Importance of duodenal stump reinforcement to prevent stump leakage after gastrectomy: a large-scale multicenter retrospective study (KSCC DELICATE study).

BACKGROUND: The significance of reinforcement of the duodenal stump with seromuscular sutures and the effectiveness of reinforced staplers in preventing duodenal stump leakage remain unclear. We aimed to explore the importance of duodenal stump reinforcement and determine the optimal reinforcement method for preventing duodenal stump leakage. METHODS: This retrospective cohort study was conducted between January 1, 2012 and December 31, 2021, with data analyzed between December 1, 2022 and September 30, 2023. This multicenter study across 57 institutes in Japan included 16,475 patients with gastric cancer who underwent radical gastrectomies. Elective open or minimally invasive (laparoscopic or robotic) gastrectomy was performed in patients with gastric cancer. RESULTS: Duodenal stump leakage occurred in 153 (0.93%) of 16,475 patients. The proportions of males, patients aged ≥ 75 years, and ≥ pN1 were higher in patients with duodenal stump leakage than in those without duodenal stump leakage. The incidence of duodenal stump leakage was significantly lower in the group treated with reinforcement by seromuscular sutures or using reinforced stapler than in the group without reinforcement (0.72% vs. 1.19%, p = 0.002). Duodenal stump leakage incidence was also significantly lower in high-volume institutions than in low-volume institutions (0.70% vs. 1.65%, p = 0.047). The rate of duodenal stump leakage-related mortality was 7.8% (12/153). In the multivariate analysis, preoperative asthma and duodenal invasion were identified as independent preoperative risk factors for duodenal stump leakage-related mortality. CONCLUSIONS: The duodenal stump should be reinforced to prevent duodenal stump leakage after radical gastrectomy in patients with gastric cancer.

The Feasibility and Reliability of Upper Arm-Worn Apple Watch Heart Rate Monitoring for Surgeons During Surgery: Observational Study.

BACKGROUND: Health care professionals, particularly those in surgical settings, face high stress levels, impacting their well-being. Traditional monitoring methods, like using Holter electrocardiogram monitors, are impractical in the operating room, limiting the assessment of physicians' health. Wrist-worn heart rate monitors, like the Apple Watch, offer promise but are restricted in surgeries due to sterility issues. OBJECTIVE: This study aims to assess the feasibility and accuracy of using an upper arm-worn Apple Watch for heart rate monitoring during robotic-assisted surgeries, comparing its performance with that of a wrist-worn device to establish a reliable alternative monitoring site. METHODS: This study used 2 identical Apple Watch Series 8 devices to monitor the heart rate of surgeons during robotic-assisted surgery. Heart rate data were collected from the wrist-worn and the upper arm-worn devices. Statistical analyses included calculating the mean difference and SD of difference between the 2 devices, constructing Bland-Altman plots, assessing accuracy based on mean absolute error and mean absolute percentage error, and calculating the intraclass correlation coefficient. RESULTS: The mean absolute errors for the whole group and for participants A, B, C, and D were 3.63, 3.58, 2.70, 3.93, and 4.28, respectively, and the mean absolute percentage errors were 3.58%, 3.34%, 2.42%, 4.58%, and 4.00%, respectively. Bland-Altman plots and scatter plots showed no systematic error when comparing the heart rate measurements obtained from the upper arm-worn and the wrist-worn Apple Watches. The intraclass correlation coefficients for participants A, B, C, and D were 0.559, 0.651, 0.508, and 0.563, respectively, with a significance level of P<.001, indicating moderate reliability. CONCLUSIONS: The findings of this study suggest that the upper arm is a viable alternative site for monitoring heart rate during surgery using an Apple Watch. The agreement and reliability between the measurements obtained from the upper arm-worn and the wrist-worn devices were good, with no systematic error and a high level of accuracy. These findings have important implications for improving data collection and management of the physical and mental demands of operating room staff during surgery, where wearing a watch on the wrist may not be feasible.

Robotic surgery for simultaneous gastric and rectal cancers.

The number of patients with multiple primary malignancies is increasing due to the improvements in diagnostic techniques, which increases the necessity of simultaneous resection. Meanwhile, minimally invasive robotic surgery is becoming popular in Japan, and its use in multiple cancer resection will increase. We present our experience with the settings and ports placement when using the da Vinci Xi system for simultaneous resection of rectal and gastric cancer.

Association of tumor size in pathological T4 colorectal cancer with desmoplastic reaction and prognosis.

Background: Tumor size in pathological T4 (pT4) colorectal cancer (CRC) is associated with oncological prognosis; however, its relation to epithelial-mesenchymal transition (EMT)-associated histology is unclear. We aimed to investigate the association of tumor size with oncological prognosis and EMT. Methods: We performed a retrospective analysis of 95 patients with primary CRC who underwent radical surgery and were consecutively diagnosed with pT4. Results: Both 3-y disease-free survival (DFS) and cancer-specific survival (CSS) were significantly higher in patients with tumor size ≥50 mm than in those with tumor size <50 mm (P = .009 and P = .011, respectively). The independent factors identified in the multivariate analysis for DFS were pathological lymph node metastasis (hazard ratio [HR], 2.551; 95% confidence interval [CI], 1.031-6.315; P = .043), distant metastasis (HR, 2.511; 95% CI, 1.140-5.532; P = .022), tumor size (HR, 0.462; 95% CI, 0.234-0.913; P = .026), and adjuvant chemotherapy (HR, 0.357; 95% CI, 0.166-0.766; P = .008). The independent factors identified in multivariate analysis for CSS were tumor location (HR, 10.867; 95% CI, 2.539-45.518; P = .001) and tumor size (HR, 0.067; 95% CI, 0.014-0.321; P < .001). In pT4 CRC, smaller tumor size was associated with nonmature desmoplastic reaction and EMT-related histology. Conclusions: Tumor size ≥50 mm was associated with a better DFS and CSS than that of <50 mm, in patients with pT4 CRC. Smaller tumor size with advanced invasion likely reflects a more biologically aggressive phenotype in pT4 CRC.

Risk and Protective Factors for Postoperative Complications in Elderly Patients With Colorectal Cancer.

AIM: This study aimed to evaluate perioperative factors, including nutritional status and sarcopenia on short-term postoperative complications, determine the risk factors for postoperative complications, and clarify potential preoperative interventions and optimal surgical procedures to improve short-term outcomes in elderly patients with colorectal cancer (CRC). PATIENTS AND METHODS: This retrospective, single-centre cohort study analysed the factors and short-term postoperative complications of CRC in a cohort of 101 patients aged ≥80 years who underwent radical resection between 2013 and 2020. Nutritional status was evaluated by calculating the controlling nutritional status. RESULTS: The median age was 83 years, and the frequency of sarcopenia was 39.6%. Short-term postoperative complications occurred in 24 patients. Risk factors for short-term postoperative complications in multivariate analysis were sarcopenia combined with nutritional disorders and open surgical approach. CONCLUSION: The status of nutrition and sarcopenia must be considered in order to predict and improve postoperative outcomes. If possible, a laparoscopic approach should be selected to prevent poor postoperative outcomes.

Comparison of Risk Factors for Locally Advanced Lower Rectal Cancer Recurrence Evaluated by Magnetic Resonance Imaging and Pathological Factors Analysed by Longitudinal Slicing Method.

BACKGROUND/AIM: We compared the risk factors for locally advanced lower rectal cancer (LALRC) recurrence evaluated by preoperative magnetic resonance imaging (MRI) and pathological factors analysed via the longitudinal slicing method to identify high risk groups for recurrence. PATIENTS AND METHODS: This retrospective single-institution cohort study analysed 45 consecutive patients who underwent curative surgery for LALRC. Data were analysed by an experienced radiologist and pathologist. RESULTS: Final preoperative extramural venous invasion (EMVI) and extramural depth of invasion (EMD) determined via MRI were significantly associated with EMVI and EMD determined via pathological analysis. The log-rank test for disease-free survival based on initial preoperative factors showed significantly poor prognoses for circumferential resection margin (CRM)-positive, EMVI-positive, and EMD-positive patients. CONCLUSION: Final preoperative EMVI and EMD determined via MRI correlated with pathological EMVI and EMD, especially in patients who did not undergo preoperative treatment. CRM, EMVI, and EMD determined via preoperative MRI were significant risk factors for recurrence.

Highly sensitive detection of a HER2 12-base pair duplicated insertion mutation in lung cancer using the Eprobe-PCR method.

Somatic mutation in human epidermal growth factor receptor-related 2 gene (HER2) is one of the driver mutations in lung cancer. HER2 mutations are found in about 2% of lung adenocarcinomas (ADCs). Previous reports have been based mainly on diagnostic screening by Sanger sequencing or next-generation sequencing (NGS); however, these methods are time-consuming and complicated. We developed a rapid, simple, sensitive mutation detection assay for detecting HER2 12 base pair-duplicated insertion mutation based on the Eprobe-mediated PCR method (Eprobe-PCR) and validated the sensitivity of this assay system for clinical diagnostics. We examined 635 tumor samples and analyzed HER2 mutations using the Eprobe-PCR method, NGS, and Sanger sequencing. In a serial dilution study, the Eprobe-PCR was able to detect mutant plasmid DNA when its concentration was reduced to 0.1% by mixing with wild-type DNA. We also confirmed amplification of the mutated plasmid DNA with only 10 copies per reaction. In ADCs, Eprobe-PCR detected the HER2 mutation in 2.02% (9/446), while Sanger sequencing detected it in 1.57% (7/446). Eprobe-PCR was able to detect the mutation in two samples that were undetectable by Sanger sequencing. All non-ADC samples were wild-type. There were no discrepancies between frozen and formalin-fixed paraffin-embedded tissues in the nine samples. HER2 mutations detected by NGS data validated the high sensitivity of the method. Therefore, this new technique can lead to precise molecular-targeted therapies.

Transvaginal Hybrid NOTES Procedure for Treatment of Gallstone Ileus.

Gallstone ileus is a rare mechanical bowel obstruction, and previously reported cases have been treated laparoscopically with good results. Although transvaginal hybrid NOTES without a minilaparotomy has been reported to decrease the incidence of surgical wound complications, to our knowledge, this procedure has not been used previously to treat gallstone ileus. We present a case of a 63-year-old woman who underwent transvaginal hybrid NOTES procedure for treatment of gallstone ileus. This case was admitted to our hospital following acute-onset abdominal pain and vomiting. We diagnosed gallstone ileus with cholecystoduodenal fistula by computed tomography and performed totally laparoscopic surgery using only three 5 mm abdominal ports with transvaginal specimen extraction and enterectomy. The patient's postoperative course was uneventful, and laparoscopic cholecystectomy and fistula repair were performed 8 months after the initial surgery. The patient experienced additional pain relief and good cosmetic outcomes. In conclusion, using transvaginal hybrid NOTES may become a future option to minimize the invasiveness of other laparoscopic procedures.

Prognostic potential of the MDM2 309T>G polymorphism in stage I lung adenocarcinoma.

The MDM2 protein plays an important role in the regulation of cell proliferation and apoptosis via ubiquitination and proteasome-mediated degradation of p53. The genetic polymorphism rs2279744 (c.309T>G) of the MDM2 gene is reportedly associated with susceptibility and/or prognosis in various cancers. In this study, we investigated the risk factors for worse survival in patients with lung adenocarcinoma (AC). We examined the association between c.309T>G and the prognosis of lung cancer by retrospectively reviewing 453 lung cancer patients. We studied both, clinicopathological and genetic characteristics, including the c.309T>G, p53 Arg72Pro, EGFR, KRAS, and p53 mutations. Associations between these factors and survival outcome were analyzed using Cox proportional hazards models. The frequencies of MDM2 polymorphisms were T/T, 20.8%; T/G, 48.6%, and G/G, 30.7%. The overall survival (OS) of AC patients with pathological stage I disease and the MDM2 T/T genotype was significantly shorter than that of those with the T/G or G/G genotypes (P = 0.02). Multivariate analysis revealed that the MDM2 T/T genotype was an independent, significant prognostic factor (hazard ratio [HR] = 2.23; 95% confidence interval [CI]: 1.07-4.65; P = 0.03). The MDM2 T/T genotype was predictive of poorer survival in a Japanese population. Genotyping for this polymorphism might predict the clinical outcomes of stage I AC patients.

A case of splenic metastasis of ovarian cancer treated with complete laparoscopic splenectomy and transvaginal specimen extraction.

A 61-year-old woman was diagnosed with right inguinal lymph node and splenic metastasis of ovarian serous cystadenocarcinoma. We performed right inguinal lymph node dissection and total laparoscopic splenectomy in the supine position followed by transvaginal specimen extraction (TVSE). First, using three ports, we extracted the right inguinal lymph node. We repaired the posterior wall of the inguinal canal using a mesh plug. We added two ports and displaced the spleen from the retroperitoneum and lifted it using a snake retractor, disconnecting the hilum using an automatic suturing device. Next, the posterior wall of the vagina was intraperitoneally incised. And an Alexis® laparoscopic system was inserted into the vagina. The cap maintained aeroperitoneum, a collection bag was inserted in the abdominal cavity via the vagina, and the spleen was collected. When the spleen was removed from the body, partial fragmentation of the organ was required in the bag. Organ fragmentation was performed only within the bag, and we made sure not to tear the bag. The vaginal wound was laparoscopically sutured. The patient had no operative complications and was able to actively ambulate at the first day after surgery due to a slight postoperative pain. Total laparoscopic splenectomy with TVSE in the supine position may be a safe and feasible method for selected female patients. This technique enables minimally invasive surgery for female patients with splenic disease.

Impact of the Bim Deletion Polymorphism on Survival Among Patients With Completely Resected Non-Small-Cell Lung Carcinoma.

PURPOSE: A deletion polymorphism of the Bim gene has been reported to be a prognostic factor for patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors in the Asian population. We investigated the impact of the Bim deletion polymorphism on survival among patients with completely resected NSCLC. PATIENTS AND METHODS: The Bim polymorphism was detected by polymerase chain reaction analysis. We measured overall survival (OS) and recurrence-free survival rates in 411 patients and postrecurrence survival (PRS) in 94 patients who experienced recurrence and received additional anticancer therapy. RESULTS: The Bim deletion polymorphism was detected in 61 patients (14.8%). OS rates were significantly lower for patients with the Bim deletion polymorphism than for those with the wild-type sequence. On multivariable analysis, the Bim deletion polymorphism was identified as an independent prognostic factor for OS (hazard ratio, 1.98; 95% CI, 1.17 to 3.36; P = .011). Among the 94 patients who experienced recurrence and were treated with anticancer therapy, patients with the Bim deletion polymorphism showed significantly poorer PRS than those with the wild-type sequence (median, 9.8 months v 26.9 months, respectively; P < .001). Multivariable analysis revealed that the Bim deletion polymorphism was an independent predictor of PRS (hazard ratio, 3.36; 95% CI, 1.75 to 6.47; P < .001). This trend remained apparent in subgroup analyses stratified by EGFR status, histology, and therapeutic modality. CONCLUSION: The Bim deletion polymorphism is a novel indicator of shortened PRS among patients with recurrent NSCLC treated with anticancer therapy in the Asian population.

Eprobe-mediated screening system for somatic mutations in the KRAS locus.

Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) loci are largely predictive of resistance to epidermal growth factor receptor (EGFR) therapy in colorectal cancer (CRC). A highly sensitive detection system for the KRAS gene mutations is urgently needed; however, conventional methods have issues with feasibility and cost performance. Here, we describe a novel detection system using a fluorescence 'Eprobe' capable of detecting low level KRAS gene mutations, via real-time PCR, with high sensitivity and simple usability. We designed our Eprobes to be complementary to wild-type (WT) KRAS or to the commonly mutated codons 12 and 13. The WT Eprobe binds strongly to the WT DNA template and suppresses amplification by blocking annealing of the primer during PCR. Eprobe-PCR with WT Eprobe shows high sensitivity (0.05-0.1% of plasmid DNA, 1% of genomic DNA) for the KRAS mutation by enrichment of the mutant type (MT) amplicon. Assay performance was compared to Sanger sequencing using 92 CRC samples. Discrepancies were analyzed by mutation genotyping via Eprobe-PCR with full match Eprobes for 7 prevalent mutations and the next generation sequencing (NGS). Significantly, the Eprobe system had a higher sensitivity for detecting KRAS mutations in CRC patient samples; these mutations could not be identified by Sanger sequencing. Thus, the Eprobe approach provides for highly sensitive and convenient mutation detection and should be useful for diagnostic applications.

Single-nucleotide polymorphism (c.309T>G) in the MDM2 gene and lung cancer risk.

Murine double minute 2 (MDM2) is a negative regulator of p53. A single-nucleotide polymorphism (SNP) (rs2279744: c.309T>G) in the promoter region of the MDM2 gene has been shown to result in higher levels of MDM2 RNA and protein. Regarding the contribution of c.309T>G in the MDM2 gene to the lung cancer risk, previous studies are conflicting. In order to evaluate the association between c.309T>G and the lung cancer risk, a case-control study was performed. The MDM2 genotypes were determined in 762 lung cancer patients and in 700 cancer-free control subjects using the Smart Amplification Process. Statistical adjustment was performed for gender, age and pack-years of smoking. The distributions of c.309T>G (T/T, T/G, G/G) were 20.1, 49.7, 30.2% in the case group and 21.7, 47.9, 30.4% in the healthy-control group. There were no overall associations between the MDM2 genotypes and the risk of lung cancer [T/G genotype: Adjusted odds ratio (AOR), 1.30; 95% confidence interval (CI), 0.88-1.93; and G/G genotype: AOR, 1.18; 95% CI, 0.78-1.80]. The subgroup analysis of gender, histology, smoking status and epidermal growth factor receptor mutation status also indicated that there was no association with lung cancer. Additionally, the genotypes did not have an effect on the age at the time of diagnosis of lung cancer (P=0.25). In conclusion, the G allele frequency in the lung cancer cases was 0.551, which was similar to other studies. The results of the present study suggest that the c.309T>G is not significantly associated with lung cancer.

Assessment of DDR2, BRAF, EGFR and KRAS mutations as therapeutic targets in non-adenocarcinoma lung cancer patients.

Molecular-targeted therapy has not been established in non-adenocarcinoma lung cancer (non-AdLC), as no targets that affect the clinical efficacy of molecular-targeted drugs have yet been identified. In this study, we investigated the frequency of genetic variations in discoidin domain receptor 2 (DDR2), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-AdLC patients, in order to evaluate the possibility of genetic mutations in these genes being used as therapeutic targets for the treatment of patients with non-AdLC. For this purpose, we enrolled 150 non-AdLC patients who had undergone surgery at the Gunma University Hospital between December, 2003 and December, 2012. Genetic mutations in the EGFR, KRAS, DDR2 and BRAF genes were detected by a sequencing method or probe assay using DNA derived from cancer tissues. No somatic mutations in DDR2 or BRAF were detected in non-AdLC patients. Conversely, genetic mutations in EGFR exon 19 were found in 3 squamous cell carcinoma (SCC) and 3 adenosquamous carcinoma patients, whereas KRAS codon 12 mutations were also found in 3 SCC patients and 1 large-cell neuroendocrine carcinoma patient. EGFR and KRAS mutations were mutually exclusive. This study indicated that, although DDR2 and BRAF mutations may only rarely be used as therapeutic targets, EGFR and KRAS mutations may represent candidate therapeutic targets, at least in the non-AdLC patients investigated.

Postrecurrence survival of surgically resected pulmonary adenocarcinoma patients according to EGFR and KRAS mutation status.

The aim of this study was to investigate the prognosis of pulmonary adenocarcinoma patients following postoperative recurrence, according to epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) gene mutation status and recurrence site. In total 58 adenocarcinoma patients with recurrence following surgical resection were retrospectively evaluated between 2002 and 2011. The patients were divided into groups according to the presence or absence of EGFR and KRAS mutations and the clinicopathological characteristics, recurrence sites and postrecurrence survival were compared. EGFR and KRAS mutations were detected in 26 (45%) and 11 patients (19%), respectively. Initial recurrence was distant in 25 (43%), local in 17 (29%) and both distant and local in 16 cases (28%). In EGFR-mutant (EGFR+) cases, bilateral/contralateral lung recurrence was a frequent finding. EGFR+ cases exhibited significantly better outcomes compared to KRAS+ and EGFR-KRAS- (wild-type) cases. The 2-year post-recurrence survival rates were 81, 18 and 47% in EGFR+, KRAS+ and wild-type cases, respectively. The patients with distant organ recurrence exhibited significantly worse survival compared with those without distant recurrence in wild-type, but not in the EGFR+ cases or the entire cohort. Multivariate analysis revealed that EGFR mutations and a number of recurrent lesions were the only statistically significant independent predictors of postrecurrence prognosis. Our results indicated distinct survival differences in recurrent adenocarcinoma patients according to driver mutations. Patients with EGFR-mutated tumors exhibited increased survival, regardless of recurrence at distant sites, whereas patients with KRAS-mutated adenocarcinoma exhibited poor outcome following postoperative recurrence. Therefore, the assessment of driver mutations is essential for predicting postrecurrence survival following surgical resection.

SNP (-617C>A) in ARE-like loci of the NRF2 gene: a new biomarker for prognosis of lung adenocarcinoma in Japanese non-smoking women.

PURPOSE: The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the NRF2 gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the NRF2 gene as a prognostic biomarker in lung cancer. EXPERIMENTAL DESIGN: We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.-617C>A; rs6721961) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the NRF2 gene and patients' overall survival. RESULTS: Patients harboring wild-type (WT) homozygous (c.-617C/C), SNP heterozygous (c.-617C/A), and SNP homozygous (c.-617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.-617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying NRF2 SNP homozygous alleles (c.-617A/A) and the 309T (WT) allele in the MDM2 gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank p = 0.021). CONCLUSION: SNP homozygous (c.-617A/A) alleles in the NRF2 gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.

Rapid detection of SNP (c.309T>G) in the MDM2 gene by the Duplex SmartAmp method.

BACKGROUND: Genetic polymorphisms in the human MDM2 gene are suggested to be a tumor susceptibility marker and a prognostic factor for cancer. It has been reported that a single nucleotide polymorphism (SNP) c.309T>G in the MDM2 gene attenuates the tumor suppressor activity of p53 and accelerates tumor formation in humans. METHODOLOGY: In this study, to detect the SNP c.309T>G in the MDM2 gene, we have developed a new SNP detection method, named "Duplex SmartAmp," which enabled us to simultaneously detect both 309T and 309G alleles in one tube. To develop this new method, we introduced new primers i.e., nBP and oBPs, as well as two different fluorescent dyes that separately detect those genetic polymorphisms. RESULTS AND CONCLUSIONS: By the Duplex SmartAmp method, the genetic polymorphisms of the MDM2 gene were detected directly from a small amount of genomic DNA or blood samples. We used 96 genomic DNA and 24 blood samples to validate the Duplex SmartAmp by comparison with results of the conventional PCR-RFLP method; consequently, the Duplex SmartAmp results agreed totally with those of the PCR-RFLP method. Thus, the new SNP detection method is considered useful for detecting the SNP c.309T>G in the MDM2 gene so as to judge cancer susceptibility against some cellular stress in the clinical setting, and also to handle a large number of samples and enable rapid clinical diagnosis.