Genetic interactions reveal distinct biological and therapeutic implications in breast cancer.

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53mut-AURKAamp and endocrine therapy resistance, germline BRCA1mut-MYCamp and improved sensitivity to PARP inhibitors, and TP53mut-MYBamp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations.

Comprehensive genomic profiling of breast cancers characterizes germline-somatic mutation interactions mediating therapeutic vulnerabilities.

Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.

An In Vivo CRISPR Screen Identifies That SNRPC Promotes Triple-Negative Breast Cancer Progression.

Dysregulation of RNA-binding proteins (RBP) is one of the characteristics of cancer. Investigating the biological functions and molecular mechanisms of abnormal RBPs can help uncover new cancer biomarkers and treatment strategies. To identify oncogenic RBPs in triple-negative breast cancer (TNBC), we employed an in vivo CRISPR screen and a TNBC progression model, which revealed small nuclear ribonucleoprotein polypeptide C (SNRPC), a subunit of the U1 small nuclear ribonucleoprotein particle (U1 snRNP), as a key modulator of TNBC progression. SNRPC was frequently upregulated, which corresponded to poor prognosis in patients with TNBC. SNRPC ablation significantly impaired the proliferation, migration, and invasion of TNBC cells in vitro and in vivo. In addition, SNRPC was essential for the stability of U1 snRNP and contributed to the RNA Pol II-controlled transcriptional program. Knockdown of SNRPC decreased RNA Pol II enrichment on a subset of oncogenes (TNFAIP2, E2F2, and CDK4) and reduced their expression levels. Furthermore, SNRPC deletion was confirmed to inhibit TNBC progression partially through regulation of the TNFAIP2-Rac1-ß-catenin signaling pathway. Taken together, this data suggests that SNRPC plays an oncogenic role in TNBC, is a marker of poor prognosis, and may be a valuable therapeutic target for patients with intractable TNBC. SIGNIFICANCE: A functional CRISPR screen identifies SNRPC as an RNA-binding protein that promotes the aggressiveness of breast cancer by facilitating Pol II-controlled transcription of oncogenes.

Effect of pneumovesicoscopic cohen surgery with adjustable suspension technique through the urethra on the treatment of primary vesicoureteral reflux disease in infants.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of pneumovesicoscopic Cohen surgery with an adjustable suspension technique through the urethra for the treatment of primary vesicoureteral reflux disease in infants. METHODS: This study retrospectively analysed the clinical data of 31 infants who underwent pneumovesicoscopic Cohen surgery with an adjustable suspension technique through the urethra in our hospital from January 2019 to December 2020. We also collected the clinical data of 29 infants who underwent open Cohen surgery in our hospital from January 2015 to December 2018 as a control variable. The clinical efficacy of the two groups was compared. RESULT: All pneumovesicoscopic Cohen surgeries were successfully completed and no patients were converted to open surgery. The amount of bleeding, duration of postoperative analgesia, duration of postoperative haematuria, incision size and length of hospital stay in the pneumovesicoscopic surgery group were significantly lower than those in the open surgery group (P < 0.05). The operation time of the pneumovesicoscopic surgery group was significantly longer than that of the open surgery group (P < 0.05). Both groups were followed for six months after surgery. At the 6-month follow-up time, there were no significant differences in the degree of hydronephrosis, renal scarring, renal atrophy, glomerular filtration rate, or KIM-1 and MCP-1 expression between the two groups (P > 0.05). CONCLUSION: Pneumovesicoscopic Cohen surgery with an adjustable suspension technique through the urethra for the treatment of primary vesicoureteral reflux disease in infants was safe and effective. This procedure had the advantages of less trauma, quick recovery and good cosmetic effects.

Single-site laparoscopic high ligation of the extraperitoneal hernia sac with an epidural needle for incarcerated ovarian hernia in infants.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of single-site laparoscopic extraperitoneal hernia sac ligation with an epidural needle for incarcerated ovarian hernias in infants and young children. METHODS: The clinical data of 38 infants with incarcerated ovarian hernias who underwent single-site laparoscopic extradural needle extraperitoneal hernia sac ligation from January 2015 to January 2018 were retrospectively analysed. RESULTS: All procedures were successfully performed using laparoscopy with no need for conversion to open surgery. The time of hospital stay was 1.30 ± 0.39 days. During hospitalization and follow-up, there were no complications, such as intestinal or bladder injury, abdominal wall vascular injury, ovarian atrophy, hernia recurrence or contralateral indirect hernia. However, three patients experienced complications, including two cases of poor healing of the umbilical incision and one case of suture granuloma. CONCLUSIONS: Single-site laparoscopic high ligation of the extraperitoneal hernia sac with an epidural needle is a safe and feasible method for the treatment of incarcerated ovarian hernias in infants and young children. It has the advantages of minimal trauma, no scarring and good cosmetic effects.

Laparoscopic-assisted Soave procedure for Hirschsprung disease: 10-year experience with 106 cases.

BACKGROUND: The purpose of this study was to summarize the clinical experience and 10 year follow-up results of laparoscopic assisted Soave procedure for the treatment of long-segment Hirschsprung disease (HD). METHODS: From January 2010 to February 2020, 106 children with long-segment HD participated in this study. The laparoscopic-assisted Soave procedure was performed for the treatment of long-segment HD. The follow-up time was two weeks, one month, and three months after the operation, and then every six months to one year. RESULTS: The operation was successful for all 106 children. All patients were discharged 5-7 days after the operation. The median time in surgery was 150 (100-190) minutes, and the median volume of bleeding was 6 (3-10) ml. The short-term postoperative daily defecation frequency was 4-11 times, 3-7 times within 6 months, and 2-3 times after 6-12 months. Postoperative complications included anastomotic leakage in two cases, perianal dermatitis in 13 cases, anastomotic stenosis in four cases, adhesive bowel obstruction in two cases, enterocolitis in 16 cases, soiling in 11 cases, and constipation recurrence in three cases. CONCLUSIONS: The laparoscopic-assisted Soave procedure is a safe and effective surgical method for treating long-segment HD, and it causes little trauma or bleeding and has a fast postoperative recovery. Yet some complications may occur. Preoperative diagnosis, intraoperative and postoperative standardized processing can reduce the postoperative complications.

Single-port laparoscopic percutaneous closure of the internal ring for scarless repair of inguinal hernias in girls.

PURPOSE: The purpose of this study was to summarize the clinical experience with laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle for inguinal hernias in girls. MATERIAL AND METHODS: A total of 462 girls with inguinal hernias participated in this study from January 2013 to June 2019. Laparoscopic percutaneous extraperitoneal closure of the internal ring via an epidural needle was used to treat these patients. RESULTS: All 462 girls with an inguinal hernia successfully underwent laparoscopic surgery. The operative times for unilateral and bilateral inguinal hernias were 15 (11-25) minutes and 23 (18-33) minutes, respectively. All patients were discharged 1-2 days after the operations. During the hospitalization and follow-up periods, none of the following complications were observed: hernia recurrence, umbilical hernia, abdominal wall vascular injury, intestinal injury or bladder injury. However, there were six patients with complications: two cases of poor healing of the umbilical incision, three cases of suture granulomas and one case of groin traction pain and discomfort. CONCLUSION: Laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle is a safe and feasible method for the treatment of inguinal hernias in girls. This method has the advantages of limited trauma, no scarring and a good cosmetic effect.

Clinical Efficacy of an Indwelling Transanal Tube for the Prevention of Anastomotic Leakage After Hirschsprung's Disease: A Single Center Experience with Chinese Patients.

Background: The aim of this study was to investigate the clinical effectiveness of an indwelling transanal tube for the prevention of anastomotic leakage (AL) after a radical operation for Hirschsprung's disease (HD). Methods: We retrospectively analyzed the clinical data from 158 patients who had undergone laparoscopic-assisted Soave procedures for HD at our hospital from May 2015 to May 2019. Patients were divided into two groups depending upon whether the anal drainage tube was retained or not retained: an indwelling group (group A, n = 86) and a no-indwelling group (group B, n = 72). Results: All 158 children had a successful operation by a laparoscopic technique. There was no significant difference in the duration of the operation, the length of the incision, the amount of bleeding, or the postoperative hospitalization time between the two groups. Compared with the no-indwelling group, maintaining the transanal tube had significant advantages for preventing incidences of AL (P < .05). The 4-year follow-up showed that the incidence of postoperative enterocolitis with the indwelling transanal tube was significantly lower than in the group without the drainage tube (P < .05). Conclusions: The laparoscopic-assisted Soave procedure with an indwelling transanal tube is a safe and feasible method for the treatment of HD in children. This method can not only drain intestinal contents but also reduce the occurrence of AL.

Characterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing.

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.

Testicular descent and fixation through a scrotal stria incision for the treatment of palpable cryptorchidism in children aged <3 years: 10-year experience with 1034 cases.

This study was performed to summarize our clinical experience with testicular descent and fixation through a scrotal stria incision for the treatment of palpable cryptorchidism in children. This study included 1034 children with palpable cryptorchidism from March 2009 to March 2019. A scrotal stria incision was used to perform testicular descent and fixation. Overall, 1020 children successfully underwent surgical testicular descent and fixation through a scrotal stria incision, and 14 patients underwent conversion to inguinal incision surgery. All patients were discharged 1-2 days after the operation. During hospitalization and follow-up, 55 patients developed complications, including 10 patients with testicular retraction, 7 with poor healing of the incision, and 38 with a scrotal hematoma. No patients developed testicular atrophy, an indirect inguinal hernia, or a hydrocoele. Testicular descent and fixation through a scrotal stria incision for the treatment of palpable cryptorchidism in children is safe and feasible in well-selected cases. This method has the advantages of no scarring and a good cosmetic effect.

The Safety and Effectiveness of Laparoscopic versus Open Surgery for Congenital Hypertrophic Pyloric Stenosis in Infants.

BACKGROUND This study aimed to investigate the safety and effectiveness of laparoscopic pyloromyotomy for infants with congenital hypertrophic pyloric stenosis. MATERIAL AND METHODS The clinical data of 233 infants with congenital hypertrophic pyloric stenosis who were treated at our hospital from January 2013 to January 2018 were analyzed retrospectively. The patients were divided into 2 groups: the laparoscopic group (group A, n=126) and the conventional operation group (group B, n=107). RESULTS Laparoscopic surgery was successfully performed in all patients in the laparoscopic group, and none of the surgeries were converted to open surgery. Compared with traditional surgery, laparoscopic surgery has obvious advantages in operation time (29.8±12.9 minutes versus 37.2±17.5 minutes, P=0.012), postoperative feeding time (10.3±2.2 hours versus 15.2±4.1 hours, P=0.035), postoperative hospitalization time (2.8±0.7 days versus 3.5±1.9 days, P=0.013), incision length (0.9±0.2 cm versus 3.3±0.8 cm, P=0.002) and poor wound healing (0 versus 6, P=0.007). No complications, such as bleeding, gastric perforation, duodenal injury, abdominal infection or recurrent vomiting, were observed in the 2 groups. The growth and development (weight and height) of the infants in both groups were normal. CONCLUSIONS Laparoscopic pyloromyotomy has the same safety and effectiveness as the traditional operation and has the advantages of less trauma, faster recovery and cosmetically pleasing incisions.

Transscrotal transverse incision for the treatment of middle and low cryptorchidism in children: experience from 796 cases.

BACKGROUND: The purpose of this study was to summarize our clinical experience with transscrotal transverse incision in the treatment of low and middle cryptorchidism in children. METHODS: A total of 796 children with low or middle cryptorchidism participated in this study from March 2012 to May 2018. Transscrotal transverse incision was used to treat low and middle cryptorchidism. Symptoms and signs were followed up at 1 week, 1 month, 3months and every six to 12 months thereafter. RESULTS: Testicular descent fixation through transverse scrotal incision was successfully performed in all 796 children. All patients were discharged 1-2 days after the operation. During hospitalization and follow-up, 35 patients had complications, including 7 cases of cryptorchidism recurrence, 5 cases of poor scrotal incision healing, and 23 cases of scrotal haematoma. There were no complications, such as bladder injury, testicular atrophy, inguinal hernia or hydrocele. CONCLUSION: Transscrotal transverse incision is a safe and feasible method for the treatment of middle and low cryptorchidism. It has the advantages of less trauma and an aesthetic scar after operation.

Metabolomics as a potential method for predicting thyroid malignancy in children and adolescents.

PURPOSE: To identify potential metabolic biomarkers for distinguishing malignant and benign thyroid nodules in children and adolescents using a metabolomics approach. METHODS: A total of 96 consecutive patients (median age 14.29 ± 2.31 years, range 9-18 years) who underwent thyroidectomy and 40 healthy controls were enrolled. Patients were assigned to the papillary thyroid carcinoma and benign thyroid adenoma groups according to postoperative pathologic biopsy. Plasma samples were preoperatively collected, and multivariate analysis was performed to identify differential metabolites. RESULTS: Papillary thyroid carcinoma could be distinguished not only from healthy serum but also from benign thyroid adenoma according to the metabolic profiles. A total of 17 metabolites were identified. Compared with those from benign thyroid adenoma patients and healthy controls, the metabolites from papillary thyroid carcinoma patients, including leucine, lactate, alanine, glycine, acetate, lysine and choline, were increased, while glucose was decreased. CONCLUSION: The metabolomics method based on proton nuclear magnetic resonance has great potential for identifying papillary thyroid carcinoma in children and adolescents. Lactate and glycine may be used as potential serum markers for the diagnosis of papillary thyroid carcinoma.

Laparoscopic Disconnected Pyeloplasty to Treat Ureteropelvic Junction Obstruction (UPJO) in Children.

BACKGROUND The aim of this study was to assess the safety and clinical effectiveness of laparoscopic disconnected pyeloplasty in treating ureteropelvic junction obstruction (UPJO) in children. MATERIAL AND METHODS We retrospectively analyzed the clinical data of 122 young children with UPJO treated from February 2015 to February 2018 at our hospital. According to the surgery type, the patients were divided into 2 groups: a laparoscopic surgery group (group A, n=69) and a traditional open surgery group (group B, n=53). RESULTS The success rate of laparoscopic disconnected pyeloplasty was 100%, and none of the patients were converted to open surgery. The mean duration of use of painkillers was 27.6±11.3 h in group A and 58.2±18.2 h in group B (p=0.012), the postoperative hospital stay was 7.8±1.5 days in group A and 11.5±2.6 days in group B (p=0.041), and the length of the incision was 1.5±0.4 cm in group A and 5.2±1.1 cm in group B (p=0.007). The incidence rate of poor surgical wound healing was 0% in group A and 7.5% in group B (p=0.020). The incidence rate of ureteral stricture was 4.3% in group A and 3.8% in group B (p=0.874) during follow-up. The 1-year follow-up showed that both the anterior and posterior diameters and glomerular filtration rate were significantly improved from the preoperation period. CONCLUSIONS Laparoscopic disconnected pyeloplasty to treat UPJO in young children has the same early clinical effectiveness and safety as open surgery, and this procedure has the advantages of minimal trauma, quick recovery, and good cosmetic effect.

Single-Site Laparoscopic Percutaneous Extraperitoneal Closure of the Internal Ring Using an Epidural Needle for Children with Inguinal Hernia.

BACKGROUND This study evaluated the safety and effectiveness of single-site laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle for children with inguinal hernia. MATERIAL AND METHODS We retrospectively analyzed clinical data of 542 children with inguinal hernia who underwent single-site laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle at our hospital from June 2014 to June 2017. RESULTS All patients successfully underwent surgery and none were converted to conventional surgery. Abdominal vascular injury, vasectomy injury, testicular vascular injury, umbilical hernia, iatrogenic cryptorchidism, testicular atrophy, hydrocele, hernia recurrence, and scrotal edema were not reported during the perioperative period. A follow-up of these patients was performed for 12-24 months. During the follow-up period, umbilical hernia, iatrogenic cryptorchidism, testicular atrophy, and hydrocele were not noted, but 3 cases of hernia recurrence were found. CONCLUSIONS The single-site laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle for children with inguinal hernia is safe and effective, and this procedure has the advantages of minimal trauma, no scarring, and good cosmetic effect.

Laparoscopic Percutaneous Extraperitoneal Internal Ring Closure for Pediatric Inguinal Hernia: 1,142 Cases.

Purpose: The purpose of this study was to summarize the clinical experience of the laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle for the treatment of inguinal hernias. Methods: There were 1,142 children with an isolated inguinal hernia who participated in this study from January 2013 to May 2018. An epidural needle was used to treat the indirect inguinal hernia with laparoscopic assistance. Symptoms and signs were followed up at 1 week, 3 months, and every 1-2 years after the operation. Results: All 1,142 children underwent laparoscopic surgery successfully. All patients were discharged 1-2 days after the operation. During the hospitalization and follow-up, there were 21 patients with complications, including 6 cases of hernia recurrence, 7 cases of poor healing of the umbilical incision, 5 cases of suture granuloma and 3 cases of groin traction pain discomfort. None of the following complications occurred: abdominal wall vascular injury, deferent duct injury, umbilical hernia, iatrogenic cryptorchidism, testicular atrophy, hydrocele, or scrotal oedema. Conclusion: Laparoscopic percutaneous extraperitoneal closure of the internal ring using an epidural needle is a safe and feasible method for the treatment of inguinal hernias in children. This method has the advantages of less trauma, no scarring and a good cosmetic effect.