Site-Specific Mutagenesis Screening in KRASG12D Mutant Library to Uncover Resistance Mechanisms to KRASG12D Inhibitors.

KRAS plays a crucial role in regulating cell survival and proliferation and is one of the most commonly mutated oncogenes in human cancers. The novel KRASG12D inhibitor, MRTX1133, demonstrates promising antitumor efficacy in vitro and in vivo. However, the development of acquired resistance in treated patients presents a considerable challenge to sustained therapeutic effectiveness. In response to this challenge, we conducted site-specific mutagenesis screening to identify potential secondary mutations that could induce resistance to MRTX1133. We screened a range of KRASG12D variants harboring potential secondary mutations, and 44 representative variants were selected for in-depth validation of the pooled screening outcomes. We identified eight variants (G12D with V9E, V9W, V9Q, G13P, T58Y, R68G, Y96W, and Q99L) that exhibited substantial resistance, with V9W showing notable resistance, and downstream signaling analyses and structural modeling were conducted. We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.

Surgical quality assessment for the prospective study of oncologic outcomes after laparoscopic modified complete mesocolic excision for nonmetastatic right colon cancer (PIONEER study).

BACKGROUND: The modified complete mesocolic excision (mCME) procedure for right-sided colon cancer is a tailored approach based on the original complete mesocolic excision (CME) methodology. Limited studies evaluated the safety and feasibility of laparoscopic mCME using objective surgical quality assessments in patients with right colon cancer. The objectives of the PIONEER study were to evaluate oncologic outcomes after laparoscopic mCME and to identify optimal clinically relevant endpoints and values for standardizing laparoscopic right colon cancer surgery based on short-term outcomes of procedures performed by expert laparoscopic surgeons. MATERIALS AND METHODS: This is an ongoing prospective, multi-institutional, single-arm study conducted at five tertiary colorectal cancer centers in South Korea. Study registrants included 250 patients scheduled for laparoscopic mCME with right-sided colon adenocarcinoma (from the appendix to the proximal half of the transverse colon). The primary endpoint was 3-year disease-free survival. Secondary outcomes included 3-year overall survival, incidence of morbidity in the first 4 weeks postoperatively, completeness of mCME, central radicality, and distribution of metastatic lymph nodes. Survival data will be available after the final follow-up date (June 2024). RESULTS: The postoperative complication rate was 12.9%, with a major complication rate of 2.7%. In 87% of patients, central radicality was achieved with dissection at or beyond the level of complete exposure of the superior mesenteric vein. Mesocolic plane resection with an intact mesocolon was achieved in 75.9% of patients, as assessed through photographs. Metastatic lymph node distribution varied by tumor location and extent. Seven optimal clinically relevant endpoints and values were identified based on the analysis of complications in low-risk patients. CONCLUSIONS: Laparoscopic mCME for right-sided colon cancer produced favorable short-term postoperative outcomes. The identified optimal clinically relevant endpoints and values can serve as a reference for evaluating surgical performance of this procedure.

Clinical Activity of TGF-ß Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study.

PURPOSE: The study was to determine the activity and safety of the TGF-ß inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. RESULTS: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-ß inhibitor, in this rare and difficult-to-treat desmoid tumor.

Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial.

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10-4) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20+ B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.

Development of a deep learning based image processing tool for enhanced organoid analysis.

Contrary to 2D cells, 3D organoid structures are composed of diverse cell types and exhibit morphologies of various sizes. Although researchers frequently monitor morphological changes, analyzing every structure with the naked eye is difficult. Given that deep learning (DL) has been used for 2D cell image segmentation, a trained DL model may assist researchers in organoid image recognition and analysis. In this study, we developed OrgaExtractor, an easy-to-use DL model based on multi-scale U-Net, to perform accurate segmentation of organoids of various sizes. OrgaExtractor achieved an average dice similarity coefficient of 0.853 from a post-processed output, which was finalized with noise removal. Correlation between CellTiter-Glo assay results and daily measured organoid images shows that OrgaExtractor can reflect the actual organoid culture conditions. The OrgaExtractor data can be used to determine the best time point for organoid subculture on the bench and to maintain organoids in the long term.

Pretreatment MRI-detected extramural venous invasion as a prognostic and predictive biomarker for neoadjuvant chemoradiotherapy in non-metastatic rectal cancer: a propensity score matched analysis.

OBJECTIVES: This study evaluated pretreatment magnetic resonance imaging (MRI)-detected extramural venous invasion (pmrEMVI) as a predictor of survival after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Medical records of 1184 patients with rectal adenocarcinoma who underwent TME between January 2011 and December 2016 were reviewed. MRI data were collected from a computerized radiologic database. Cox proportional hazards analysis was used to assess local, systemic recurrence, and disease-free survival risk based on pretreatment MRI-assessed tumor characteristics. After propensity score matching (PSM) for pretreatment MRI features, nCRT therapeutic outcomes according to pmrEMVI status were evaluated. Cox proportional hazards analysis was used to identify risk factors for early recurrence in patients receiving nCRT. RESULTS: Median follow-up was 62.8 months. Among all patients, the presence of pmrEMVI was significantly associated with worse disease-free survival (DFS; HR 1.827, 95% CI 1.285-2.597, p = 0.001) and systemic recurrence (HR 2.080, 95% CI 1.400-3.090, p < 0.001) but not local recurrence. Among patients with pmrEMVI, nCRT provided no benefit for oncological outcomes before or after PSM. Furthermore, pmrEMVI( +) was the only factor associated with early recurrence on multivariate analysis in patients receiving nCRT. CONCLUSIONS: pmrEMVI is a poor prognostic factor for DFS and SR in patients with non-metastatic rectal cancer and also serves as a predictive biomarker of poor DFS and SR following nCRT in LARC. Therefore, for patients who are positive for pmrEMVI, consideration of alternative treatment strategies may be warranted. CLINICAL RELEVANCE STATEMENT: This study demonstrated the usefulness of pmrEMVI as a predictive biomarker for nCRT, which may assist in initial treatment decision-making in patients with non-metastatic rectal cancer. KEY POINTS: • Pretreatment MRI-detected extramural venous invasion (pmrEMVI) was significantly associated with worse disease-free survival and systemic recurrence in patients with non-metastatic rectal cancer. • pmrEMVI is a predictive biomarker of poor DFS following nCRT in patients with LARC. • The presence of pmrEMVI was the only factor associated with early recurrence on multivariate analysis in patients receiving nCRT.

A giant, rapidly growing intra­abdominal desmoid tumor of mesenteric origin in an adolescent male: A case report and literature review.

A desmoid tumor is a fibroblastic proliferation of mesenchymal origin, which has no metastasizing potential but is locally aggressive. Although treatment has shifted to observation and active surveillance for newly diagnosed patients with desmoid tumors, intra-abdominal mesenteric tumors or tumors that persistently grow and provoke symptoms may need prompt surgical treatment. There have only been a small number of case reports that illustrate large sporadic intra-abdominal mesentery-deriving desmoid tumors in which the longest diameter was ≥19 cm. In the present study, an adolescent male patient with a rapidly growing 38-cm long sporadic intra-abdominal desmoid tumor of mesenchymal origin is reported. The patient was treated with chemotherapy followed by surgical resection due to non-responsiveness and progression of symptoms, then with maintenance adjuvant chemotherapy to prevent recurrence due to the large size of the tumor. Despite the rapid growth of the tumor and its high occupancy in the intra-abdominal cavity, an R0 resection was successful with organ preservation. The patient has been recurrence-free for 2 years, and further follow-up is expected in the future.

Postchemoradiation magnetic resonance imaging circumferential resection margin predicts treatment failure after multidisciplinary directed sphincter preservation in low rectal cancer.

BACKGROUND: This study aimed to review the magnetic resonance imaging (MRI) features of patients with low rectal cancer (LRC) undergoing preoperative chemoradiotherapy (CRT) and investigate the risk factors for treatment failure after sphincter preserving surgery following preoperative CRT based on multidisciplinary approach. OBJECTIVES: Patients who underwent standard CRT and sphincter preserving radical surgery for LRC between January 2000 and December 2011 were retrospectively reviewed. Sphincter preservation failure (SPF) was defined as any one of the following: positive pathologic circumferential resection margin, local recurrence, failure to repair ileostomy, or permanent stoma formation due to anastomotic complications. RESULTS: Among the 191 patients, there were no overall significant differences between sphincter preservation success (n = 161) and SPF (n = 30) groups. SPF group showed a higher MRI circumferential resection margins (mrCRM) positive rate before and after CRT (before CRT: 33.3% vs. 16.1%, p = 0.027; after CRT: 23.3% vs. 6.2%, p = 0.002). Multivariate analysis showed that only mrCRM after CRT was associated with SPF (hazard ratio = 4.596, p = 0.005). SPF group showed worse 5-year cancer-specific survival (51% vs. 92.7%, p < 0.001). CONCLUSIONS: MRI-based assessment of the tumor after CRT plays a crucial role in predicting the success and feasibility of sphincter preservation as well as oncological outcomes in patients with LRC.

Hepatic arterial infusion in combination with systemic chemotherapy in patients with hepatic metastasis from colorectal cancer: a randomized phase II study - (NCT05103020) - study protocol.

BACKGROUND: Although 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis. METHODS: This is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate. DISCUSSION: This is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.

Neoadjuvant chemotherapy versus upfront surgery as the initial treatment for patients with resectable, synchronous colorectal cancer liver metastases.

BACKGROUND: Although perioperative chemotherapy has been the standard treatment for colorectal cancer with resectable liver metastases (CRLM), studies that have compared neoadjuvant chemotherapy (NAC) and upfront surgery, especially in the setting of synchronous metastases are rare. METHODS: We compared perioperative outcomes, overall survival (OS) and overall survival after recurrence (rOS) in a retrospective study of 281 total and 104 propensity score-matched (PSM) patients who underwent curative resection, with or without NAC, for synchronous CRLM, from 2006 to 2017. A Cox regression model was developed for OS. RESULTS: After PSM, 52 NAC and 52 upfront surgery patients with similar baseline characteristics were compared. Postoperative morbidity, mortality, and 5-year OS rate (NAC: 78.9%, surgery: 64.0%; p = 0.102) were similar between groups; however, the NAC group had better rOS (NAC: 67.3%, surgery: 31.5%; p = 0.049). Initial cancer stage (T4, N1-2), poorly differentiated histology, and >1 hepatic metastases were independent predictors of worse OS. Based on these factors, patients were divided into low-risk (≤1 risk factor, n = 115) and high-risk (≥2 risk factors, n = 166) groups. For high-risk patients, NAC yielded better OS than upfront surgery (NAC: 74.5%, surgery: 53.2%; p = 0.024). CONCLUSIONS: Although NAC and upfront surgery-treated patients had similar perioperative outcomes and OS, better postrecurrence survival was shown in patients with NAC. In addition, NAC may benefit patients with worse prognoses; therefore, physicians should consider patient disease risk before initiating treatment to identify patients who are most likely to benefit from chemotherapy.

Effect of High-Versus Low-Frequency of Abdominopelvic Computed Tomography Follow-Up Testing on Overall Survival in Patients With Stage II Or III Colon Cancer.

BACKGROUND: Intensive surveillance of colon cancer by using the abdominopelvic computed tomography (AP-CT) is common in real world practice; however, it is still unclear whether high-frequency surveillance using AP-CT in patients with these risk factors is superior to that in the low-frequency surveillance. PATIENTS AND METHODS: We retrospectively reviewed 1803 patients with stage II-III colon cancer receiving curative surgery between January 1, 2005 to December 31, 2015. We evaluated the average scan-to-scan intervals of postoperative AP-CT testing and assigned patients with an interval of 5 to 8 and 9 to 13 months to the high-frequency (HF) and low-frequency (LF) groups, respectively. The cutoff value of preoperative and postoperative CEA levels was 5 ng/mL. We also applied propensity score matching (PSM) and inverse probability of treatment weighting to adjust clinicopathologic differences between the 2 groups. RESULTS: We matched 1:1 for each surveillance group yielding a cohort of 776 matched patients. After PSM, Baseline demographics were overall well balanced between 2 groups. Stage III (OR, 2.00; 95% Confidence interval [CI], 1.21-3.30) and postoperative CEA elevation (OR, 2.30; 95% CI, 1.08-4.92) were independent risk factors of recurrence in multivariate analyses. Patient in the HF group had more surgery plus chemo- or radiotherapy as postrecurrence treatment than patient in the LF group (46.2% vs. 23.1%, P = .017). This trend was retained after PSM, although it is not significant (44.4% vs. 23.1%, P = .060). However, survival outcomes of high-frequency AP-CT surveillance were not superior to those of low-frequency surveillance in all subgroups, including stage III (HR 0.99, 95% CI 0.40-2.47) and postoperative CEA elevation (HR 1.36, 95% CI 0.45-4.11). CONCLUSION: High-frequency AP-CT testing is associated with a higher proportion of surgery plus chemo- or radiotherapy as postrecurrence treatment, without improvement in 5-year overall survival.

Palliative surgery as a bridge to systemic treatment for malignant bowel obstruction due to peritoneal metastases: A retrospective, case-control study.

BACKGROUND: High-quality data on palliative surgery in patients with malignant bowel obstruction (MBO) caused by peritoneal metastases (PM) are lacking. We aimed to determine the utility of palliative surgery for such patients. METHODS: We retrospectively analyzed patients considered for surgery for MBO, caused by PM, in our department from January 2019 to October 2020. None of them could tolerate a diet, despite conservative treatment. We investigated the clinical characteristics and perioperative outcomes and calculated overall survival (OS). Kaplan-Meier survival analysis was performed, with the log-rank test to evaluate differences in OS rates. Multivariate Cox regression was performed to determine prognostic factors. RESULTS: Sixty (67%) patients underwent surgery, whereas, 30 (33%) received the best supportive care (BSC) treatment. A better (p = 0.002) median OS was observed in patients undergoing surgery (3.9 months) than in those receiving BSC (2.6 months). Severe complications were observed in 12 (20%) patients, including 30-day mortality (7 patients). Forty-eight (80%) patients in the surgery group could tolerate a diet and the hospital stay (mean ± standard deviation) was 20.0 ± 23.1 days. Re-obstruction was observed in five (8.3%) patients after 78.6 ± 63.3 days. Patients in the postoperative chemotherapy group exhibited a better (p < 0.001) median OS (12.3 months) than did those in the no-postoperative chemotherapy group (3.5 months). Only postoperative chemotherapy (hazard ratio 0.264, 95% confidence interval 0.143-0.487, p < 0.001) was identified as an independent prognostic factor. CONCLUSIONS: Compared with BSC, surgery is associated with a better OS in patients with MBO due to PM. Surgery should be considered as a bridge to systemic treatment for such patients.

Therapeutic Implications of TGF-ß Pathway in Desmoid Tumor Based on Comprehensive Molecular Profiling and Clinicopathological Properties.

(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-ß signaling pathway. Moreover, we selected the combination treatment comprising TGF-ß inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-ß inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-ß inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.

Difference in medical service use among Korean gastric cancer survivors according to regional healthcare vulnerabilities: a cohort study.

PURPOSE: This study investigated the relationship between medical service use and healthcare vulnerability, pre- and post-gastric cancer diagnosis. Differences between healthcare-vulnerable and healthcare-nonvulnerable regions identified inequities that require intervention. METHODS: This cohort study was done using the National Health Insurance claims data of patients diagnosed with gastric cancer between 2004 and 2013. The Position Value for Relative Comparison Index was used to determine whether the patients lived in a healthcare-vulnerable region. Medical service use was classified into annual outpatient treatment, hospitalization days, and emergency treatment. We used a generalized linear model to which the Poisson distribution was applied and compared regional differences in medical service use. RESULTS: A total of 1797 gastric cancer patients who had survived 5 years post-diagnosis were included in the study, of which 14.2% lived in healthcare-vulnerable regions. The patients in vulnerable regions surviving 5-7 years post-diagnosis had a higher number of outpatient visits than those in nonvulnerable regions. Furthermore, hospitalization days were lesser for patients in vulnerable regions who survived 6 years post-diagnosis than those in nonvulnerable regions; however, this number increased in the seventh year. CONCLUSIONS: Our results suggest that gastric cancer survivors living in healthcare-vulnerable regions have a higher probability of increased medical service use 5 years post-diagnosis compared with patients in nonvulnerable regions, which may significantly increase healthcare disparities over time. Therefore, in the future, additional research is needed to elucidate the causes of the disparities in healthcare use and the results of the differences in health outcomes.

Risk of Anorectal Cancer Associated with Benign Anal Inflammatory Diseases: A Retrospective Matched Cohort Study.

PURPOSE: The purpose of our study was to evaluate the relationship between benign anal inflammatory diseases and anorectal cancer and assess its risk factors. METHODS: A retrospective matched cohort study was conducted that included data from 2002 to 2013. The National Health Insurance Service National Sample Cohort data from 2002 to 2013 was used for the study. Of a total study population of 143,884 individuals, 28,110 individuals with anal fissures were assigned to the case group, while 115,774 individuals without anal fissures were assigned to the control group based on the 1:4 propensity score matching age, sex, and year (case: diagnosed year, control: health service received year). RESULTS: The risk of anorectal cancer was higher in the case group (hazard ratio [HR]: 1.95, 95% confidence interval [CI]: 1.51-2.53) compared to the control group. After grouping anorectal cancers into anal cancer and rectal cancer, the risk remained higher in the case group (anal cancer HR: 2.79, 95% CI: 1.48-5.27; rectal cancer HR: 1.82, 95% CI; 1.37-2.42). The case group was further categorized into patients with fissures and patients with fistulas; patients with fissures showed a higher risk of developing anorectal cancer than patients with fistulas (HR: 2.05, 95% CI: 1.53-2.73 vs. HR: 1.73, 95% CI: 1.13-2.66). Study participants in their 30s and 40s had a 4.19- and 7.39-times higher risk of anorectal cancer compared to those in the higher age groups (0.64-1.84), while patients who did not have inflammatory bowel disease (IBD) had a higher risk of developing anorectal cancer (HR: 2.09, 95% CI: 1.56-2.80). CONCLUSIONS AND RELEVANCE: Patients with anal fistulas or fissures have an increased risk of being diagnosed with anorectal cancer, especially at a young age and even without IBD.

Phase II Clinical Trial of Eribulin-Gemcitabine Combination Therapy in Previously Treated Patients With Advanced Liposarcoma or Leiomyosarcoma.

PURPOSE: Monotherapy with eribulin or gemcitabine has been found to be moderately effective in treating soft-tissue sarcomas (STS). In this study, we evaluated the efficacy and safety of eribulin-gemcitabine combination therapy for the two most common histologic types of STS, liposarcoma and leiomyosarcoma. PATIENTS AND METHODS: In this nonrandomized, multicenter, phase II study, we included patients with progressive disease who had received one or two courses of chemotherapy that included doxorubicin. Patients were administered 1.4 mg/m2 eribulin and 1,000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks), with null and alternative hypotheses of PFSR12wks ≤20.0% and ≥40.0%, respectively. Exploratory biomarker analyses with next-generation sequencing (NGS) were performed on pretreatment tumor samples. RESULTS: Among the 37 patients included, the overall PFSR12wks was 73.0%, achieving the primary endpoint. The objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 5.6 months, and 31.9 months, respectively, without differences according to histologic type. New safety signals and treatment-related deaths were not documented. NGS-based transcriptome analysis revealed that functional enrichment in the TGFß pathway was mostly associated with a poor outcome, whereas single genetic alterations largely failed to predict treatment outcome. CONCLUSIONS: Eribulin-gemcitabine combination therapy showed promising activity and an acceptable safety profile in patients with liposarcoma or leiomyosarcoma. Gene expression profiling with pathway enrichment analysis would have possibilities to have predictive value for survival outcome, necessitating further investigation to confirm.

A case of caecal "PECOMA": An uncommon entity.

INTRODUCTION AND IMPORTANCE: World Health Organization (WHO) defines PEComa as a mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. The symptoms and clinical signs of PEComa patients are nonspecific. Hence, diagnosis is usually difficult. Since it's a rare diagnosis, further research might help in understanding the disease better. CASE PRESENTATION: The patient in this study was an asymptomatic patient, who did colonoscopy as part of a regular check-up. A submucosal cecal tumor was detected in colonoscopy, and apart from that, all other investigative parameters were within normal limits. CLINICAL DISCUSSION: Laparoscopic Ileocecectomy was performed, and the histopathology report was suggestive of Pecomatosis (PEComa - Perivascular epithelioid cell tumor). The PEComas, neoplasms with perivascular epithelioid cell differentiation, are mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells (PEC). The characteristic features of PEC are the positivity of melanocytic markers and smooth muscle markers. CONCLUSION: Perivascular epithelioid tumors are mostly rare in the gastrointestinal tract, and even more unusual to be detected in Cecum. Surgery is the mainstay of the treatment, although, adjuvant therapy has been tried in recent times. The patients have to be kept in close follow-up, as there are reported cases of recurrences and distant metastasis.

Detection of circulating KRAS mutant DNA in extracellular vesicles using droplet digital PCR in patients with colon cancer.

Background: Extracellular vesicles secreted by tumor cells contain double-stranded DNA called extracellular vesicle DNA (evDNA). EvDNA is genomic DNA that reflects cancer driver mutations. However, the significance of evDNA analysis in the diagnosis and surveillance of colon cancer remains unclear. This study aimed to investigate the clinical utility of extracellular vesicles and evDNA isolated from the plasma of colon cancer patients harboring KRAS G12D and G13D mutations. Methods: Cell-free DNA (cfDNA) and evDNA were collected from the plasma of 30 patients with colon cancer. KRAS mutation status (G12D and G13D) was detected using a droplet digital polymerase chain reaction assay (ddPCR). Sensitivity and specificity were evaluated in patients with wild-type KRAS tumors. Mutation status was correlated with carcinoembryonic antigen (CEA) levels and overall survival (OS). Results: Thirty cfDNA and evDNA pairs showed a KRAS fractional abundance (FA) ranging from 0 to 45.26% and 0 to 83.81%, respectively. When compared with eight wild-type KRAS samples, cfDNA exhibited 70% sensitivity and 100% specificity, whereas evDNA achieved 76.67% sensitivity and 100% specificity. The concentration of evDNA was significantly lower than that of cfDNA, but it obtained a higher FA than cfDNA, while showing a positive correlation with CEA. Conclusions: Our findings demonstrate the feasibility of evDNA as a complementary tool to aid current methods of patient evaluation in the diagnosis and surveillance of colon cancer.

Single-incision laparoscopic surgery compared to conventional laparoscopic surgery for appendiceal mucocele: a series of 116 patients.

BACKGROUND: Although the safety and feasibility of conventional laparoscopic surgery (CLS) for appendiceal mucocele (AM) has been reported, studies on single-incision laparoscopic surgery (SILS) for AM have not been reported. Here, we aimed to compare the perioperative and short-term outcomes between SILS and CLS for AM and to evaluate the oncological safety of SILS. METHODS: We retrospectively analyzed the medical records of patients, diagnosed based on computed tomography findings, who underwent laparoscopic surgery for AM between 2010 and 2018 at one institution. We excluded patients strongly suspected of having malignant lesions and those with preoperative appendiceal perforation. Patients were divided into two groups-CLS and SILS. Pathological outcomes and long-term results were investigated. The median follow-up period was 43.7 (range: 12.3-118.5) months. RESULTS: Ultimately, 116 patients (CLS = 68, SILS = 48) were enrolled. Patient demographic characteristics did not differ between the groups. The preoperative mucocele diameter was greater in the CLS than in the SILS group (3.2 ± 2.9 cm vs. 2.3 ± 1.4 cm, P = 0.029). More extensive surgery (right hemicolectomies and ileocecectomies) was performed in the CLS than in the SILS group (P = 0.014). Intraoperative perforation developed in only one patient per group. For appendectomies and cecectomies, the CLS group exhibited a longer operation time than the SILS group (63.3 ± 24.5 min vs. 52.4 ± 17.3 min, P = 0.014); the same was noted for length of postoperative hospital stay (2.9 ± 1.8 days vs. 1.7 ± 0.6 days, P < 0.001). The most common AM etiology was low-grade appendiceal mucinous neoplasm (71/116 [61.2%] patients); none of the patients exhibited mucinous cystadenocarcinoma. Among these 71 patients, there were 8 patients with microscopic appendiceal perforation or positive resection margins. No recurrence was detected. CONCLUSIONS: SILS for AM is feasible and safe perioperatively and in the short-term and yields favorable oncological outcomes. Despite the retrospective nature of the study, SILS may be suitable after careful selection of AM patients.

Association between Fusobacterium nucleatum and patient prognosis in metastatic colon cancer.

Recent evidence suggests that Fusobacterium nucleatum (Fn) is associated with the development and progression of colorectal cancer. We aimed to delineate the clinical implications of Fn in metastatic colon cancer. We performed quantitative polymerase chain reaction (qPCR) using DNA samples from synchronous metastatic colon cancer patients with either formalin-fixed paraffin-embedded (FFPE) archival primary site tumor samples or fresh colon tissues. Progression-free survival (PFS)1 and PFS2 were defined as PFS of first- and second-line palliative settings. qPCR for Fn was successfully performed using 112 samples (FFPE, n = 61; fresh tissue, n = 51). Forty-one and 68 patients had right-sided and left-sided colon cancer, respectively. Patients with Fn enriched right-sided colon cancers had shorter PFS1 (9.7 vs. 11.2 months) than the other subgroups (HR 3.54, 95% confidence interval [CI] 1.05-11.99; P = 0.04). Fn positive right-sided colon was also associated with shorter PFS2 (3.7 vs. 6.7 months; HR 2.34, 95% CI 0.69-7.91; P = 0.04). In the univariate analysis, PFS1 was affected by differentiation and Fn positive right-sided colon cancer. The multivariate analysis showed that differentiation (HR 2.68, 95% CI 1.40-5.14, P = 0.01) and Fn positive right-sided colon (HR 0.40, 95% CI 0.18-0.88, P = 0.02) were associated with PFS1. Fn enrichment in right sided colon was not associated with overall survival (OS). Fn enrichment has significantly worse prognosis in terms of PFS1 and PFS2 in patients with right-sided metastatic colon cancers.