Neoadjuvant Chemoradiotherapy For Rectal Cancer Research Articles

Association of Collagen Changes in Distal Anastomotic Margin and Anastomotic Stenosis after Neoadjuvant Chemoradiotherapy for Rectal Cancer.

Neoadjuvant chemoradiotherapy (nCRT) for rectal cancer can lead to structural changes in collagen in the tumor microenvironment and increase the risk of postoperative anastomotic stenosis (AS). However, the quantitative relationship between AS and collagen has not been defined. This study is to quantitatively analyze the collagen features in rectal cancer and explore the relationship between the changes of collagen and postoperative anastomotic stenosis after nCRT. This is a retrospective study. A total of 371 patients with rectal cancer were included. Collagen features in the resection margin of rectal cancer anastomosis was extracted by multiphoton imaging. The least absolute shrinkage operator logistic regression was performed to select features related to AS and the collagen score (CS) was constructed. Area under the receiver operating curve (AUROC) and decision curve analysis were performed to evaluate the discrimination and clinical benefit of the nomogram. The probability of AS was 23% in the training cohort and 15.9% in the validation cohort. In the training cohort, the distance between tumor and resection margin, anastomotic leakage and CS were independent risk factors for postoperative AS in univariate and multivariate analyses. A nomogram was constructed based on these results. The prediction nomogram showed good discrimination (AUROC 0.864; 95% CI 0.776 to 0.952) and was validated in the validation cohort (AUROC 0.918; 95% CI 0.851 to 0.985). CS is an independent risk factor for AS in rectal cancer after nCRT. The predictive model based on CS can predict the occurrence of postoperative AS.

Impact of Sarcopenia on Treatment Outcomes and Toxicity in Locally Advanced Rectal Cancer

Background and Objectives: Sarcopenia, a condition characterized by muscle mass loss, is prevalent in up to 68% of rectal cancer patients and has been described as a negative prognostic factor, impacting overall survival and tumor response. While there are extensive data on rectal cancer globally, only a handful of studies have evaluated the role of sarcopenia in locally advanced rectal cancer (LARC). Our study aimed to investigate the relationship between sarcopenia, overall response rate, and toxicity in patients who underwent total neoadjuvant treatment (TNT) for LARC. Materials and Methods: We performed a retrospective study of patients with rectal cancer treated with TNT and surgery with curative intent between 2021 and 2023 at Prof. Dr. Ion Chiricuta Institute of Oncology, Cluj-Napoca. Sarcopenia was assessed on MRI images by measuring the psoas muscle area (PMA) at the level of the L4 vertebra before and after neoadjuvant therapy. The primary endpoints were the overall complete response rate (oCR) and acute toxicity. Results: This study included 50 patients with LARC. The oCR rate was 18% and was significantly associated with post-treatment sarcopenia (OR 0.08, p = 0.043). Patients who did not achieve a clinical or pathologic complete response had, on average, an 8% muscle loss during neoadjuvant therapy (p = 0.022). Cystitis and thrombocytopenia were significantly associated with post-treatment sarcopenia (p = 0.05 and p = 0.049). Conclusions: Sarcopenia and loss of psoas muscle during neoadjuvant therapy were negatively associated with tumor response in locally advanced rectal cancer. Thrombocytopenia and cystitis are more frequent in sarcopenic than non-sarcopenic patients undergoing neoadjuvant chemoradiation for rectal cancer.

Physical activity at diagnosis is associated with tumor downstaging after neoadjuvant chemoradiotherapy in patients with rectal cancer

BackgroundPatients with rectal cancer are often treated with neoadjuvant chemoradiotherapy, followed by a waiting period and surgical resection. Good or complete response to neoadjuvant chemoradiotherapy might enable organ preservation, which highlights the need to increase response rates. Pre-clinical studies suggest that physical activity during neoadjuvant chemoradiotherapy may improve tumor downstaging. PurposeTo investigate whether physical activity and physical functioning of patients with rectal cancer at diagnosis are associated with tumor downstaging after neoadjuvant chemoradiotherapy. Materials and methodsPatients were included if they participated in the Dutch Prospective ColoRectal Cancer Cohort, a nationwide cohort providing an infrastructure for scientific research, and received neoadjuvant chemoradiotherapy for rectal cancer. Tumor downstaging was dichotomized into good/complete or moderate/poor downstaging. Physical activity (total physical activity, moderate-to-vigorous physical activity (MVPA), and Dutch physical activity guideline adherence) and physical functioning were assessed using questionnaires. Logistic regression analyses were performed to examine associations of physical activity and physical functioning with tumor downstaging, adjusted for relevant confounders. Results268 patients (aged 62 ± 11 years, 33 % female) with rectal cancer were included. Patients with moderate (OR = 2.07; 95%CI = 1.07 – 4.07; p = 0.03) or high (OR = 2.05; 95%CI = 1.05 – 4.07; p = 0.04) levels of MVPA were more likely to have good/complete tumor downstaging than patients with low levels. No significant associations with tumor downstaging were found for total physical activity, Dutch physical activity guideline adherence, and physical functioning. ConclusionsWe found augmented tumor downstaging in patients with rectal cancer with moderate or high levels of self-reported MVPA before the start of neoadjuvant chemoradiotherapy compared to patients with low levels.

Machine learning in predicting pathological complete response to neoadjuvant chemoradiotherapy in rectal cancer using MRI: a systematic review and meta-analysis.

To evaluate the performance of machine learning models in predicting pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer using magnetic resonance imaging. We searched PubMed, Embase, Cochrane Library, and Web of Science for studies published before March 2024. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was used to assess the methodological quality of the included studies, random-effects models were used to calculate sensitivity and specificity, I2 values were used for heterogeneity measurements, and subgroup analyses were carried out to detect potential sources of heterogeneity. A total of 1699 patients from 24 studies were included. For machine learning models in predicting pCR to nCRT, the meta-analysis calculated a pooled area under the curve (AUC) of 0.91 (95% CI, 0.88-0.93), pooled sensitivity of 0.83 (95% CI, 0.74-0.89), and pooled specificity of 0.86 (95% CI, 0.80-0.91). We investigated 6 studies that mainly contributed to heterogeneity. After performing meta-analysis again excluding these 6 studies, the heterogeneity was significantly reduced. In subgroup analysis, the pooled AUC of the deep-learning model was 0.93 and 0.89 for the traditional statistical model; the pooled AUC of studies that used diffusion-weighted imaging (DWI) was 0.90 and 0.92 in studies that did not use DWI; the pooled AUC of studies conducted in China was 0.93, and was 0.83 in studies conducted in other countries. This systematic study showed that machine learning has promising potential in predicting pCR to nCRT in patients with locally advanced rectal cancer. Compared to traditional machine learning models, although deep-learning-based studies are less predominant and more heterogeneous, they are able to obtain higher AUC. Compared to traditional machine learning models, deep-learning-based studies are able to obtain higher AUC, although they are less predominant and more heterogeneous. Together with clinical information, machine learning-based models may bring us closer towards precision medicine.

Acute Toxicities and Treatment tolerance of Neoadjuvant Chemoradiation in Rectal Cancer: A Tertiary Cancer Centre Analysis

Aims: To assess acute toxicities and treatment tolerance in patients of carcinoma rectum of NACTRT at a tertiary care centre of North-East India. Materials and Methods: A total of 50 patients of histologically proven Rectal Adenocarcinoma recruited from July 2022 to May 2023 were included in the study. All patients were planned for either NACTRT (n=44) or Total Neoadjuvant Treatment (TNT)(n=6) followed by assessment for surgery. A total dose of 50.4Gy/28# was planned with concurrent oral chemotherapy with T. Capecitabine at a dose of 825 mg/m2 twice daily. Acute toxicities were assessed using RTOG grading criteria. Patients’ toxicity assessment was done weekly with clinical examination and laboratory parameters. Patients were also assessed at the end of RT and 4 weeks post completion of NACTRT. Results: All patients could complete the prescribed dose of EBRT (50.4Gy/28#) over a period of 6 weeks. On toxicity assessment, Grade-I dermatitis was seen in 14 patients (56%), Grade-II in 14 patients (54%), Grade-III in 2 patients (7.6%). In lower gastrointestinal toxicities, Grade-I diarrhea occurred for 4 patients (50%), Grade-II diarrhea in 3 patients (37.5%) and Grade III diarrhea in 1 patient (7.6%). Grade-I genitourinary toxicity was observed in 4 patients (8%). Hematological toxicities were seen for 40 patients of which Grade-I, Grade-II, Grade-III Anemia were seen in 10 (38.4%), 14 (54%), 2 (7.6%) patients respectively. Grade 1 and Grade 2 leucopenia were seen in 4 (57%) and 3 (43%) patients respectively. Deranged LFT was seen for 7 patients (15%), out of whom dose modifications were required for 5 patients (10%). Treatment was put on hold for 3 patients (6%) for 3 days due to grade 3 toxicities. Conclusion: NACTRT in rectal cancer patients was associated with acceptable toxicities and treatment tolerance. Modern EBRT techniques like IMRT should be evaluated in an effort to further reduce the radiation related toxicities.

Role of body mass index in anastomotic leakage after curative treatment for rectal cancer.

Anastomotic leakage (AL) represents a severe complication after rectal surgery, leading to significant morbidity, mortality, and increased healthcare costs. Despite improvements in surgical methods and perioperative care, the challenge of AL persists. Explore the impact of body mass index (BMI) on the risk of AL following curative treatment for rectal cancer, providing insight into its predictive value. Retrospective review. Data were collected from a single tertiary center, emphasizing the specialized postoperative outcomes in a high-care setting. The study population was comprised patients who underwent sphincter-saving surgery combined with neoadjuvant chemoradiation for rectal cancer from 2001 to 2011. Patients with anastomotic stenosis were excluded. The primary outcome investigated was the occurrence of AL post-surgery. Secondary outcomes included the assessment of local cancer recurrence rates within the AL group. 224; 13 excluded. Of 237 patients who underwent surgery, 13 with anastomotic stenosis were excluded from this study. Of the remaining 224, 15 individuals (6.3%) developed AL. A potential association between higher BMI and increased AL risk was identified. Additionally, the study noted a higher incidence of local rectal cancer recurrence in the group that developed leakage. The findings suggest BMI as a significant predictive factor for AL after curative rectal cancer treatment. This emphasizes the need for heightened awareness and possible preoperative counseling for obese patients regarding their increased risk of postoperative leakage. The study was retrospective with all the inherit biases of such studies. The sample size was small and this may have introduced a type 2 statistical error.

Rectal Cancer Survival for Residual Carcinoma In Situ Versus Pathologic Complete Response After Neoadjuvant Therapy.

Pathologic complete response after neoadjuvant chemoradiotherapy for rectal cancer is associated with improved survival. It is unclear whether residual carcinoma in situ portends a similar outcome. To compare the survival of patients with locally advanced rectal cancer who received neoadjuvant therapy and achieved pathologic carcinoma in situ versus pathologic complete response. Retrospective cohort study. National public database. A total of 4594 patients in the National Cancer Database from 2006 to 2016 with locally advanced rectal cancer who received neoadjuvant therapy, underwent surgery, and had node-negative ypTis or ypT0 on final pathology were included. Of these, 4321 patients (94.1%) had ypT0 and 273 (5.9%) had ypTis on final pathology. Overall survival. The median age was 60 years, and 1822 patients (39.7%) were women. On initial staging, 54.5% (n = 2503) had stage II disease and 45.5% (n = 2091) had stage III disease. The ypTis group had decreased overall survival compared to the ypT0 group (HR 1.42; 95% CI, 1.04-1.95; p = 0.028). Other factors associated with decreased overall survival were older age at diagnosis, increasing Charlson-Deyo score, and poorly differentiated tumor grade. Variables associated with improved survival were female sex, private insurance, and receipt of both neoadjuvant and adjuvant chemotherapy. For the total cohort, there was no difference in survival between clinical stage II and stage III. Standard therapy versus total neoadjuvant therapy could not be abstracted. Overall survival was defined as the time from surgery to death from any cause or last contact, allowing for some erroneously misclassified deaths. ypTis is associated with worse overall survival than ypT0 for patients with locally advanced rectal cancer who receive neoadjuvant chemoradiotherapy followed by surgery. For this cohort, clinical stage was not a significant predictor of survival. Prospective trials comparing survival for these pathologic outcomes are needed. See Video Abstract . ANTECEDENTESLa respuesta patológica completa después de la quimiorradioterapia neoadyuvante para el cáncer de recto se asocia con una mayor supervivencia. No está claro si el carcinoma residual in situ presagia un resultado similar.OBJETIVOComparar la supervivencia de pacientes con cáncer de recto localmente avanzado que recibieron terapia neoadyuvante y lograron un carcinoma patológico in situ versus una respuesta patológica completa.DISEÑOEstudio de cohorte retrospectivo.ESCENARIOBase de datos pública nacional.PACIENTESSe incluyeron 4,594 pacientes de la Base de Datos Nacional de Cáncer de 2006 a 2016 con cáncer de recto localmente avanzado que recibieron terapia neoadyuvante, fueron sometidos a cirugía y tuvieron ganglios negativos, ypTis o ypT0 en el reporte patológico final. 4.321 (94,1%) tuvieron ypT0 y 273 (5,9%) tuvieron ypTis en el reporte final.PRINCIPALES MEDIDAS DE RESULTADOSupervivencia general.RESULTADOSLa mediana de edad fue de 60 años. 1.822 pacientes (39,7%) fueron mujeres. El 54,5% (n = 2.503) tuvo la enfermedad en estadio II y el 45,5% (n = 2.091) tuvo la enfermedad en estadio III según la estadificación inicial. El grupo ypTis tuvo una supervivencia general reducida en comparación con el grupo ypT0 (HR 1,42, IC 95 % 1,04-1,95, p = 0,028). Otros factores asociados con una menor supervivencia general fueron una edad más avanzada al momento del diagnóstico, un aumento de la puntuación de Charlson-Deyo y un grado tumoral poco diferenciado. Las variables asociadas con una mejor supervivencia fueron el sexo femenino, el seguro privado y la recepción de quimioterapia neoadyuvante y adyuvante. Para la cohorte total, no hubo diferencias en la supervivencia entre el estadio clínico 2 y el estadio 3.LIMITACIONESNo se pudo resumir el tratamiento estándar versus el tratamiento neoadyuvante total. La supervivencia general se definió como el tiempo transcurrido desde la cirugía hasta la muerte por cualquier causa o último contacto, lo que permite algunas muertes erróneamente clasificadas.CONCLUSIONESypTis se asocia con una peor supervivencia general que ypT0 en pacientes con cáncer de recto localmente avanzado que reciben quimiorradioterapia neoadyuvante seguida de cirugía. Para esta cohorte, el estadio clínico no fue un predictor significativo de supervivencia. Se necesitan ensayos prospectivos que comparen la supervivencia de estos resultados patológicos. ( Traducción-Dr Osvaldo Gauto ).

An immune-related gene prognostic prediction risk model for neoadjuvant chemoradiotherapy in rectal cancer using artificial intelligence.

This study aimed to establish and validate a prognostic model based on immune-related genes (IRGPM) for predicting disease-free survival (DFS) in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy, and to elucidate the immune profiles associated with different prognostic outcomes. Transcriptomic and clinical data were sourced from the Gene Expression Omnibus (GEO) database and the West China Hospital database. We focused on genes from the RNA immune-oncology panel. The elastic net approach was employed to pinpoint immune-related genes significantly impacting DFS. We developed the IRGPM for rectal cancer using the random forest technique. Based on the IRGPM, we calculated prognostic risk scores to categorize patients into high-risk and low-risk groups. Comparative analysis of immune characteristics between these groups was conducted. In this study, 407 LARC samples were analyzed. The elastic net identified a signature of 20 immune-related genes, forming the basis of the IRGPM. Kaplan-Meier survival analysis revealed a lower 5-year DFS in the high-risk group compared to the low-risk group. The receiver operating characteristic (ROC) curve affirmed the model's robust predictive capability. Validation of the model was performed in the GSE190826 cohort and our institution's cohort. Gene expression differences between high-risk and low-risk groups predominantly related to cytokine-cytokine receptor interactions. Notably, the low-risk group exhibited higher immune scores. Further analysis indicated a greater presence of activated B cells, activated CD8 T cells, central memory CD8 T cells, macrophages, T follicular helper cells, and type 2 helper cells in the low-risk group. Additionally, immune checkpoint analysis revealed elevated PDCD1 expression in the low-risk group. The IRGPM, developed through random forest and elastic net methodologies, demonstrates potential in distinguishing DFS among LARC patients receiving standard treatment. Notably, the low-risk group, as defined by the IRGPM, showed enhanced activation of adaptive immune responses within the tumor microenvironment.

Clinical and pathological parameters predicting pathologic complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective The aim of this study is to identify possible clinical predictors of complete response after neoadjuvant treatment in locally advanced rectal cancer (LARC) patients. Background Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision and postoperative adjuvant chemotherapy for LARC is the standard of care with a local recurrence rate of only 5–10%. On the other hand, various people react differently to neoadjuvant CRT. Neoadjuvant CRT is well received by the majority of patients, with a pathologic complete response (pCR) occurring in 10–30% of cases. Predicting the response to neoadjuvant CRT is crucial from a clinical standpoint, since patients with pCR have a better prognosis and may require a different treatment plan than patients without pCR. As a result, predicting pCR following neoadjuvant CRT for rectal cancer continues to be extremely useful for treating physicians. To identify the clinical and pathological variables linked to a full response to preoperative CRT for rectal cancer, we assessed a group of patients with pCR in this study. Patients and methods The study included 153 patients with LARC that were enrolled in the study based on specific inclusion and exclusion criteria. Patients were treated by standard neoadjuvant therapy. Surgical resection was planned for 6–8 weeks after the completion of neoadjuvant CRT, irrespective of the response to CRT. Pathological examination was performed to assess pathological response in the resected specimen. pCR was defined as the absence of viable tumor cells in the surgical specimen, including lymph nodes. Results After neoadjuvant chemoradiation, the pCR rate for rectal cancer patients was 20.8%; patients were split into pCR and non-pCR groups. Age, sex, BMI, performance score, tumor stage, tumor differentiation, tumor location, and surgical method were all evenly distributed across the two groups. The results of the multivariate analysis showed that pretreatment lymph node status, tumor size, and a carcinoembryonic antigen level of less than or equal to 5 ng/ml were independent risk factors of an elevated likelihood of pCR, as was an interval of more than or equal to 8 weeks between the completion of chemoradiation and treatment. Conclusion The pCR in rectal cancer following neoadjuvant chemoradiation is predicted by pretreatment carcinoembryonic antigen level of less than or equal to 5 ng/ml, an interval of more than or equal to 8 weeks between the end of chemoradiation and surgical resection, tumor size greater than 5 cm, and pretreatment lymph node status. By utilizing these predictive variables, we are able to forecast patients’ outcomes and create flexible treatment plans. In certain, very specific situations, a wait-and-see policy might be appropriate.

Radiomics of skeletal muscle helps to predict gastrointestinal toxicity in locally advanced rectal cancer patients receiving neoadjuvant chemoradiotherapy

BackgroundThe skeletal muscle index (SMI) can serve as a surrogate for a patient’s nutritional status, which is associated with treatment toxicity. This study aims to investigate the potential of baseline skeletal muscle radiomics features to predict gastrointestinal toxicity of neoadjuvant chemoradiotherapy for rectal cancer. MethodsA total of 214 rectal cancer patients (115, 49 and 50 in the training, internal and external validation set, respectively) who underwent neoadjuvant pelvic radiotherapy with capecitabine and irinotecan were retrospectively identified. The skeletal muscle at the level of the third lumber vertebra was contoured, and the radiomics features were extracted from computed tomography scans. In the training set, the least absolute shrinkage and selection operator (LASSO) regression algorithm was applied to select features that were most significantly associated with grade 3–4 gastrointestinal toxicity (diarrhea, nausea, vomiting and proctitis). The predictive performance and clinical utility were estimated using the area under the receiver operator characteristic curve (AUC), F1-score and decision curve analysis (DCA). ResultsNine features, including the SMI and eight radiomics features, were associated with grade 3–4 gastrointestinal toxicity and included in the logistic regression. This combined predictive model, which incorporated the SMI and radiomics features, showed better discrimination than the SMI alone, with an AUC of 0.856 (95 % CI: 0.782–0.929) in the training cohort, 0.812 (95 % CI: 0.667–0.956) in the internal validation cohort and 0.745 (95 % CI: 0.600–0.890) in the external validation cohort. DCA further verified the clinical utility of the combined predictive model. ConclusionRadiomics features of skeletal muscle were significantly associated with gastrointestinal toxicity. The predictive model incorporating the SMI and radiomics features exhibits favorable discrimination and may be highly informative for clinical decision-makings.

Racial Disparities in Receipt of Guideline-Concordant Care for Early-Onset Colorectal Cancer in the United States.

Young individuals racialized as Black are more likely to die after a colorectal cancer (CRC) diagnosis than individuals racialized as White in the United States. This study examined racial disparities in receipt of timely and guideline-concordant care among individuals racialized as Black and White with early-onset CRC. Individuals age 18-49 years racialized as non-Hispanic Black and White (self-identified) and newly diagnosed with CRC during 2004-2019 were selected from the National Cancer Database. Patients who received recommended care (staging, surgery, lymph node evaluation, chemotherapy, and radiotherapy) were considered to have received guideline-concordant care. Odds ratios (ORs) were adjusted for age and sex. The decomposition method was used to estimate the relative contribution of demographic characteristics (age and sex), comorbidities, health insurance, and facility type to the racial disparity in receipt of guideline-concordant care. The product-limit method was used to evaluate differences in time to treatment between patients racialized as Black and White. Of the 84,882 patients with colon cancer and 62,573 patients with rectal cancer, 20.8% and 14.5% were racialized as Black, respectively. Individuals racialized as Black were more likely to not receive guideline-concordant care for colon (adjusted OR [aOR], 1.18 [95% CI, 1.14 to 1.22]) and rectal (aOR, 1.27 [95% CI, 1.21 to 1.33]) cancers. Health insurance explained 28.2% and 21.6% of the disparity among patients with colon and rectal cancer, respectively. Individuals racialized as Black had increased time to adjuvant chemotherapy for colon cancer (hazard ratio [HR], 1.28 [95% CI, 1.24 to 1.32]) and neoadjuvant chemoradiation for rectal cancer (HR, 1.42 [95% CI, 1.37 to 1.47]) compared with individuals racialized as White. Patients with early-onset CRC racialized as Black receive worse and less timely care than individuals racialized as White. Health insurance, a modifiable factor, was the largest contributor to racial disparities in receipt of guideline-concordant care in this study.

Relationships between Microbiome and Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

Gut microbiome is known to be involved in antitumor immunotherapy and chemotherapy responses; however, few research has focused on the role of gut microbiome in the setting of concurrent chemoradiotherapy (CCRT). In this study, we investigated the tumor microbiome dynamics in patients undergoing neoadjuvant CCRT for locally advanced rectal cancer and sought to determine whether the diversity and composition of microbiome affect treatment response. A total of 103 samples from 26 patients with locally advanced rectal cancer were collected and 16S ribosomal RNA amplicon sequencing was performed. All patients underwent neoadjuvant CCRT followed by surgical resection between 2008 and 2016. Samples were obtained from both tumor and normal rectal tissue at pre- and post-CCRT. According to the American Joint Committee on Cancer tumor regression grading (TRG) system, patients were divided into responders (TRG 0, 1) and non-responders (TRG 2, 3). We performed diversity, taxonomy, and network analyses to compare responders and non-responders. Then, we established the Bayesian network model to predict treatment response in patients with rectal cancer. Overall, we detected 1260 microbial genera from 287 families, 132 orders, 56 classes, and 32 phyla in the bacteria kingdom. Between tumor and normal rectal tissues, there was no difference in microbial diversity and composition. On the other hand, there was a significant decrease in diversity and compositional alterations when comparing pre- and post-CCRT samples (all p<0.001). Ten patients (38.5%) were classified as responders and 16 patients (61.5%) were classified as non-responders. In both groups, CCRT significantly reduced microbial diversity and altered their composition, but it was more pronounced in non-responders. In taxonomic analysis of pre-CCRT samples, butyrate-producing bacteria were differentially enriched in responders. Meanwhile, in post-CCRT samples, opportunistic pathogen were overrepresented in non-responders. The network analysis revealed that butyrate-producing bacteria had strong interactions in responders, whereas opportunistic pathogen demonstrated strong interactions in non-responders (Pearson's coefficient>0.5). Finally, five microbes were selected as the optimal set for the response prediction model, which yielded an area under the curve value of 82.33%. CCRT significantly changed the diversity and composition of microbiome, especially in non-responders. Several microbes might be related with treatment response. These findings highlight the potential of microbiome to play an important role as a biomarker in patients with rectal cancer. (NCT02533271).

Combination of irinotecan silicasome nanoparticles with radiation therapy sensitizes immunotherapy by modulating the activation of the cGAS/STING pathway for colorectal cancer

Our previous clinical trial (Identifier: NCT02605265) revealed that addition of irinotecan (IRIN) to neoadjuvant chemoradiotherapy for rectal cancer could improve the curative effect. However, the adverse effects caused by IRIN limited the wide application of IRIN chemoradiotherapy. This study aimed to explore the mechanism under the synergistic effects of IRIN plus radiation therapy in colorectal cancer (CRC) cells and optimization of IRIN delivery via a silicasome nanocarrier in vivo. Our results revealed that compared with single IRIN or radiation treatment, IRIN combined with radiation therapy remarkably activated the intracellular cGAS/STING pathway, and promoted the expression levels of major histocompatibility complex class I (MHC-I) and programmed death ligand 1 (PD-L1). Further, a silicasome (mesoporous silica nanoparticle coated with lipid bilayer) nanocarrier was utilized to improve the delivery of IRIN with enhanced efficacy and reduced side effects. In the MC38 CRC syngeneic tumor model, IRIN silicasome combined with radiation therapy demonstrated a greater antitumor efficacy than free IRIN plus radiation therapy. Flow cytometry showed the increased number of CD4+ T cells, CD8+ T cells, and dendritic cells (DCs) in tumor in the IRIN silicasome plus radiation group. The immunofluorescence staining further confirmed the activated immune microenvironment with the elevated interferon-γ (IFN-γ) deposition. Besides, the antitumor effect of IRIN silicasome plus radiation therapy was synergistically enhanced by anti-PD-1 immunotherapy. These findings indicated that the combination of IRIN silicasome with radiation therapy could sensitize immunotherapy by manipulating the cGAS/STING pathway serving as a new strategy for CRC treatment.

Size and depth of residual tumor after neoadjuvant chemoradiotherapy in rectal cancer - implications for the development of new imaging modalities for response assessment.

With the shift towards organ preserving treatment strategies in rectal cancer it has become increasingly important to accurately discriminate between a complete and good clinical response after neoadjuvant chemoradiotherapy (CRT). Standard of care imaging techniques such as CT and MRI are well equipped for initial staging of rectal tumors, but discrimination between a good clinical and complete response remains difficult due to their limited ability to detect small residual vital tumor fragments. To identify new promising imaging techniques that could fill this gap, it is crucial to know the size and invasion depth of residual vital tumor tissue since this determines the requirements with regard to the resolution and imaging depth of potential new optical imaging techniques. We analyzed 198 pathology slides from 30 rectal cancer patients with a Mandard tumor regression grade 2 or 3 after CRT that underwent surgery. For each patient we determined response pattern, size of the largest vital tumor fragment or bulk and the shortest distance from the vital tumor to the luminal surface. The response pattern was shrinkage in 14 patients and fragmentation in 16 patients. For both groups combined, the largest vital tumor fragment per patient was smaller than 1mm for 38% of patients, below 0.2mm for 12% of patients and for one patient as small as 0.06mm. For 29% of patients the vital tumor remnant was present within the first 0.01mm from the luminal surface and for 87% within 0.5mm. Our results explain why it is difficult to differentiate between a good clinical and complete response in rectal cancer patients using endoscopy and MRI, since in many patients submillimeter tumor fragments remain below the luminal surface. To detect residual vital tumor tissue in all patients included in this study a technique with a spatial resolution of 0.06mm and an imaging depth of 8.9mm would have been required. Optical imaging techniques offer the possibility of detecting majority of these cases due to the potential of both high-resolution imaging and enhanced contrast between tissue types. These techniques could thus serve as a complimentary tool to conventional methods for rectal cancer response assessment.

Efficacy Of 18FDG-PET/CT In Predicting Response After Neoadjuvant Chemoradiation In Rectal Cancer

Introduction: Neoadjuvant chemoradiation (NACRT) may result in significant response in rectal cancer. Conventional imaging may not be accurate. 18FDG-PET/CT scan has shown promising results for monitoring the response to NACRT. The aim of this study is to evaluate the role of 18FDG-PET/CT scan in predicting pathological response after NACRT in carcinoma rectum. Methods: Thirty-two consecutive patients with locally advanced rectal cancer were enrolled. Patients underwent NACRT comprising of external beam radiotherapy and concomitant infusional 5-FU based chemotherapy. It was followed 6 weeks later by total mesorectal excision. All patients underwent FDG-PET/CT before and minimum 6 weeks after the completion of NACRT. Maximum standardized uptake (SUVmax) value was calculated. The tumor regression grade (TRG) in resected specimen was scored according to the Mandard criteria. TRG 1-2 was considered as responders and TRG 3-5, non-responders. The SUVmax within the tumor was correlated to differentiate pathological responders from non-responders. Results: Fourteen of 30 patients were excluded due to protocol deviation. Following NACRT, 7 (50%) patients were classified as responders (TRG 1-2) and 7 (50%) non-responders (TRG 3-5). There were no significant differences in pre NACRT SUVmax between responders (12.05±2.81) and non-responders (17.65±7.20) (p=0.079). The mean post-NACRT SUVmax was significantly lower in responders than non-responders (6.4 vs 10.8; p=0.024). To compare the response using ROC curve analysis (AUC=0.83), and considering a cut-off post SUVmax as 7.0, the sensitivity was 57.14%, specificity 71.43%, positive predictive value (PPV) 66.67%, negative predictive value (NPV) 62.50%, and the overall accuracy was 64.28% to differentiate pathological responders from non-responders. Conclusion: These preliminary results suggest that 18FDG-PET/CT could be a potentially useful tool in predicting response after NACRT in locally advanced rectal cancer. Post SUVmax of 7.0 appears to be the best predictor tumor response following NACRT.

Metagenomic Analysis of Intratumoral Microbiome Linking to Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

To assess taxonomic and functional characteristics of tumor-bearing microbiota and its association with response to neoadjuvant chemoradiation therapy (nCRT) in patients with locally advanced rectal cancer. We performed metagenomic sequencing of biopsy tumoral tissues from 73 patients with locally advanced rectal cancer before nCRT. Patients were classified into poor responders (PR) and good responders (GR) according to response to nCRT. Subsequent investigation of network alteration, key community, microbial biomarkers, and function related to nCRT responses were carried out. The network-driven analysis systematically revealed 2 co-occurring bacteria modules that exhibited opposite relationship with rectal cancer radiosensitivity. In the 2 modules, prominent alteration of global graph properties and community structure was observed between networks of PR and GR group. By quantifying changes in between-group association patterns and abundances, a total of 115 discriminative biomarker species linked to nCRT response were found, and 35 microbial variables were selected to establish the optimal randomForest classifier for nCRT response prediction. It yielded an area under the curve value of 85.5% (95% CI, 73.3%-97.8%) in the training cohort and 88.4% (95% CI, 77.5%-99.4%) in the validation cohort. In a comprehensive consideration, 5 key bacteria showed high relevance with inducing resistance to nCRT, including Streptococcus equinus, Schaalia odontolytica, Clostridium hylemonae, Blautia producta, and Pseudomonas azotoformans. One key hub including several butyrate-formation bacteria involving with driving network alteration from GR to PR indicate that microbiota-derived butyrate may also be involved in reducing the antitumor effects of nCRT, especially Coprococcus. The functional analysis of metagenome linked the nitrate and sulfate-sulfur assimilation, histidine catabolic process, and resistance to cephamycin to the reduced therapeutic response. It also linked to leucine degradation, isoleucine biosynthesis, taurine, and hypotaurine metabolism to the improved response to nCRT. Our data offer novel potential microbial factors and shared metagenome function linked to resistance to nCRT.

A Comprehensive Prediction Model Based on MRI Radiomics and Clinical Factors to Predict Tumor Response After Neoadjuvant Chemoradiotherapy in Rectal Cancer

To establish a prediction model for the efficacy of neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC), using pretreatment magnetic resonance imaging (MRI) multisequence image features and clinical parameters. Patients with clinicopathologically confirmed LARC were included (training and validation datasets, n=100 and 27, respectively). Clinical data of patients were collected retrospectively. We analyzed MRI multisequence imaging features. The tumor regression grading (TRG) system proposed by Mandard et al was adopted. Grade 1-2 of TRG was a good response group, and grade 3-5 of TRG was a poor response group. In this study, a clinical model, a single sequence imaging model, and a comprehensive model combined with clinical imaging were constructed, respectively. The area under the subject operating characteristic curve (AUC) was used to evaluate the predictive efficacy of clinical, imaging, and comprehensive models. The decision curve analysis method evaluated the clinical benefit of several models, and the nomogram of efficacy prediction was constructed. The AUC value of the comprehensive prediction model is 0.99 in the training data set and 0.94 in the test data set, which is significantly higher than other models. Radiomic Nomo charts were developed using Rad scores obtained from the integrated image omics model, circumferential resection margin(CRM), DoTD, and carcinoembryonic antigen(CEA). Nomo charts showed good resolution. The calibrating and discriminating ability of the synthetic prediction model is better than that of the single clinical model and the single sequence clinical image omics fusion model. Nomograph, based on pretreatment MRI characteristics and clinical risk factors, has the potential to be used as a noninvasive tool to predict outcomes in patients with LARC after nCRT.

A Strict Patient Selection Protocol Could Be the Key to Success for Transanal Minimally Invasive Surgery (TAMIS).

In recent years, the local excision of benign rectal lesions or early-stage rectal cancers using minimally invasive surgical techniques has replaced radical interventions that caused impairment in patients' quality of life. The aim of the present study was to investigate the feasibility of transanal minimally invasive surgery (TAMIS), as well as its excision quality, its oncologic outcomes, and its impact on anorectal function. Patients who underwent TAMIS at a single colorectal unit of a tertiary university hospital from 2015 until 2020 for benign rectal lesions or early-stage malignant rectal lesions, along with unsuitable patients for radical interventions, were included in the present study. Twenty-five patients underwent TAMIS for rectal lesions. Their median distance from the anal verge was 7 cm (range 4-12 cm) and their median size was 3.8 cm (range 2-6 cm). The median operative duration was 75 minutes (range 30-150 minutes) and the median hospitalization interval was 2 days (range 1-6 days). In addition, the negative resection rate was 100% and the recurrence rate was 4% during an average follow-up period of 30 months (range 3-36 months). Two patients (8%) presented short-term complications, and in 1 patient (4%) a hybrid technique was required. Seventeen patients (68%) reported moderate incontinence symptoms 6 weeks postoperatively that subsided in all patients 3 months postoperatively. TAMIS seemed to be a feasible technique with adequate oncologic outcomes and high excision quality, which preserved patients' quality of life. The impact of TAMIS on anorectal function after neoadjuvant chemoradiotherapy for rectal cancer should be further investigated, however.

Changes in colorectal cancer treatment during the COVID-19 pandemic in Japan: Interrupted time-series analysis using the National Database of Japan

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic forced us to accept changes in our usual diagnostic procedures and treatments for colorectal cancer. This study aimed to determine the impact of the pandemic on colorectal cancer treatment in Japan. MethodsThe number of colorectal surgeries, stoma constructions, stent placements or long tube insertions, and neoadjuvant chemoradiotherapies were determined each month using sampling datasets from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. The observation periods before and during the pandemic were January 2015 to January 2020 and April 2020 to January 2021, respectively. An interrupted time-series analysis was used to estimate the changes in the number of procedures during the pandemic. ResultsThe number of endoscopic surgeries for colon cancer significantly decreased in April and July 2020 and for rectal cancer in April 2020. Additionally, the number of laparoscopic and open surgeries for colon cancer significantly decreased in July 2020 and October 2020, respectively. The number of stoma constructions and stent placements or long tube insertions did not increase during the observation period. Neoadjuvant chemoradiotherapy for rectal cancer significantly increased in April 2020 but levels returned shortly thereafter. These results suggest that the recommendations to overcome the pandemic proposed by expert committees, including the replacement of laparoscopic surgery with open surgery, stoma construction to avoid anastomotic leak, and replacement of surgery on the ileus with stent placement, were not widely implemented in Japan. However, as an exception, neoadjuvant chemoradiotherapy for rectal cancer was performed as an alternative treatment to delay surgery in small quantities. ConclusionA declining number of surgeries raises concerns about cancer stage progression; however, we found no evidence to suggest cancer progression from the trajectory of the number of stoma constructions and stent placements. In Japan, even during the pandemic, conventional treatments were performed.

Neoadjuvant Chemoradiation for Rectal Cancer Achieves Satisfactory Tumour Regression and Local Recurrence – Result of a Dedicated Multi-disciplinary Approach from a South Asian Centre

BackgroundPre-operative long-course chemoradiotherapy (CRT) for rectal cancer has resulted in improvement in rates of restorative rectal resection and local recurrence by inducing tumour downstaging and downsizing. Total mesorectal excision (TME) is a standardised surgical technique of low anterior resection aimed at the prevention of local tumour recurrence. The purpose of this study was to evaluate tumour response following CRT in a standardised group of patients with rectal cancer.MethodsOne hundred and thirty-one patients (79 male; 52 female, median age 57; interquartile range 47–62 years) of 153 with rectal cancer who underwent pre-operative long-course CRT were treated by standardised open low anterior resection at a median of 10 weeks post-CRT. Sixteen of 131 (12%) were 70 years or older. Median follow-up at the time of analysis was 15 months (interquartile range 6–45 months). Pathology reports were analysed based on AJCC-UICC classification using the TNM system. Data recorded were overall/subgrades of tumour regression; good, moderate or poor, lymph node harvest, local recurrence, disease-free and overall survival using standard statistical methods.Results78% showed tumour regression post-CRT; 43% displayed good tumour regression/response while 22% had poor tumour regression/response. All patients had a pre-operative T-stage of either T3 or T4. Post-operation, good responders had a median T stage of T2 vs. T3 in poor responders (P = 0.0002). Overall, the median lymph node harvest was < 12. There was no difference in the number of nodes harvested in good vs. poor responders (Good/moderate-6 nodes vs. Poor- 8; P = 0.31). Good responders tended to have a lesser number of malignant nodes vs. poor responders (P = 0.31). Overall, local recurrence was 6.8% and the anal sphincter preservation rate was 89%. Predicted 5-year disease-free and overall survival were similar between good and poor responders.ConclusionLong-course CRT resulted in satisfactory tumour regression and enabled consideration for safe, sphincter-saving resection in rectal cancer. A dedicated multi-disciplinary team approach achieved a global benchmark for local recurrence in a resource-limited setting.