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The totally extraperitoneal repair (TEP) technique has been widely performed, and compared with open surgery, TEP results in less postoperative pain and similar surgical outcomes in the treatment of inguinal hernias. However, TEP has a longer learning curve than does conventional surgery.The data for patients who underwent TEP for inguinal hernias by a single surgeon between April 2017 and July 2019 were analyzed retrospectively. The cumulative summation (CUSUM) method and the following two variables were used to analyze the learning curve: (1) the operation event (OE), including intraoperative complications and conversion to open surgery; and (2) the operation score (OS), as calculated by the operation time, patient body mass index, and disease characteristics.The CUSUM chart showed three phases for both the OE and OS. The former reached a first inflection point after the 85th case and decreased after the 200th case, and the latter reached a plateau after the 101st case and decreased after the 203rd case. The operation time was longer in phases 1 and 2 than in phase 3 (64.2 min versus 47.9 min versus 31.1 min; p 0.001), and the OS was lower in phase 3 than in the other phases (71.9 points versus 106.4 points versus 142.7 points; p 0.001). Ten cases of intraoperative complications were observed, all in the first and second phases (p = 0.011).At least approximately 100 cases are required for the initial learning period, and an additional 103 cases are required for the accumulation of additional experience. Surgical competency can be gained after 203 TEPs are performed.

Background. Volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) is an advanced form of radiotherapy (RT) technology. The purpose of this study was to report long-term treatment outcomes in patients with locally advanced rectal cancer undergoing VMAT-SIB based concurrent chemoradiotherapy (CRT). Methods. Between January 2016 and January 2018, a total of 22 patients with operable stage II-III rectal adenocarcinoma were recruited for the pre-designed VMAT-SIB RT protocol. All patients underwent standard diagnostic and staging work-up. The RT target volumes included the following areas: PTV1 = mesorectum that contained gross tumors and enlarged lymph node regions and PTV2 = mesorectum and regional lymphatics from L4-5/S1 to 3-4 cm below the tumor or levator ani muscle, excluding PTV1. The VMAT-SIB dose prescription was as follows: PTV1 = 52.5 Gy/daily 2.1 Gy/25 fractions, PTV2 = 45 Gy/daily 1.8 Gy/25 fractions. Results. The mean age of the study population was 64 (range, 18-84) years, and 15 (68.2%) patients were male. Radical operation (total mesorectal excision) was performed by either low anterior resection, ultralow anterior resection, or abdominal perineal resection. All five (22.7%) of the patients with confirmed increasing serum carcinoembryonic antigen (CEA) level at diagnosis showed normalization of serum CEA level after the planned treatment. Among 20 patients who underwent preoperative CRT and surgery, tumor down staging in T- and N-stages was achieved in 10 patients (50%) and 13 patients (65%), respectively, with 20% of ypT0/Tis. With a median follow-up of 54.2 (range, 22.6-61.1) months, the 5-year disease-free survival, overall survival, and local control rates were 64.6%, 81.8%, and 84.4%, respectively. Five patients developed distant metastasis and one developed local recurrence as a first event. Two cases with anastomosis site leakage, three with adhesive ileus, and two with abscess formation were observed during postoperative periods. Conclusions. The current VMAT-SIB-based CRT protocol provided acceptable treatment and toxicity outcomes.

Supplementary Fig. S3. Allele frequencies of spatial mutation catalogs. A, The mutant allele frequencies are shown for the mutations in the five spatial categories. B, Mutant allele frequencies (y-axis) are shown for the total number of mutations observed in the biopsies from primary and metastatic lesions with significantdifference between them.

Purpose: Gastric adenoma (GA) is a premalignant lesion that precedes intestinal-type gastric carcinoma (GC). However, genetic progression mechanisms from GA to GC have not been clarified.Experimental Design: We performed whole-exome sequencing–based mutational analyses for 15 synchronous pairs of attached GAs and GCs.Results: There was no significant difference in the number of driver mutations or copy-number alterations between GAs and GCs. Well-known mutations of TP53, APC, RNF43, and RPL22 were recurrently detected in synchronous GA/GC pairs. In addition, we discovered novel KDM6A, PREX2, FAT1, KMT2C, GLI3, and RPL22 mutations and hypermutation in GAs, but did not identify recurrent drivers for GA-to-GC progression. Clonal structure analyses revealed that most GA/GC pairs exhibit parallel evolution with early divergence rather than stepwise evolution during GA-to-GC progression. Of note, three cases were identified as clonally nonrelated GA/GC pairs despite the lack of histologic differences. We found differences in dominant mutational signatures 1, 6, 15, and 17 in GA/GC trunks, GA branches, and GC branches. Compared with our previous work on synchronous colon adenoma/carcinoma genome structures, where most drivers were in the trunk with parallel evolution, synchronous GA/GC genomes showed a different model of parallel evolution, with many drivers in the branches.Conclusions: The preferred sequence of mutational events during GA-to-GC progression might be more context-dependent than colon adenoma progression. Our results show that nonclonal synchronous GA/GC is common and that GA genomes have already acquired distinct genomic alterations, suggesting caution in the diagnosis of synchronous GA and GC, especially in residual or recurrent cases. Clin Cancer Res; 24(19); 4715–25. ©2018 AACR.

Supplementary Table S1. The description of whole-exome sequencing data Supplementary Table S2. Somatic point mutations and indels identified across 15 synchronous gastric adenoma and gastric carcinom genomes Supplementary Table S3. Copy number alterations identified across 15 synchronous gastric adenoma and gastric carcinom genomes Supplementary Table S4. The description of targeted panel sequencing data Supplementary Table S5. Recurrent regions of copy number alterations

Purpose: The intratumoral heterogeneity (ITH) and the evolution of genomic architectures associated with the development of distant metastases are not well understood in colorectal cancers.Experimental Design: We performed multiregion biopsies of primary and liver metastatic regions from five colorectal cancers with whole-exome sequencing and copy number profiling.Results: In addition to a substantial level of genetic ITH, multiregion genetic profiling identifies the subclonal mutational architecture, leading to the region-based or spatial categorization of somatic mutations and the inference of intratumoral evolutionary history of cancers. The universal mutations (those observed in all the regional biopsies) are enriched in known cancer genes such as APC and TP53 with distinct mutational spectra compared with biopsy- or region-specific mutations, suggesting that major operative mutational mechanisms and their selective pressures are not constant across the metastatic progression. The phylogenies inferred from genomic data show branching evolutionary patterns where some primary biopsies are often segregated with metastastic lesions. Our analyses also revealed that copy number changes such as the chromosomal gains of c-MYC and chromothripsis can be region specific and the potential source of genetic ITH.Conclusions: Our data show that the genetic ITH is prevalent in colorectal cancer serving as a potential driving force to generate metastasis-initiating clones and also as a means to infer the intratumoral evolutionary history of cancers. The paucity of recurrent metastasis-clonal events suggests that colorectal cancer distant metastases may not follow a uniform course of genomic evolution, which should be considered in the genetic diagnosis and the selection of therapeutic targets for the advanced colorectal cancer. Clin Cancer Res; 21(19); 4461–72. ©2015 AACR.

Supplementary Table 1. Clinicopathological and sequencing information of the cases and regional biopsies

Supplementary Table 2. The mutations observed at least once for the regional biopsies across five CRC genomes. Genomic coordinates are according to hg19. The sequencechanges (Ref and Alt as reference and mutant sequences, respectively) are shown with the corresponding functional categories as reported by ANNOVAR. The ANNOVARreports are shown in the separate column (Annovar description). The color schemes for SC (spatial categories) are as shown in Main Figure 1. The mutations in the biopsies of primary (black; P) and metastatic lesions (purple; M) are shown in the matrix.