Radiomic score for lung nodules as a prognostic biomarker in locally advanced rectal cancer patients: A bi-institutional study.

BACKGROUND: Undetermined lung nodules are common in locally advanced rectal cancer (LARC) and lack precise risk stratification. This study aimed to develop a radiomic-based score (Rad-score) to distinguish metastasis and predict overall survival (OS) in patients with LARC and lung nodules. METHODS: Retrospective data from two institutions (July 10, 2006-September 24, 2015) was used to develop and validate the Rad-score for distinguishing lung nodule malignancy. The prognostic value of the Rad-score was investigated in LARC cohorts, leading to the construction and validation of a clinical and radiomic score (Cli-Rad-score) that incorporates both clinical and radiomic information for the purpose of improving personalized clinical prognosis prediction. Descriptive statistics, survival analysis, and model comparison were performed to assess the results. RESULTS: The Rad-score demonstrated great performance in distinguishing malignancy, with C-index values of 0.793 [95% CI: 0.729-0.856] in the training set and 0.730 [95% CI: 0.666-0.874] in the validation set. In independent LARC cohorts, Rad-score validation achieved C-index values of 0.794 [95% CI: 0.737-0.851] and 0.747 [95% CI: 0.615-0.879]. Regarding prognostic prediction, Rad-score effectively stratified patients. Cli-Rad-score outperformed the clinicopathological information alone in risk stratification, as evidenced by significantly higher C-index values (0.735 vs. 0.695 in the internal set and 0.618 vs. 0.595 in the external set). CONCLUSIONS: CT-based radiomics could serve as a reliable and powerful tool for lung nodule malignancy distinction and prognostic prediction in LARC patients. Rad-score predicts prognosis independently. Incorporation of Cli-Rad-score significantly enhances the persionalized clinical prognostic capacity in LARC patients with lung nodules.

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

Background: The 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. Methods: A 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). Results: Nine 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. Conclusion: Radiomics 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.

Long-term outcomes in a retrospective cohort of patients with rectal cancer with complete response after total neoadjuvant therapy: a propensity-score weighted analysis.

Background: The watch-and-wait (W&W) strategy is a novel treatment option for patients with rectal cancer who have a strong desire for organ preservation. The study aimed to explore the long-term outcomes of the W&W strategy in a large cohort of rectal cancer patients who achieved a clinical complete response (cCR) after consolidation total neoadjuvant therapy (TNT), and to compare with patients who achieved a pathological complete response (pCR) after radical surgery. Methods: The W&W group comprised patients who were assessed as having a cCR after consolidation TNT and adopted the W&W strategy. Patients who underwent standard resection and achieved a pCR were compared as a reference. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier analysis with log-rank test was used to compare survival outcomes. Results: We included 89 and 171 patients in the W&W and pCR groups, respectively. The median follow-up period was 45 and 58 months for the W&W and pCR groups, respectively. After IPTW adjustment, the 2-year local regrowth/recurrence rate for the W&W and pCR groups were 9.9% and 2.0%, respectively (p < 0.001). The W&W and pCR groups had similar 5-year outcomes, including overall survival, disease-free survival, and distant metastasis-free survival (all p > 0.05). No significant difference was observed in the rates of distant metastasis between patients in the W&W group with local regrowth and those without local regrowth (25% versus 6.2%, p = 0.119). Conclusion: Patients who were managed with a W&W strategy after consolidation TNT had favorable survival outcomes, which were similar to those of patients with a pCR. The rate of local regrowth in W&W patients was lower in our study than in other studies as a result of the implementation of consolidation TNT.

Pangenomic analysis of Chinese gastric cancer.

Pangenomic study might improve the completeness of human reference genome (GRCh38) and promote precision medicine. Here, we use an automated pipeline of human pangenomic analysis to build gastric cancer pan-genome for 185 paired deep sequencing data (370 samples), and characterize the gene presence-absence variations (PAVs) at whole genome level. Genes ACOT1, GSTM1, SIGLEC14 and UGT2B17 are identified as highly absent genes in gastric cancer population. A set of genes from unaligned sequences with GRCh38 are predicted. We successfully locate one of predicted genes GC0643 on chromosome 9q34.2. Overexpression of GC0643 significantly inhibits cell growth, cell migration and invasion, cell cycle progression, and induces cell apoptosis in cancer cells. The tumor suppressor functions can be reversed by shGC0643 knockdown. The GC0643 is approved by NCBI database (GenBank: MW194843.1). Collectively, the robust pan-genome strategy provides a deeper understanding of the gene PAVs in the human cancer genome.

Prognostic significance of tumor deposits in radically resected gastric cancer: a retrospective study of a cohort of 1915 Chinese individuals.

BACKGROUND: Tumor deposits (TDs) have been identified as an independent prognostic factor in gastric cancer (GC). However, the associated clinicopathological factors and how to simply and reasonably incorporate TD into the TNM staging system remain undetermined. The aim of the current study was therefore to assess the significance of TD among radically resected GC patients. METHODS: We retrospectively reviewed 1915 patients undergoing radical resection between 2007 and 2012. The patients were classified into two groups according to TD status (absent vs. present), and the clinicopathologic characteristics, DFS, and OS were compared. Associations of TD presence with other clinicopathologic factors were evaluated by logistic regression analysis. Univariate and multivariate Cox regression analyses were performed to determine the prognostic factors for DFS and OS in the primary cohort. Propensity score matching (PSM) was performed to reduce the possibility of selection bias according to the presence of TD. External validation of previously proposed modified staging systems incorporating TD was conducted. RESULTS: The detection rate of TD was 10.5% (201/1915). The presence of TD was significantly related to unfavorable clinicopathologic variables, including advanced T and N categories. According to the multivariate Cox regression analysis, the presence of TD was identified as an independent prognostic factor for DFS and OS in the primary cohort (both P < 0.001). In the after-PSM cohort, TD presence also significantly shortened DFS and OS. In the external validation, one system that incorporated TD into the pTNM stage had the best performance. CONCLUSIONS: The presence of TD was significantly associated with poor survival in radically resected GC patients. The incorporation of TD into the TNM staging system can further improve the predictive capability. A multicenter cohort with a large sample size is needed to determine the appropriate method of incorporation.

A study protocol of a randomized phase II trial of perioperative chemoimmunotherapy verses perioperative chemoimmunotherapy plus preoperative chemoradiation for locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma: the NeoRacing study.

BACKGROUND: Perioperative chemotherapy (ChT) and preoperative chemoradiation (CRT) are both the standard treatments for locally advanced gastric cancer (LAGC). CRT can achieve a higher pathological complete regression (pCR) rate, but whether this higher pCR rate can be transformed into a long-term survival benefit remains inconclusive. Therefore, relevant studies are in progress. On the other hand, immunotherapy has been established for the first-line treatment of advanced gastric cancer (AGC) and has been widely explored in the perioperative setting. The combination of chemotherapy/radiotherapy and immunotherapy may have a synergistic effect, which will lead to a better antitumor effect. The preliminary reports of ongoing studies show promising results, including a further improved pCR rate. However, the preferred treatment combination for LAGC is still not established. To solve this problem, we are carrying out this randomized phase II trial, which aims to evaluate the efficacy and safety of perioperative chemotherapy plus the use of PD-1 antibody with or without preoperative chemoradiation for LAGC. METHODS: Eligible patients with LAGC or gastroesophageal junction (GEJ) adenocarcinoma were randomized to receive perioperative ChT, PD-1 antibody, surgery with (Arm A) or without preoperative CRT (Arm B), and PD-1 antibody maintenance until one year after surgery. The primary endpoint of this study is that the pCR rate of Arm A will be significantly higher than that of Arm B. The secondary endpoints include the pathological partial regression (pPR) rate, R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), safety and surgical complications. Moreover, several explorative endpoints will be evaluated to find and validate the predictive biomarkers of immunotherapy. DISCUSSION: The results of the NeoRacing study will provide important information concerning the application of PD-1 antibody in LAGC patients during the perioperative setting. Meanwhile, the two treatment protocols will be compared in terms of efficacy and safety. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05161572 . Registered 17 December 2021 - Retrospectively registered.

A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis.

Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2 (PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP's activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4-YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.

Neoadjuvant versus Postoperative Chemoradiotherapy is Associated with Improved Survival for Patients with Resectable Gastric and Gastroesophageal Cancer.

BACKGROUND: The optimal timing of chemoradiotherapy (CRT) for patients with localized gastric cancer remains unclear. This study aimed to compare the survival outcomes between neoadjuvant and postoperative CRT for patients with gastric and gastroesophageal junction (GEJ) cancer. METHODS: This retrospective study analyzed 152 patients with gastric (42%) or GEJ (58%) adenocarcinoma who underwent definitive surgical resection and received either neoadjuvant or postoperative CRT between 2005 and 2017 at the authors' institution. The primary end point of the study was overall survival (OS). RESULTS: The median follow-up period was 37.5 months. Neoadjuvant CRT was performed for 102 patients (67%) and postoperative CRT for 50 patients (33%). The patients who received neoadjuvant CRT were more likely to be male and to have a GEJ tumor, positive lymph nodes, and a higher clinical stage. The median radiotherapy (RT) dose was 50.4 Gy for neoadjuvant RT and 45.0 Gy for postoperative RT (p < 0.001). The neoadjuvant CRT group had a pathologic complete response (pCR) rate of 26% and a greater rate of R0 resection than the postoperative CRT group (95% vs. 76%; p = 0.002). Neoadjuvant versus postoperative CRT was associated with a lower rate of any grade 3+ toxicity (10% vs. 54%; p < 0.001). The multivariable analysis of OS showed lower hazards of death to be independently associated neoadjuvant versus postoperative CRT (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.36-0.91; p = 0.020) and R0 resection (HR 0.50; 95% CI 0.27-0.90; p = 0.021). CONCLUSIONS: Neoadjuvant CRT was associated with a longer OS, a higher rate of R0 resection, and a lower treatment-related toxicity than postoperative CRT. The findings suggest that neoadjuvant CRT is superior to postoperative CRT in the treatment of gastric and GEJ cancer.

The role of nutritional assessment for predicting radiotherapy-induced adverse events in patients with gastric cancer.

OBJECTIVE: The aim of this study was to investigate the role of nutritional factors in predicting radiotherapy-associated toxicities for gastric cancer patients. METHODS: A total of 285 gastric cancer patients who underwent radiotherapy in our hospital (Fudan University Shanghai Cancer Center) between 2010 and 2017 were included in this retrospective study. Nutritional status assessment included body weight loss (BWL), body mass index (BMI), serum albumin, nutrition risk screening 2002(NRS-2002), patient-generated subjective global assessment(PG-SGA) and nutritional risk index (NRI). RESULTS: Of all patients, 19.6% were underweight (BMI<18.5 kg/m2), 25.6% were hypoalbuminemia (<35 g l-1) and 48.8% lost ≥10% of body weight in the 6-month interval before radiotherapy(BWL). Meanwhile, 73.3%, 78.6 and 47.2% of the patients were diagnosed as malnutrition based on NRS-2002, PG-SGA and NRI, respectively. Hematological adverse events were present in 91.2% (≥Grade 1) and 20.4% (≥Grade 3) of the patients. Non-hematological adverse events occurred in 89.8% (≥Grade1) and 14.4% (≥Grade 3) of the patients. Multivariate analyses indicated that only hypoalbuminemia(<35 g l-1) was independent predictor for Grade 3/4 hematological and non-hematological adverse events. Meanwhile, higher BWL(≥10%) was also independent predictor for Grade 3/4 non-hematological adverse events. NRS-2002, PG-SGA and NRI score were not associated with treatment-induced adverse events. CONCLUSION: BWL and serum albumin are useful factors for predicting severe adverse events in gastric cancer patients who undergo radiotherapy. ADVANCES IN KNOWLEDGE: The use of nutritional factors in predicting severe adverse events enables implementation of individualized treatment strategies for early and intensive nutritional interventions in high-risk patients.

Immune Score Predicts Outcomes of Gastric Cancer Patients Treated with Adjuvant Chemoradiotherapy.

BACKGROUND: Substantial evidence has demonstrated that tumor-infiltrating lymphocytes (TILs) are correlated with patient prognosis. The TIL-based immune score (IS) affects prognosis in various cancers, but its prognostic impact in gastric cancer (GC) patients treated with adjuvant chemoradiotherapy remains unclear. METHODS: A total of 101 GC patients who received chemoradiotherapy after gastrectomy were retrospectively analyzed in this study. Immunohistochemistry staining for CD3+ and CD8+ T-cell counts in both tumor center (CT) and invasive margin (IM) regions was built into the IS. Patients were then divided into three groups based on their differential IS levels. The correlation between IS and clinical parameters was analyzed. The prognostic impact of IS and clinical parameters was evaluated using Kaplan-Meier analysis and Cox proportional hazard regression analysis. Receiver operating characteristic (ROC) curves were plotted to compare the area under the curve (AUC) of IS with other clinical parameters. Nomograms for disease-free survival (DFS) and overall survival (OS) prediction were constructed based on the identified parameters. RESULTS: Finally, 20 (19.8%), 57 (56.4%), and 24 (23.8%) GC patients were identified with low, intermediate, and high IS levels, respectively. GC patients with higher IS levels exhibited better DFS (p < 0.001) and OS (p < 0.001). IS was an independent prognostic factor for both DFS (p < 0.001) and OS (p < 0.001) in multivariate analysis. IS presented a better predictive ability than the traditional pathological tumor-node-metastasis (pTNM) staging system (AUC: 0.801 vs. 0.677 and 0.800 vs. 0.660, respectively) with respect to both DFS and OS. The C-index of the nomograms for DFS and OS prediction was 0.737 and 0.774, respectively. CONCLUSIONS: IS is a strong predictive factor for both DFS and OS in GC patients treated with adjuvant chemoradiotherapy, which may complement the traditional pTNM staging system.

Preoperative Chemoradiotherapy Versus Postoperative Chemoradiotherapy for Patients With Locally Advanced Gastric Cancer: A Retrospective Study Based on Propensity Score Analyses.

PURPOSE: Although adjuvant chemoradiotherapy (CRT) used to be recommended as a standard of care for locally advanced gastric cancer, this suggestion has been strongly challenged recently. However, clear evidence regarding the optimization of radiotherapy is lacking. The purpose of this study was to compare the effectiveness of preoperative CRT versus that of postoperative CRT for resectable or potentially resectable gastric cancer. METHODS: From January 2005 to December 2017, patients with clinical stage III/IVa (i.e., T3-4aN+M0 or T4bNxM0) locally advanced gastric cancer were retrospectively identified. Survival after preoperative CRT and postoperative CRT was assessed by unadjusted, propensity score matching (PSM) and inverse probability of treatment weight (IPTW) analyses. Moreover, exploratory subgroup analyses were performed, and toxicity and patterns of failure were also investigated. RESULTS: The median follow-up time was 32.5 months. A total of 82 and 463 patients were enrolled in the preoperative and postoperative CRT groups, respectively. After propensity score matching, preoperative CRT was associated with improved overall survival (OS) and disease-free survival (DFS) compared with postoperative CRT (3-year OS: 72.6 vs. 54.4%, log-rank p = 0.0021; 3-year DFS: 61.7 vs. 44.7%, log-rank p = 0.002). The unadjusted and IPTW analyses yielded consistent results. A complete pathologic response was achieved in 13.4% of the preoperative CRT group. Although the incidence of grade 3 or 4 adverse effects and surgical complications were similar between the two groups, significantly fewer patients experienced treatment interruptions or dose reductions due to toxic effects in the preoperative CRT setting than in the postoperative CRT setting (3.7 vs. 10.6%, p = 0.049). CONCLUSIONS: Compared with postoperative CRT, preoperative CRT was associated with improved OS and DFS, superior treatment compliance and comparable surgical complications for patients with locally advanced gastric cancer. Our findings provide important evidence for the optimal combination modalities of surgery and CRT in the absence of randomized clinical data.

Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer.

BACKGROUND: Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. METHODS: Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. RESULTS: In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. CONCLUSIONS: These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.

Regulation of the regeneration of intestinal stem cells after irradiation.

BACKGROUND: Radiation enteritis is common in cancer patients with abdominal and pelvic malignant tumors that have received radiotherapy. Regeneration of intestinal stem cells is a critical process for intestine self-repairing post-irradiation. In this study, we attempted to find out the molecules that promote the regeneration of intestinal stem cells to repair the irradiation damage. METHODS: Male C57BL/6 mice were given a single dose of 12 Gy irradiation, and in vitro cultured organoids were given 6 Gy X-rays to construct the regeneration of intestinal stem cells. Hematoxylin and eosin (H&E) staining was performed for morphological observation. In situ hybridization was used to detect the expression of Lgr5, and immunofluorescence staining was adopted to detect the expression of CD44. FACS was used to sort CD44 positive cells of crypts. RNA was then extracted, and RNA-Seq was performed. The Wnt11 over-expression cell line was constructed to collect the Wnt11 conditioned medium (CM). RESULTS: The results showed both Lgr5 and CD44 located at the bottom of normal crypts. The expression of Lgr5 was lower at day 3.5, 5, but recovered at day 10 post-irradiation compared with the control. However, the expression of CD44 was higher at day 3.5, 5, but recovered at day 10 post-irradiation compared with the control group. The quantitative real-time polymerase chain reaction (qRT-PCR) assay showed consistent results. RNA-Seq results showed that Wnt11 was over-expressed in the irradiation group. After irradiation adding Wnt11 condition medium to culture, the intestinal organoids resulted in a bigger size and more buddings of the newborn organoids compared with the control group. CONCLUSIONS: The expression of CD44 increases during the radiation-induced regeneration of intestinal stem cells while Lgr5 decreases, adding Wnt11 CM can facilitate the proliferation of the newborn organoids after irradiation. Wnt11 is a potential target to promote the regeneration of intestinal stem cells to repair the radiation injury.

Antitumor Effect of Cycle Inhibiting Factor Expression in Colon Cancer via Salmonella VNP20009.

BACKGROUND: Colon cancer is one of the major causes of morbidity and mortality worldwide. Cycle inhibiting factors (Cifs) have been shown to deamidate Nedd8, resulting in cell cycle arrest. OBJECTIVE: To determine the antitumor effect of Cifs on colon cancer by using attenuated Salmonella typhimurium VNP20009. METHODS: The VNP-SOPE2-cif and VNP-SOPE2-cif-C/A plasmids were transfected into attenuated Salmonella typhimurium VNP20009. The efficiency and specificity of the Cif promoter were validated in colon cancer SW480 cell lines. Western blotting was subsequently performed to evaluate cell cycle regulators, including P21, P27 and Wee1. In vivo, the antitumor effect of VNP20009 was evaluated in a colon cancer xenograft model. RESULTS: Firstly, VNP-SOPE2-cif and VNP-SOPE2-cif-C/A were selectively expressed both in the bacterial and colon cancer cells. Cif expression in SW480 cells via the VNP tumor-targeted expression system induced the accumulation of Wee1, p21 and p27 expression. Moreover, tumor growth was significantly inhibited in the mice with VNP-SOPE2-cif compared to the mice with VNP with the empty construct. CONCLUSION: These results suggest that Cif gene delivered by VNP20009 is a promising approach for the treatment of colon cancer.

Quantifying skeletal muscle wasting during chemoradiotherapy with Jacobian calculations for the prediction of survival and toxicity in patients with gastric cancer.

BACKGROUND AND PURPOSE: This study aims to investigate changes in body composition during adjuvant chemoradiotherapy (CRT) quantitatively and visually in patients with gastric cancer and evaluate the correlation of the changes with survival and toxicity. MATERIALS AND METHODS: A total of 182 gastric cancer patients who underwent surgery and adjuvant CRT were included. CT images at the level of the third lumbar vertebra (L3) were analyzed to assess the areas of muscles. We further proposed a framework to quantify muscle changes using Jacobian calculations. Jacobian value (Jac) was calculated for each voxel of muscle by measuring the ratio of muscle changes, where Jac <1 indicated shrinkage and Jac >1 indicated expansion. Variances between the pre- and post-CRT body composition were quantitatively computed, and their impact on toxicity and long-term outcomes were studied. RESULTS: The skeletal muscle index decreased from 44.4 ± 7.4 cm2/m2 to 43.6 ± 7.0 cm2/m2 after CRT. Skeletal muscle wasting and Jac 0.35 ≥ 5% were negatively associated with overall survival (p = 0.036 and p = 0.008, respectively). A new prediction model combining clinical variables and Jacobian features was constructed, and yielded a c statistic of 0.78 (95% CI 0.68-0.87). Jac 0.75 to Jac 1.15 (-25%

Patient-Derived Organoids Predict Chemoradiation Responses of Locally Advanced Rectal Cancer.

Accumulating evidence indicates that patient-derived organoids (PDOs) can predict drug responses in the clinic, but the ability of PDOs to predict responses to chemoradiation in cancer patients remains an open question. Here we generate a living organoid biobank from patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NACR) enrolled in a phase III clinical trial. Our co-clinical trial data confirm that rectal cancer organoids (RCOs) closely recapitulate the pathophysiology and genetic changes of corresponding tumors. Chemoradiation responses in patients are highly matched to RCO responses, with 84.43% accuracy, 78.01% sensitivity, and 91.97% specificity. These data imply that PDOs predict LARC patient responses in the clinic and may represent a companion diagnostic tool in rectal cancer treatment.

HUPAN: a pan-genome analysis pipeline for human genomes.

The human reference genome is still incomplete, especially for those population-specific or individual-specific regions, which may have important functions. Here, we developed a HUman Pan-genome ANalysis (HUPAN) system to build the human pan-genome. We applied it to 185 deep sequencing and 90 assembled Han Chinese genomes and detected 29.5 Mb novel genomic sequences and at least 188 novel protein-coding genes missing in the human reference genome (GRCh38). It can be an important resource for the human genome-related biomedical studies, such as cancer genome analysis. HUPAN is freely available at http://cgm.sjtu.edu.cn/hupan/ and https://github.com/SJTU-CGM/HUPAN .