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Background Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC). Since response to radiotherapy (RT) is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve complete response (CR) is fundamental. Recently, an early tumour regression index (ERI) was introduced to predict pathological CR (pCR) after nCRT in LARC patients. The primary endpoints will be the increase of CR rate and the evaluation of feasibility of delta radiomics-based predictive MRI guided Radiotherapy (MRgRT) model. Methods Patients affected by LARC cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0 without high risk features will be enrolled in the trial. Neoadjuvant CRT will be administered using MRgRT. The initial RT treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum and 45 Gy in 25 fractions on the drainage nodes. Chemotherapy with 5-fluoracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla MRI will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated: if ERI will be inferior than 13.1, the patient will continue the original treatment; if ERI will be higher than 13.1 the treatment plan will be reoptimized, intensifying the dose to the residual tumor at the 11 th fraction to reach 60.1 Gy. At the end of nCRT instrumental examinations are to be performed in order to restage patients. In case of stable disease or progression, the patient will undergo surgery. In case of major or complete clinical response, conservative approaches may be chosen. Patients will be followed up to evaluate toxicity and quality of life. The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. Discussion This clinical trial investigates the impact of RT dose escalation in poor responder LARC patients identified using ERI, with the aim of increasing the probability of CR and consequently an organ preservation benefit in this group of patients. Trial registration ClinicalTrials.gov Identifier: NCT04815694 (25/03/2021).

Purpose To investigate the association between increased fetal nuchal translucency (NT) and maternal folate receptor alpha autoantibodies (FRAA) positivity, and to evaluate the subsequent risk of non‐syndromic autism spectrum disorder (ASD) in offspring. Methods A total of 3600 first‐trimester ultrasounds were screened at a fetal medicine center. Among these, 27 fetuses with markedly increased NT (≥ 3.5 mm) underwent invasive prenatal diagnosis, including karyotyping, CGH array, and postnatally whole‐exome sequencing (WES) when standard tests were negative. Maternal serum samples were tested for FRAA using ELISA. Eleven pregnancies with negative genetic testing were followed longitudinally, and neurodevelopmental outcomes in children were assessed up to 36 months using ADOS‐2 and DSM‐5 criteria. Findings Among the 11 fetuses with negative genetic outcomes, 4 mothers tested positive for FRAA. All four FRAA‐positive offspring were later diagnosed with ASD, while only one of the seven FRAA‐negative offspring received an ASD diagnosis. FRAA‐positive cases exhibited markedly increased NT (≥ 3.5 mm) but no pathogenic genetic variants, suggesting an immune‐mediated etiology. FRAA levels persisted in maternal and neonatal serum, implying ongoing exposure during gestation. Conclusion FRAA positivity in pregnancies with isolated markedly increased NT may serve as an early biomarker of increased ASD risk in offspring. These findings support the hypothesis of an immune‐metabolic mechanism contributing to ASD and suggest potential preventive interventions such as folinic acid supplementation. Maternal folate receptor alpha autoantibodies (FRAA) were associated with isolated increased fetal nuchal translucency and subsequent autism spectrum disorder (ASD) in offspring. FRAA positivity may represent an early biomarker of neurodevelopmental risk, suggesting potential preventive strategies such as folinic acid supplementation.

The aim of this study was to identify stage II colon cancer patients with a high risk of recurrence. All patients who underwent surgery for stage II colon cancer (CC) were retrospectively enrolled and sub-grouped according to TNM staging (IIa-b-c) and stage IIa in high (IIaHR) and low risk (IIaLR) according to pathologic features. The primary outcomes measured were the 5-year overall survival (OS) and disease-free survival (DFS). A total of 214 patients were reviewed. Only a maximum tumor diameter<4 cm in the IIaLR group was associated with a higher recurrence rate than a large tumor size (5-year DFS 71.7%vs.87.6%, p = 0.028). The DFS in the large IIaLR CC group was better than that in the IIaHR and IIb-c groups (5-year DFS: 92.7%vs.79.3%, p = 0.023). In contrast, the recurrence rate in the small IIaLR CC group was similar to that in the IIaHR, IIb-c stage CC group. In stage IIa CC evaluation of the tumor size as a prognostic factor may help identify patients who could benefit from additional postoperative therapy.

Ciliopathies are rare congenital disorders caused by defects in the structure or function of cilia, which can lead to a wide range of clinical manifestations. Among them, a subset known as skeletal ciliopathies exhibits significant phenotypic overlap and primarily affects skeletal development. This group includes several syndromes with overlapping but distinct clinical features, such as short-rib polydactyly syndrome (SRPS), Jeune asphyxiating thoracic dystrophy (JATD), Mainzer–Saldino syndrome (MZSDS), and cranioectodermal dysplasia (CED), also called Sensenbrenner syndrome. The most characterized features of skeletal ciliopathies are short stature, rhizomelic limb shortening, and thoracic narrowing to varying extents, with JATD presenting the most severe form. Here, we report a fetus with an extension of skeletal ciliopathy phenotype and compound heterozygous variants in the IFT140 gene. The affected fetus had multiple malformations, including increased nuchal transparency (NT), shortened and thick long bones, hypoplastic tibia and fibula, absence of bladder, flat nose, and frontal bossing. Our findings expand the mutation spectrum of IFT140, and the clinical spectrum associated with skeletal ciliopathies, highly relevant in diagnosis prenatal settings.

Background Expression levels of CD133, a cancer stem cell marker, and of the α-subunit of the dystroglycan (α-DG) complex, have been previously reported to be altered in colorectal cancers. Methods Expression levels of CD133 and α-DG were assessed by immunohistochemistry in a series of colon cancers and their prognostic significance was evaluated. Results Scattered cells positive for CD133 were rarely detected at the bases of the crypts in normal colonic mucosa while in cancer cells the median percentage of positive cells was 5% (range 0–80). A significant correlation was observed with pT parameter and tumor stage but not with tumor grade and N status. Recurrence and death from disease were significantly more frequent in CD133-high expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor groups for both disease-free (p = 0.002) and overall (p = 0.008) survival. Expression of α-DG was reduced in a significant fraction of tumors but low α-DG staining did not correlate with any of the classical clinical-pathological parameters. Recurrence and death from the disease were significantly more frequent in α-DG-low expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor tumors for both disease-free (p = 0.02) and overall (p = 0.02) survival. Increased expression of CD133, but not loss of α-DG, confirmed to be an independent prognostic parameters at a multivariate analysis associated with an increased risk of recurrence (RR = 2.4; p = 0.002) and death (RR = 2.3; p = 0.003). Conclusions Loss of α-DG and increased CD133 expression are frequent events in human colon cancer and evaluation of CD133 expression could help to identify high-risk colon cancer patients.

Purpose To evaluate whether metabolic changes in the primary tumour during and after preoperative radiochemotherapy (RCT) can predict the histopathological response in patients with locally advanced rectal cancer as well as disease-free survival (DFS) and overall survival (OS). Methods Consecutive patients with cT2–4 N0-2 rectal adenocarcinoma were included. 18 F-FDG PET/CT was performed at baseline, at the end of the second week of RCT (early PET/CT) and before surgery (late PET/CT). The PET/CT results were compared with histopathological data (ypT0 N0 vs. ypT1–4 N0–2 as well as TRG1 vs.TRG2–5) and survival. Results The study included 126 patients. Among 124 patients in whom TNM classification was available, 28 (22.6 %) were ypT0 N0, and among all 126 patients, 31 (24.6 %) were TRG1. The areas under the curve of the early response index (RI) for identifying non-complete pathological response (non-cPR) were 0.74 (95 % CI 0.61 – 0.87) for ypT1–4 N0–2 patients and 0.75 (95 % CI 0.62 – 0.88) for TRG2–5 patients. The optimal cut-off for differentiating patients with non-cPR and cPR was found to be a reduction of 61.2 % (83.1 % sensitivity and 65 % specificity in ypT1–4 N0–2 patients; 85.4 % sensitivity and 65.2 % specificity in TRG2–5 patients). The optimal cut-off for late RI could not be found. The qualitative analysis of images obtained after RCT demonstrated 81.5 % sensitivity and 61.3 % specificity in predicting TRG2–5. After a median follow-up of 68 months, the low number of patients with local/distant recurrence or who had died did not allow the value of PET/CT for predicting DFS and OS to be calculated. Conclusion The early assessment of response to RCT by 18 F-FDG PET/CT can predict non-cPR allowing practical modification of preoperative treatment. Conversely, late RI is not sufficiently accurate for guiding the decision as to whether local excision or even observation is appropriate in an individual patient. Qualitative analysis of late PET/CT images is also not sensitive enough alone to rule out the presence of residual disease.

The negative results in terms of morbidity, mortality and survival among emergency treated patients affected by colorectal cancer are well known. The specific contribution of emergency surgery to adverse outcome is not clear because of the presence in all series of other possible determinants of a poor prognosis. We used a case‐control study design to compare a group of 50 patients operated on for cancer of the rectum and left colon presented as emergencies in our department during the last 14 years, and an equal number of patients who underwent elective procedures during the same period. All records of these patients were reviewed and matched for age, stage, tumor location, and medical comorbidities (coronaropathy, diabetes mellitus, cerebral vascular deficiency, chronic obstructive pulmonary disease). Outcome measures included length of hospital stay, morbidity, mortality, and actuarial 5‐year survival. Univariate and multivariate analysis of factors potentially influencing survival was performed on the entire population of 100 patients. Age, tumor location, stage of disease, and medical comorbidities were well matched by intent of the study design. Overall surgical morbidity (44% versus 12% P = 0.0004), length of hospital stay (16, 64 versus 10, 97 days P = 0.0026) and postoperative mortality (4% versus 0% P = 0.4949) resulted higher in the emergency group. Actuarial overall 5‐year survival was not different between the two groups. The only variables independently predictive of survival in multivariate analysis were age and rectal location of the tumor. Postoperative surgical mortality and long‐term survival appear not to be influenced by emergency presentation of colorectal cancer; the negative impact of the emergency procedures is confined to the immediate postoperative period and is probably connected to the acute medical pathology often presented by patients in emergency situations. Dealing with this kind of patient’s accurate preoperative assessment and solution of acute medical pathologies before surgical treatment are mandatory.

SummaryBackgroundWatch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is generally intensive, because local regrowth (with the potential for salvage) occurs in 25% of patients, and distant metastases occur in 10% of patients. It is unclear for how long these patients should be followed up. To address this issue, we did conditional survival modelling using the International Watch & Wait Database (IWWD), which is a large-scale registry of patients with a clinical complete response after neoadjuvant chemotherapy who have been managed by a watch-and-wait strategy. MethodsWe did a retrospective, multicentre registry study using a dataset from the IWWD, which includes data from 47 clinics across 15 countries. We selected patients (aged ≥18 years) with rectal cancer who had a clinical complete response after neoadjuvant chemotherapy, and who were subsequently managed by a watch-and-wait strategy between Nov 25, 1991, and Dec 31, 2015. Patients who had not achieved a clinical complete response or who had undergone any surgical procedure were excluded. The criteria used for defining a clinical complete response and the specific surveillance strategies were at the discretion of each participating centre. We used conditional survival modelling to estimate the probability of patients remaining free of local regrowth or distant metastasis for an additional 2 years after sustaining a clinical complete response or being distant metastasis-free for 1, 3, and 5 years from the date of the decision to commence watch and wait. The primary outcomes were conditional local regrowth-free survival at 3 years, and conditional distant metastasis-free survival at 5 years. FindingsWe identified 793 patients in the IWWD with clinical complete response who had been managed by a watch-and-wait strategy. Median follow-up was 55·2 months (IQR 36·0–75·6). The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88·1% (95% CI 85·8–90·9), for 3 years was 97·3% (95·2–98·6), and for 5 years was 98·6% (97·6–100·0). The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93·8% (92·3–95·9), for 3 years was 97·8% (96·6–99·3), and for 5 years was 96·6% (94·0–98·9). InterpretationThese results suggest that the intensity of active surveillance in patients with rectal cancer managed by a watch-and-wait approach could be reduced if they achieve and maintain a clinical complete response within the first 3 years of starting this approach. FundingEuropean Registration of Cancer Care, financed by the European Society of Surgical Oncology, the Champalimaud Foundation Lisbon, the Bas Mulder Award, granted by the Alpe d’HuZes Foundation and the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre.

BackgroundRectum-preservation for locally advanced rectal cancer has been proposed as an alternative to total mesorectal excision (TME) in patients with major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The purpose of this study was to report on the short-term outcomes of ReSARCh (Rectal Sparing Approach after preoperative Radio- and/or Chemotherapy) trial, which is a prospective, multicenter, observational trial that investigated the role of transanal local excision (LE) and watch-and-wait (WW) as integrated approaches after neoadjuvant therapy for rectal cancer.MethodsPatients with mid-low rectal cancer who achieved mCR or cCR after neoadjuvant therapy and were fit for major surgery were enrolled. Clinical response was evaluated at 8 and 12 weeks after completion of chemoradiotherapy. Treatment approach, incidence, and reasons for subsequent TME were recorded.ResultsFrom 2016 to 2019, 160 patients were enrolled; mCR or cCR at 12 weeks was achieved in 64 and 96 of patients, respectively. Overall, 98 patients were managed with LE and 62 with WW. In the LE group, Clavien–Dindo 3+ complications occurred in three patients. The rate of cCR increased from 8- to 12-week restaging. Thirty-three (94.3%) of 35 patients with cCR had ypT0–1 tumor. At a median 24 months follow-up, a tumor regrowth was found in 15 (24.2%) patients undergoing WW.ConclusionsLE for patients achieving cCR or mCR is safe. A 12-week interval from chemoradiotherapy completion to LE is correlated with an increased cCR rate. The risk of ypT > is reduced when LE is performed after cCR.

Locally recurrent rectal cancer (LRRC), which occurs in 6–12% of patients previously treated with surgery, with or without pre-operative chemoradiation therapy, represents a complex and heterogeneous disease profoundly affecting the patient’s quality of life (QoL) and long-term survival. Its management usually requires a multidisciplinary approach, to evaluate the several aspects of a LRRC, such as resectability or the best approach to reduce symptoms. Surgical treatment is more complex and usually needs high-volume centers to obtain a higher rate of radical (R0) resections and to reduce the rate of postoperative complications. Multiple factors related to the patient, to the primary tumor, and to the surgery for the primary tumor contribute to the development of local recurrence. Accurate pre-treatment staging of the recurrence is essential, and several classification systems are currently used for this purpose. Achieving an R0 resection through radical surgery remains the most critical factor for a favorable oncologic outcome, although both chemotherapy and radiotherapy play a significant role in facilitating this goal. If a R0 resection of a LRRC is not feasible, palliative treatment is mandatory to reduce the LRRC-related symptoms, especially pain, minimizing the effect of the recurrence on the QoL of the patients. The aim of this manuscript is to provide a comprehensive narrative review of the literature regarding the management of LRRC.