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BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.
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Terapia de Alvo Molecular , Neoplasias , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , República da Coreia , Terapia de Alvo Molecular/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Biomarcadores Tumorais/genética , Genômica/métodos , Mutação , Estudos Observacionais como AssuntoRESUMO
PURPOSE: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). MATERIALS AND METHODS: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. RESULTS: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0). CONCLUSION: GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.
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Anticorpos Monoclonais Humanizados , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Irinotecano/uso terapêutico , Fluoruracila/efeitos adversos , Leucovorina/efeitos adversos , Camptotecina/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
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.
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Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Oxaliplatina , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
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.
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Neoplasias do Colo , Humanos , Seguimentos , Estudos Retrospectivos , Estadiamento de Neoplasias , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/terapia , Neoplasias do Colo/patologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Skeletal muscle and BMI are essential prognostic factors for survival in colorectal cancer (CRC). However, there is a lack of understanding due to scarce studies on the continuous aspects of these variables. OBJECTIVE: This study aimed to evaluate the prognostic impact of the initial status and trajectories of muscle and BMI on overall survival (OS) and assess whether these 4 profiles within 1 year can represent the profiles 6 years later. METHODS: We analyzed 4056 newly diagnosed patients with CRC between 2010 to 2020. The volume of the muscle with 5-mm thickness at the third lumbar spine level was measured using a pretrained deep learning algorithm. The skeletal muscle volume index (SMVI) was defined as the muscle volume divided by the square of the height. The correlation between BMI status at the first, third, and sixth years of diagnosis was analyzed and assessed similarly for muscle profiles. Prognostic significances of baseline BMI and SMVI and their 1-year trajectories for OS were evaluated by restricted cubic spline analysis and survival analysis. Patients were categorized based on these 4 dimensions, and prognostic risks were predicted and demonstrated using heat maps. RESULTS: Trajectories of SMVI were categorized as decreased (812/4056, 20%), steady (2014/4056, 49.7%), or increased (1230/4056, 30.3%). Similarly, BMI trajectories were categorized as decreased (792/4056, 19.5%), steady (2253/4056, 55.5%), or increased (1011/4056, 24.9%). BMI and SMVI values in the first year after diagnosis showed a statistically significant correlation with those in the third and sixth years (P<.001). Restricted cubic spline analysis showed a nonlinear relationship between baseline BMI and SMVI change ratio and OS; BMI, in particular, showed a U-shaped correlation. According to survival analysis, increased BMI (hazard ratio [HR] 0.83; P=.02), high baseline SMVI (HR 0.82; P=.04), and obesity stage 1 (HR 0.80; P=.02) showed a favorable impact, whereas decreased SMVI trajectory (HR 1.31; P=.001), decreased BMI (HR 1.23; P=.02), and initial underweight (HR 1.38; P=.02) or obesity stages 2-3 (HR 1.79; P=.01) were negative prognostic factors for OS. Considered simultaneously, BMI >30 kg/m2 with a low SMVI at the time of diagnosis resulted in the highest mortality risk. We observed improved survival in patients with increased muscle mass without BMI loss compared to those with steady muscle mass and BMI. CONCLUSIONS: Profiles within 1 year of both BMI and muscle were surrogate indicators for predicting the later profiles. Continuous trajectories of body and muscle mass are independent prognostic factors of patients with CRC. An automatic algorithm provides a unique opportunity to conduct longitudinal evaluations of body compositions. Further studies to understand the complicated natural courses of muscularity and adiposity are necessary for clinical application.
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Neoplasias Colorretais , Obesidade , Humanos , Prognóstico , Estudos Longitudinais , Estudos Retrospectivos , Obesidade/complicações , Obesidade/epidemiologia , Estudos de Coortes , Músculos , Neoplasias Colorretais/complicaçõesRESUMO
AIM: The OPTIM1SE study observed long-term real-world outcomes of cetuximab-based infusional 5-fluorouracil (5-FU) regimens for first-line treatment of metastatic colorectal cancer (mCRC) across Asia-Pacific and Middle East regions, aiming to characterize their use, effectiveness, and safety in routine practice. METHODS: OPTIM1SE was a prospective, open-label, observational study. Patients with untreated KRAS wild-type mCRC and distant metastases were treated per locally approved labels and monitored for 3 years via electronic medical records. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). RESULTS: From November 19, 2013, to June 30, 2016, 520 patients were enrolled in 51 sites. Patients were mostly male (61.2%), with a mean age of 58.5 (±12.0) years; 420 patients received leucovorin, 5-FU, and irinotecan-based regimens and 94 received leucovorin, 5-FU, and oxaliplatin. The most common primary tumor site was the rectum (38.8%), with liver metastases (65.0%). ORR was 45.4% (95% CI, 41.1%-49.7%), including 26 patients (5.0%) with a complete response. Median PFS was 9.9 months (95% CI, 8.2-11.0); median OS (mOS) was 30.8 months (95% CI, 27.9-33.6). Higher mOS was associated with tumors of left compared with right-sided origin (hazard ratio, 0.69 [95% CI, 0.49-0.99]); higher ORR was also associated with liver metastases compared with all other metastases (55.4% vs. 40.2%). Adverse events were consistent with the known safety profile of cetuximab. CONCLUSION: Cetuximab-based 5-FU regimens were effective first-line treatments for mCRC in routine practice, particularly in patients with left-sided disease and liver metastases only.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Retais , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Cetuximab/uso terapêutico , Leucovorina/efeitos adversos , Estudos Prospectivos , Fluoruracila/efeitos adversos , Resultado do Tratamento , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas Proto-Oncogênicas p21(ras)/uso terapêutico , Camptotecina/uso terapêuticoRESUMO
Background & Aims: Fusobacterium nucleatum (FN) plays a pivotal role in the development and progression of colorectal cancer by modulating antitumor immune responses. However, the impact of FN on immune regulation in the tumor microenvironment has not been fully elucidated. Methods: The abundance of FN was measured in 99 stage III CRC tumor tissues using quantitative polymerase chain reaction. Gene expression profiles were assessed and annotated using consensus molecular subtypes (CMS), Gene Ontology (GO) analysis, and deconvolution of individual immune cell types in the context of FN abundance. Immune profiling for tumor infiltrating T cells isolated from human tumor tissues was analyzed using flow cytometry. Ex vivo tumor-infiltrating T cells were stimulated in the presence or absence of FN to determine the direct effects of FN on immune cell phenotypes. Results: Gene expression profiles, CMS composition, abundance of immune cell subtypes, and survival outcomes differed depending on FN infection. We found that FN infection was associated with poorer disease-free survival and overall survival in stage III CRC patients. FN infection was associated with T cell depletion and enrichment of exhausted CD8+ and FoxP3+ regulatory T cells in the tumor microenvironment. The presence of FN in tumors was correlated with a suppressive tumor microenvironment in a T cell-dependent manner. Conclusion: FN enhanced the suppressive immune microenvironment with high depletion of CD8+ T cells and enrichment of FoxP3+ regulatory T cells in human colorectal cancer cases. Our findings suggest a potential association for FN in adaptive immunity, with biological and prognostic implications.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/patologia , Fusobacterium nucleatum , Microambiente Tumoral , Linfócitos T CD8-Positivos/metabolismo , Imunidade Adaptativa , Fatores de Transcrição ForkheadRESUMO
BACKGROUND: Although cancer patients are increasingly admitted to the intensive care unit (ICU) for cancer- or treatment-related complications, improved mortality prediction remains a big challenge. This study describes a new ML-based mortality prediction model for critically ill cancer patients admitted to ICU. PATIENTS AND METHODS: We developed CanICU, a machine learning-based 28-day mortality prediction model for adult cancer patients admitted to ICU from Medical Information Mart for Intensive Care (MIMIC) database in the USA (n = 766), Yonsei Cancer Center (YCC, n = 3571), and Samsung Medical Center in Korea (SMC, n = 2563) from 2 January 2008 to 31 December 2017. The accuracy of CanICU was measured using sensitivity, specificity, and area under the receiver operating curve (AUROC). RESULTS: A total of 6900 patients were included, with a 28-day mortality of 10.2%/12.7%/36.6% and a 1-year mortality of 30.0%/36.6%/58.5% in the YCC, SMC, and MIMIC-III cohort. Nine clinical and laboratory factors were used to construct the classifier using a random forest machine-learning algorithm. CanICU had 96% sensitivity/73% specificity with the area under the receiver operating characteristic (AUROC) of 0.94 for 28-day, showing better performance than current prognostic models, including the Acute Physiology and Chronic Health Evaluation (APACHE) or Sequential Organ Failure Assessment (SOFA) score. Application of CanICU in two external data sets across the countries yielded 79-89% sensitivity, 58-59% specificity, and 0.75-0.78 AUROC for 28-day mortality. The CanICU score was also correlated with one-year mortality with 88-93% specificity. CONCLUSION: CanICU offers improved performance for predicting mortality in critically ill cancer patients admitted to ICU. A user-friendly online implementation is available and should be valuable for better mortality risk stratification to allocate ICU care for cancer patients.
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Background: The acute palliative care unit (APCU) bridges between active cancer treatment and hospice care. However, no study has proven the efficacy of APCU in Korea. Objective: To evaluate the first-year outcomes of the patients admitted to an APCU at a tertiary hospital in Korea. Design: The APCU admitted 205 patients between April 14, 2014, and April 30, 2015. Of these patients, 57 were evaluable for baseline and one-week follow-up Edmonton Symptom Assessment System (ESAS). Results: Of the 57 participants, 56.1% were male, with a median age of 60 years (range, 52.8-69.5 years). All patients had advanced cancer, and 42 out of 57 had terminal illnesses. The median APCU stay was 14 days (range, 10-17 days). The 42 (73.7%) patients were referred to the APCU after anticancer treatment was completed. Ten (17.5%) patients died during their stay, and 20 (35.1%) were discharged home. Among those who completed the ESAS, there were significant improvements in scores in the following symptoms: fatigue, depression, loss of appetite, and shortness of breath. Physical symptoms (pain, fatigue, nausea, drowsiness, appetite, and shortness of breath) and the total ESAS scores were significantly improved (p = 0.002 and p = 0.005, respectively). Each non-medical palliative care program, such as art and music therapy, yoga, foot massage, haircut, and body care, showed no significant differences between the group who received them and those who did not. Conclusion: During the APCU stay, the overall symptoms of inpatients were reduced. A comprehensive and multidisciplinary team approach is essential for patients who need palliative care.
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OBJECTIVE: To assess the effect of local ablative therapy (LAT) on overall survival in patients with lung metastases from colorectal cancer (CRC) compared with patients treated with systemic therapy. SUMMARY BACKGROUND DATA: CRC affects approximately 1.4 million individuals worldwide every year. The lungs are commonly affected by CRC, and there is no treatment standard for a secondary lung metastasis from CRC. METHODS: This longitudinal, retrospective cohort study (2010-2018) quantified the pulmonary and extrapulmonary tumor burden of 1143 patients by retrospectively reviewing computed tomography images captured at diagnosis. A comprehensive multidisciplinary approach informed how and when surgery and/or stereotactic body radiotherapy was administered. RESULTS: Among 1143 patients, 473 patients (41%) received LAT, with surgery first (n = 421) or stereotactic ablative radiation therapy first (n = 52) either at the time of diagnosis (n = 288), within 1âyear (n = 132), or after 1âyear (n = 53). LAT was repeated in 158 patients (33.4%, 384 total sessions) when new lung metastases were detected. The 5- and 10-year survival rates for patients treated with LAT (71.2% and 64.0%, respectively) were significantly higher than those of patients treated with systemic therapy alone (14.2% and 10.0%, respectively; P <0.001). The overall survival of patients who received LAT intervention increased as the total tumor burden decreased. CONCLUSIONS: A high long-term survival rate was achievable in a significant portion of patients with lung metastasis from CRC by the timely administrations of LAT to standard systemic therapy. The tumor burden and LAT feasibility should be included in a discussion during the follow-up period.
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Neoplasias Colorretais , Neoplasias Pulmonares , Humanos , Estudos Retrospectivos , Neoplasias Pulmonares/cirurgia , Neoplasias Colorretais/patologiaRESUMO
In the original article [...].
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Purpose: This regulatory post-marketing surveillance (PMS) study was performed to evaluate the safety and effectiveness of regorafenib on Korean patients with colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (HCC) in a real-world clinical setting. Methods: This PMS was conducted as a multi-center, prospective, observational study at 34 centers in Korea from August 2013 to August 2019. The primary objective was to evaluate the safety of regorafenib in real-world practice, with the secondary objective to investigate its effectiveness, including its overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In total, 301 patients were included in the analysis (254 patients with CRC, 14 patients with GIST, and 33 patients with HCC). The incidence rates of adverse events (AEs) were 85.0%, 78.6%, and 81.8% in patients with CRC, GIST, and HCC, respectively. The most frequent AE related to regorafenib in the three cancer types was palmar-plantar erythrodysesthesia syndrome (PPES). The ORRs of patients with CRC, GIST, and HCC were 4.7%, 0%, and 41.4%, respectively. The median PFS and OS were 2.1 and 6.1 months for CRC, respectively; 9.2 and 16.4 months for GIST, respectively; and 5.5 months and not estimated (NE) for HCC, respectively. Patients who experienced a dose modification or discontinuation of regorafenib showed significantly shorter median PFS and OS (2.2 vs. 2.6 months, respectively, P = 0.0335 for PFS; 5.3 vs. 8.5 months, respectively, P = 0.0010 for OS). Conclusion: This PMS study, which is the largest surveillance study of CRC in Korea, found no newly identified safety concerns for patients who received regorafenib in the real-world setting. Additionally, the results of this study were consisted with those previously reported in phase III trials.
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Background: Although emerging evidence suggests that periodontitis might increase the risk of cancer, comorbidity and lifestyle behaviors, such as smoking and body mass index (BMI), may have confounded this reported association. This study aimed to investigate whether chronic periodontitis is associated with cancer risk using a large, nationwide database. Methods: We conducted a population-based, retrospective cohort study using data from the Korean National Health Insurance Cohort Database obtained between January 2003 and December 2015. We included 713,201 individuals without a history of cancer who were followed up to 10 years. Confounding factors included demographic factors (age, sex, income, and residential area), lifestyle behaviors (smoking history and BMI), and comorbidities, such as hypertension, diabetes, heart failure, and pulmonary disease, using the Charlson Comorbidity Index. Multivariable Cox regression analysis was applied to estimate the adjusted hazard ratio (aHR) for cancer risk. Results: Of the 713,201 participants, 53,075 had periodontitis and were placed in the periodontitis group; the remaining 660,126 individuals were included as the control group. Overall, the cumulative incidence of cancer in the periodontitis group was 2.2 times higher than that in the control group. The periodontitis group had an increased risk of total cancer compared to the control group after adjusting for age, sex, comorbidities, BMI, and smoking history (aHR, 1.129; 95% confidence interval [CI], 1.089-1.171; P<0.0001). When examining specific cancer types, significant associations were also observed between periodontitis and stomach cancer (aHR, 1.136; 95% CI, 1.042-1.239; P=0.0037), colon cancer (aHR, 1.129; 95% CI, 1.029-1.239; P=0.0105), lung cancer (aHR, 1.127; 95% CI, 1.008-1.260; P=0.0353), bladder cancer (aHR, 1.307; 95% CI, 1.071-1.595; P=0.0085), thyroid cancer (aHR, 1.191; 95% CI, 1.085-1.308; P=0.0002), and leukemia (aHR, 1.394; 95% CI, 1.039-1.872; P=0.0270). There was no significant association between the development of secondary malignancy and periodontitis in cancer survivors who were alive 5 years after they were diagnosed with the primary malignancy. Conclusions: Periodontal disease, including periodontitis, was associated with increased risk of cancer, which persisted after controlling for confounding factors. Further prospective research is warranted to establish a causal relationship.
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Although gastrointestinal stromal tumors (GISTs) are rare disease and rectal GISTs is only 5% of total GISTs, they have the worst prognosis. Due to narrow pelvis, tumor rupture or positive resection margin are common in the management of rectal GISTs. The impact of neoadjuvant treatment on the clinical outcomes of rectal gastrointestinal stromal tumors (GISTs) remains unclear. Thus, we conducted a retrospective study to investigate the impact of neoadjuvant imatinib on rectal GIST. The cohort comprised 33 patients; of them, 10 and 23 belonged to the neoadjuvant (i.e., those who underwent neoadjuvant imatinib treatment) and the control group (i.e., those who underwent surgery without prior imatinib treatment), respectively. Neoadjuvant group was associated with more common levator ani muscle displacement (P = 0.002), and showed significantly larger radiologic tumor size (P = 0.036) than the control group. The mean tumor size was significantly decreased after imatinib treatment (6.8 cm to 4.7cm, P = 0.006). There was no significant difference in resection margin involvement (P >0.999), and sphincter preservation rates (P = 0.627) between the two groups. No difference was observed with respect to morbidities, hospital stay, local recurrence and disease-free survival. Neoadjuvant imatinib treated group had similar propensity with control group after treatment. We thought reduced tumor sized could enhance resectability and provide more chance to preserve sphincter for rectal GIST patients. Considering large tumor size and higher rate of sphincter invasion in the neoadjuvant group, imatinib treatment could be helpful as a conversion strategy to make huge and low-lying rectal GIST operable and achieve better surgical outcomes.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Neoplasias Retais , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib/uso terapêutico , Margens de Excisão , Terapia Neoadjuvante , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Estudos RetrospectivosRESUMO
PURPOSE: The combination of oxaliplatin and fluoropyrimidine for 6 months is one of the standard options for adjuvant therapy for high-risk stage II and III colorectal cancers (CRCs). The optimal duration of oxaliplatin to diminish neurotoxicity without compromising efficacy needs to be clarified. PATIENTS AND METHODS: This open-label, randomized, phase III, noninferiority trial randomly assigned patients with high-risk stage II and III CRC to 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine groups (3- and 6-month arms, respectively). The primary end point was disease-free survival (DFS), and the noninferiority margin was a hazard ratio (HR) of 1.25. RESULTS: In total, 1,788 patients were randomly assigned to the 6-month (n = 895) and 3-month (n = 893) arms, and 83.6% in the 6-month arm and 85.7% in the 3-month arm completed the treatment. The neuropathy rates with any grade were higher in the 6-month arm than in the 3-month arm (69.5% v 58.3%; P < .0001). The 3-year DFS rates were 83.7% and 84.7% in the 6-month and 3-month arms, respectively, with an HR of 0.953 (95% CI, 0.769 to 1.180; test for noninferiority, P = .0065) within the noninferiority margin. Among patients with stage III CRC treated by capecitabine plus oxaliplatin, the 3-year DFS of the 3-month arm was noninferior as compared with that of the 6-month arm with an HR of 0.713 (95% CI, 0.530 to 0.959; P = .0009). However, among patients with high-risk stage II and stage III CRC treated by infusional fluorouracil, leucovorin, and oxaliplatin, the noninferiority of the 3-month arm compared with the 6-month arm was not proven. CONCLUSION: This study suggests that adding 3 months of oxaliplatin to 6 months of capecitabine could be considered an alternative adjuvant treatment for stage III CRC (ClinicalTrials.gov identifier: NCT01092481).
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Neoplasias do Colo , Compostos Organoplatínicos , Oxaliplatina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/uso terapêuticoRESUMO
The canonical mutations in gastrointestinal stromal tumors (GISTs) are typically activating mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA). GISTs with non-canonical mutations are a heterogeneous group. Here, we examined tropomyosin-related kinase (TRK) fusion in GIST cases without KIT/PDGFRA mutations (KIT/PDGFRA wild-type (WT) GISTs). We retrospectively analyzed patients who were diagnosed with GISTs at the Yonsei Cancer Center, Severance Hospital, between January 1998 and December 2016. Thirty-one patients with KIT/PDGFRA WT GISTs were included in the analysis. TRK expression in tumor samples was assessed by pan-TRK immunohistochemistry (IHC), and the neurotrophic tyrosine receptor kinase (NTRK: the gene encoding TRK) rearrangement was analyzed by fluorescence in situ hybridization (FISH). IHC analyses revealed that five cases in this cohort exhibited a weak to moderate TRK expression. NTRK1 fusions were detected in three tumor samples, and two samples harbored NTRK3 fusions. The remaining 26 samples did not harbor NTRK fusions. Two types of NTRK fusions were detected, and the overall NTRK fusion frequency in KIT/PDGFRA WT GIST cases was 16% (5/31). Our data provide insights into the molecular alterations underpinning KIT/PDGFRA WT GISTs. More effort should be devoted to improve methods to identify this distinct disease subtype within the KIT/PDGFRA WT GIST group.
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The aim of our study is to evaluate the clinical efficacy of durvalumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) or polymerase epsilon (POLE)-mutated metastatic or unresectable colorectal cancer (mCRC) who had disease progression after standard chemotherapy. This prospective, open-label, multicenter, phase II study enrolled patients with mCRC harboring MSI-H/dMMR or POLE mutations treated with at least one prior line of therapy. The participants received durvalumab (1500 mg) every 4 weeks intravenously. The primary endpoint was the objective response rate (ORR). Of the 33 patients, 30 had MSI-H/dMMR and 3 had POLE-mutated microsatellite stable (MSS) CRC. With a median follow-up duration of 11.2 months (95% confidence interval [CI]: 7.3-15.0), the ORR was 42.4% (95% CI: 25.5-60.8). Among three patients with POLE-mutated CRC, one patient who had an exonuclease domain mutation (EDM) achieved an objective response, but the others with mutations in the non-exonuclease domain had progressive disease. Overall, the median duration of response was not reached and 85.7% of the responses were ongoing at data cutoff. The progression-free survival rate of 12 months was 58.2% (95% CI: 39.0-73.1) and the 12-month overall survival rate was 68.3% (95% CI: 48.8-81.7). Grade 3 treatment-related adverse events occurred in 36.4% of the patients and were manageable. In conclusion, durvalumab showed promising clinical activity with encouraging response rates and satisfactory survival outcomes in mCRC patients with MSI-H/dMMR or POLE EDM. In patients with POLE-mutated mCRC, clinical response to durvalumab may be restricted to those with EDM.
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Neoplasias Colorretais , Instabilidade de Microssatélites , Anticorpos Monoclonais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Humanos , Estudos ProspectivosRESUMO
INTRODUCTION: Some patients with cancer may present with progressive or persistent disease at a limited number of sites following a period of treatment response. We evaluated the safety and effectiveness of metastasis-directed radiotherapy (MRT) for oligoprogressive or oligopersistent disease in patients receiving systemic treatment for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with mCRC who received 5-fluorouracil, leucovorin, and oxaliplatin; 5-fluorouracil, leucovorin, and irinotecan; and/or capecitabine chemotherapy between 2011 and 2020 at a single institution were identified. Then, those who underwent MRT for five or fewer lesion sites while receiving systemic treatment for other metastases were categorized. The primary endpoint was time to change to systemic therapy. Secondary endpoints included MRT-related toxicity, overall survival, and local control. RESULTS: Among 4157 patients included, 91 (2%) received MRT to limited lesion sites (55 oligoprogressive and 36 oligopersistent) during systemic treatment following a period of treatment response. The median time to change to next-line systemic therapy was 5 months in the overall cohort (measured from the current chemotherapy session) and 9.5 (range, 6.0-40.6) months in the MRT group (measured from the MRT session). No severe toxicity or systemic treatment interruption was observed following MRT. The 1-year local control and overall survival rates were 69% and 99%, respectively. CONCLUSION: In patients with oligoprogressive or oligopersistent mCRC, MRT may be performed safely in conjunction with systemic treatment to maximize the benefit of systemic therapy and to prolong the time to change to systemic therapy. Further prospective studies should confirm these findings.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Fluoruracila , Humanos , Leucovorina , Metástase Neoplásica , Estudos Prospectivos , Neoplasias Retais/tratamento farmacológicoRESUMO
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.
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PURPOSE: Preclinical data indicate that response to radiotherapy (RT) depends on DNA damage repair. In this study, we investigated the role of mutations in genes related to DNA damage repair in treatment outcome after RT. MATERIALS AND METHODS: Patients with solid tumor who participated in next generation sequencing panel screening using biopsied tumor tissue between October 2013 and February 2019 were reviewed and 97 patients that received RT were included in this study. Best response to RT and the cumulative local recurrence rate (LRR) were compared according to absence or presence of missense, nonsense, and frameshift mutations in ATM and/or BRCA1/2. RESULTS: Of the 97 patients, five patients harbored mutation only in ATM, 22 in only BRCA1/2, and six in both ATM and BRCA1/2 (ATMmtBRCAmt). Propensity score matching was performed to select the control group without mutations (ATMwtBRCAwt, n=33). In total, 90 RT-treated target lesions were evaluated in 66 patients. Highest objective response rate of 80% was observed in ATMmtBRCAmt lesions (p=0.007), which was mostly durable. Furthermore, the cumulative 1-year LRR was the lowest in ATMmtBRCAmt lesions and the highest in ATMwtBRCAwt lesions (0% vs. 47.9%, p=0.008). RT-associated toxicities were observed in 10 treatments with no significant difference among the subgroups (p=0.680). CONCLUSION: Tumors with ATM and BRCA1/2 mutations exhibited superior tumor response and local control after RT compared to tumors without these mutations. The results are hypothesis generating and suggest the need for integrating the tumor mutation profile of DNA repair genes during treatment planning.