is shown that this condition is transmitted as an autosomal recessive trait, the heterozygous carriers having approximately half normal levels of C2. Furthermore, this trait was shown to be inherited in close linkage with an infrequent HL-A typw, 2,4A2. The maternal, C2-defective chromosome was shown to be transmitted by HL-AW10, W18 haplotypemthis same haplotype was described in a similar study by Fu et al. (6) to be associated with C2 deficiencymfinally, a third haplotype HL-A2,W18 carrying a defective C2 gene was demonstrated in a part of this pedigree.

Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10. Similarities to and differences from C9.

Genomic clones encompassing the entire coding region of the mouse lymphocyte pore-forming protein gene (Pfp) have been isolated and used to determine its intron-exon organization. In contrast to C9, Pfp has a simple structure, consisting of only three exons (two of which encode polypeptide), a large 5' intron, and a single, smaller intron that is situated approximately one-third of the way through the protein-coding portions of the gene. The regions encoding the homologous domains of PFP and C9 are encoded on exons 7, 8, 9, and 10 of C9, but form only approximately half of the open reading frame of exon III in Pfp. Although encoding polypeptides with related functions, the two genes possess such sharply contrasting structures as to suggest that their analogous regions may have risen independently, by a process of convergent evolution. Using a panel of somatic cell hybrid cell lines, Pfp has been mapped to chromosome 10.

Mixed lymphocyte culture determinants and C2 deficiency: LD-7a associated with C2 deficiency in four families.

Four families with C2 deficiency were studied. Among eight HL-A haplotypes involved with C2 deficiency, five were HL-A 10,W18. Three homozygotes for C2 deficiency from different families were mutually nonreactive in mixed lymphocyte cultures (MLC) and the heterozygotes from the fourth family failed to react to the homozygous cells. It appeared that identical MLC determinants were associated with all the genes from the different families that related to C2 deficiency. Further experiments identified the MLC determinant, LD-7a, as being involved. These results suggest marked linkage disequilibrium between the genes for C2 deficiency and the major histocompatibility complex (MHC). Studies of possible recombinants have offered tentative evidence for the positioning of the locus for C2 deficiency with respect to other segments of the MHC.

Severe Aspergillus endocarditis in a lung transplant recipient with a five-year survival.

We report the case of a patient with cystic fibrosis who underwent lung transplant and developed Aspergillus endocarditis and cutaneous relapse. Long-term survival was achieved with surgical and prolonged antifungal treatment. This case report emphasizes the recommendation of life-long antifungal treatment in transplant recipients who survive an episode of fungal endocarditis.

Unusual presentation of chromoblastomycosis due to Cladophialophora carrionii in a renal and pancreas transplant recipient patient successfully treated with posaconazole and surgical excision.

Chromoblastomycosis is a chronic, tropical and subtropical, subcutaneous mycosis caused by inoculation of dematiaceous molds. This disease is uncommonly reported in patients who have undergone solid organ transplantation. We describe a case of chromoblastomycosis caused by Cladophialophora carrionii that occurred 7 years after transplantation in a 58-year-old male renal and pancreatic transplant recipient. Diagnosis was based on histopathology and isolation of multiple colonies of the dematiaceous mold in pure culture. Identification was achieved by sequencing of the internal transcribed spacer regions of the rRNA. The patient was successfully treated with posaconazole and surgical excision of a residual lesion.

Clinical experience in the evaluation of 30 patients with a prior diagnosis of FG syndrome.

BACKGROUND: FG syndrome (FGS) is an X-linked disorder characterised by mental retardation, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome by Opitz and Kaveggia in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families, including the original family described by Opitz and Kaveggia. The phenotype was highly consistent in all the R961W positive patients. METHODS: In order to determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. RESULTS: The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. CONCLUSION: This report illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.

Survival improvement in Child-Pugh C cirrhotic patients with hepatocellular carcinoma diagnosed during 1990-2002.

OBJECTIVES: The aim of this study was to describe the evolution of diagnostic modalities, treatment and survival in cases of hepatocellular carcinoma (HCC) between 1990 and 2002 in Calvados. METHODS: All cases registered as HCC in the Calvados Tumour Registry from 1990 to 2002 were retrospectively reviewed. Incidence rates were standardized in comparison to the world reference population. The Kaplan-Meier method was used for survival analysis, and the log-rank test and Cox's model were used to compare patient survival according to demographic and tumour characteristics, as well as diagnosis period. Multivariate analysis were performed to determine independent prognostic factors and to assess the impact of the diagnosis period on survival. RESULTS: From 1990 to 2002, 729 cases registered as HCC were retrospectively validated. Standard incidence rates were 11.1/100,000 in men and 1.9/100,000 in women. Mean age was 66.6+/-11.8 years. Cirrhosis was present in 90.4% of cases. The cause of cirrhosis was alcohol in 66.8% of cases, HCV in 12.5%, HBV in 2.9%, haemochromatosis in 3.5%, and "other" in 13.1%. Curative treatment was possible in 14.7% of cases. Median survival was 7.15 months. On multivariate analysis, male gender, age greater than 70 years, Child-Pugh C (advanced-stage) cirrhosis, portal or suprahepatic venous thrombosis, alpha-fetoprotein (AFP) level greater than 200 ng/mL and non-curative treatment were poor prognostic factors. However, the diagnosis period was a good prognostic factor, associated with survival improvement over time in Child-Pugh C patients independent of tumour size, but not in Child-Pugh A and B. CONCLUSION: From 1990 to 2002, improvement in the survival of Child-Pugh C cirrhosis patients with HCC was observed that was apparently essentially attributable to better management of cirrhosis, and an improved balance between treatment and the degree of portal hypertension and hepatocellular insufficiency.

The trauma surgeon in the emergency department, a life saver?

BACKGROUND: The golden age of trauma has gone. 25 years ago the trauma surgeon was the life saver in the emergency department. He was the leader of the resuscitation team and made the important decisions in the process. Nowadays different factors have diminished the role of the trauma surgeon. DISCUSSION: Thanks to the decrease of severely injured patients in Europe and the advances in diagnostic and treatment possibilities the approach to trauma victims is less often operative. Furthermore, the uprising of emergency medicine specialists has taken many tasks out of the hands of the trauma surgeon. However, experienced trauma surgeons can do both critical care and acute care surgery and should be included in the decision-making process in the emergency room. CONCLUSION: Although the trauma surgeon often is no longer the captain of the ship in the emergency department, he can still play an important role in trauma care. They still are life savers.

Alteration of T-cell functions by infection with HTLV-I or HTLV-II.

Two functionally different types of human T-cell clones, one with helper function and two with specific activity, were infected with different isolates of HTLV-I and HLTV-II. Both types of human T cells showed alterations in specific function after infection with either of the HTLV subgroups. Before HTLV infection, the T-cell clone with helper function proliferates and provides help to B cells only in the presence of both a specific soluble antigen (keyhole limpet hemocyanin) and histocompatible antigen-presenting cells. After HTLV infection, these cells respond with increased proliferation and indiscriminant stimulation of polyclonal immunoglobulin production by B cells, regardless of the histocompatibility of the antigen-presenting cells or the presence of the soluble antigen. Infection of the normal cytotoxic T-cell clones led to a dimunition or loss of the cytotoxic function. The results of these studies suggest some possible mechanisms for induction of immune deficiency and of polyclonal B-cell activation by viruses of the HTLV family.

Has adherence to treatment guidelines for mid/low rectal cancer affected the management of patients? A monocentric study of 604 consecutive patients.

INTRODUCTION: In 2006 under the supervision of the French health authorities (HAS), recommendations for clinical practice (RCP) in the management of rectal cancers were first published. The primary objective of this study was to assess the impact of these guidelines on multidisciplinary management in terms of therapeutic strategies based on disease staging and quality indicators for surgical excision. Secondarily, we assessed the impact of the RCPs on postoperative and oncological outcomes. METHODS: All consecutive patients having undergone curative surgical excision for middle and low (subperitoneal) rectal cancer from 1995 to 2017 in the university hospital of Caen were included in accordance with the relevant French guidelines. They were divided into two groups: before (Gr1) and after (Gr2) 2006. For each group, a chart review was conducted on demographic variables, preoperative rectal tumor features, disease severity variables and quality of surgery variables. Postoperative and oncological outcomes were likewise assessed and compared between the two groups. RESULTS: Six hundred and four patients were included (Gr1, n=266; Gr2, n=338). Compliance with French guidelines significantly improved (i) use of magnetic resonance imaging (P<0.0001) and CT-scan (P<0.0001)]; (ii) organization of multidisciplinary tumor boards (P<0.0001) leading to suitable neo-adjuvant treatment plan classification (P<0.0001). Consequently, compliance improved widespread total mesorectal excision (P<0.0001), sphincter-sparing surgery (P=0,0005), and completeness of curative resection in the specimen (P<0.0001). Although postoperative 90-day mortality was similar, overall postoperative morbidity significantly increased in Gr2 (P<0.0001). Overall (P=0.0005) and disease-free survival (P=0.0016) of patients in Gr2 were significantly prolonged and correlated with a significant reduction in local and distant recurrences. CONCLUSION: Compliance with the relevant French guidelines improved the quality of multidisciplinary management of patients undergoing curative surgery for subperitoneal rectal cancer. However, further progress is still needed to render accession to the recommendations more comprehensive.