Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.

BACKGROUND: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS: A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).

ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

Nuclear Localization of Yes-Associated Protein Is Associated With Tumor Progression in Cutaneous Melanoma.

Yes-associated protein (YAP), an effector molecule of the Hippo signaling pathway, is expressed at high levels in cutaneous melanoma. However, the role of YAP in melanoma progression according to cellular localization is poorly understood. Tissues from 140 patients with invasive melanoma were evaluated by immunohistochemistry. Flow cytometry, western blotting, viability assays, wound healing assays, verteporfin treatment, and xenograft assays were conducted using melanoma cell lines B16F1 and B16F10 subjected to YapS127A transfection and siYap knockdown. Nuclear YAP localization was identified in 63 tumors (45.0%) and was more frequent than cytoplasmic YAP in acral lentiginous and nodular subtypes (P = .007). Compared with cytoplasmic YAP melanomas, melanomas with nuclear YAP had higher mitotic activity (P = .016), deeper invasion (P < .001), and more frequently metastasized to lymph nodes (P < .001) and distant organs (P < .001). Patients with nuclear YAP melanomas had poorer disease-free survival (P < .001) and overall survival (P < .001). Nuclear YAP was an independent risk factor for distant metastasis (hazard ratio: 3.206; 95% CI, 1.032-9.961; P = .044). Proliferative ability was decreased in siYapB16F1 (P < .001) and siYapB16F10 (P = .001) cells and increased in YapS127AB16F1 (P = .003) and YapS127AB16F10 (P = .002) cells. Cell cycle analysis demonstrated relative G1 retention in siYapB16F1 (P < .001) and siYapB16F10 (P < .001) cells and S retention in YapS127AB16F1 cells (P = .008). Wound healing assays showed that Yap knockdown inhibited cell invasion (siYapB16F1, P = .001; siYapB16F10, P < .001), whereas nuclear YAP promoted it (YapS127AB16F, P < .001; YapS127AB16F1, P = .017). Verteporfin, a direct YAP inhibitor, reduced cellular proliferation in B16F1 (P = .003) and B16F10 (P < .001) cells. Proliferative effects of nuclear YAP were confirmed in xenograft mice (P < .001). In conclusion, nuclear YAP in human melanomas showed subtype specificity and correlated with proliferative activity and proinvasiveness. It is expected that YAP becomes a useful prognostic marker, and its inhibition may be a potential therapy for melanoma patients.

Exploring Molecular Genetic Alterations and RAF Fusions in Melanoma: A Belvarafenib Expanded Access Program in Patients with RAS/RAF-Mutant Melanoma.

BACKGROUND: Melanoma incidence is on the rise in East Asia, yet studies of the molecular landscape are lacking in this population. We examined patients with melanoma who underwent next-generation sequencing (NGS) at a single tertiary center in South Korea, focusing on patients harboring NRAS or RAF alterations who received belvarafenib, a pan-RAF dimer inhibitor, through the Expanded Access Program (EAP). PATIENTS AND METHODS: Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained and annotated. Patients in the EAP received 450 mg twice daily doses of belvarafenib. RESULTS: Alterations in the RAS/RTK pathway were the most prevalent, with BRAF and NRAS alteration rates of 22.4% and 17.7%, respectively. NGS enabled additional detection of fusion mutations, including 6 BRAF and 1 RAF1 fusion. Sixteen patients with NRAS or RAF alterations received belvarafenib through the EAP, and disease control was observed in 50%, with 2 patients demonstrating remarkable responses. CONCLUSIONS: Our study highlights the value of NGS in detecting BRAF, NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib.

Importance of Local Ablative Therapies for Lung Metastases in Patients With Colorectal Cancer.

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 1 year (n = 132), or after 1 year (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.

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.

Application of Multigene Panel Testing in Patients With High Risk for Hereditary Colorectal Cancer: A Descriptive Report Focused on Genotype-Phenotype Correlation.

BACKGROUND: The genetic test solely based on the clinical features of hereditary colorectal cancer has limitations in clinical practice. OBJECTIVE: This study aimed to analyze the results of comprehensive multigene panel tests based on clinical findings. DESIGN: This was a cross-sectional study based on a prospectively compiled database. SETTING: The study was conducted at a tertiary hospital. PATIENTS: A total of 381 patients with high risk for hereditary colorectal cancer syndromes were enrolled between March 2014 and December 2019. MAIN OUTCOME MEASURES: The primary outcome was to describe the mutational spectrum based on genotype-phenotype concordance and discordance. RESULTS: Germline mutations were identified in 89 patients for polyposis hereditary colorectal cancer genes (76 in APC; 4 in PTEN; 4 in STK11; 3 in BMPR1A; 1 in POLE; 1 in POLD1), 89 patients for nonpolyposis hereditary colorectal cancer genes (41 in MLH1; 40 in MSH2; 6 in MSH6; and 2 in PMS2), and 12 patients for other cancer predisposition genes (1 in ATM; 2 in BRCA1; 1 in BRCA2; 1 in BRIP1; 1 in MLH3; 1 in NBN; 1 in PMS1; 1 in PTCH1; 1 in TP53; and 2 in monoallelic MUTYH). If we had used direct sequencing tests of 1 or 2 major genes based on phenotype, 48 (25.3%) of 190 mutations would not have been detected due to technical differences (12.1%), less frequent genotype (4.2%), unclear phenotype (3.7%), and genotype-phenotype discordance (4.7%). The genotype-phenotype discordance is probably linked to compound heterozygote, less distinctive phenotype, and insufficient information for colorectal cancer risk. LIMITATIONS: This study included a small number of patients with insufficient follow-up duration. CONCLUSIONS: A comprehensive multigene panel is expected to identify more genetic mutations than phenotype-based direct sequencing, with special utility for unclear phenotype or genotype-phenotype discordance. See Video Abstract at http://links.lww.com/DCR/B844. APLICACIN DE PRUEBAS DE PANEL MULTIGNICO EN PACIENTES CON ALTO RIESGO DE CNCER COLORRECTAL HEREDITARIO INFORME DESCRIPTIVO ENFOCADO EN LA CORRELACIN GENOTIPOFENOTIPO: ANTECEDENTES:La prueba genética basada únicamente en la característica clínica del cáncer colorrectal hereditario tiene limitaciones en la práctica clínica.OBJETIVO:Este estudio tuvo como objetivo analizar el resultado de pruebas integrales de panel multigénico basadas en hallazgos clínicos.DISEÑO:Este fue un estudio transversal basado en una base de datos recopilada prospectivamente.AJUSTE:El estudio se realizó en un hospital terciario.PACIENTES:Se inscribió un total de 381 pacientes con alto riesgo de síndromes de cáncer colorrectal hereditario entre marzo del 2014 y diciembre del 2019.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue describir el espectro mutacional basado en la concordancia y discordancia genotipo-fenotipo.RESULTADOS:Se identificaron mutaciones de la línea germinal en 89 pacientes para genes de cáncer colorrectal hereditario con poliposis (76 en APC; 4 en PTEN; 4 en STK11; 3 en BMPR1A; 1 en POLE; 1 en POLD1), 89 pacientes para genes de CCR hereditario sin poliposis (41 en MLH1; 40 en MSH2; 6 en MSH6; y 2 ​​en PMS2) y 12 pacientes por otro gen de predisposición al cáncer (1 en ATM; 2 en BRCA1; 1 en BRCA2; 1 en BRIP1; 1 en MLH3; 1 en NBN; 1 en PMS1; 1 en PTCH1; 1 en TP53; y 2 ​​en MUTYH monoalélico). Si hubiéramos utilizado pruebas de secuenciación directa de uno o dos genes principales basados ​​en el fenotipo, 48 (25,3%) de 190 mutaciones no se habrían detectado debido a diferencias técnicas (12,1%), genotipo menos frecuente (4,2%), fenotipo poco claro (3,7%) y discordancia genotipo-fenotipo (4,7%). La discordancia genotipo-fenotipo probablemente esté relacionada con el heterocigoto compuesto, el fenotipo menos distintivo y la información insuficiente para el riesgo de cáncer colorrectal.LIMITACIONES:Este estudio incluyó una pequeña cantidad de pacientes con una duración de seguimiento insuficiente.CONCLUSIONES:Se espera que un panel multigénico completo identifique más mutaciones genéticas que la secuenciación directa basada en el fenotipo, con especial utilidad para la discordancia de fenotipo o genotipo-fenotipo poco clara. Consulte Video Resumen en http://links.lww.com/DCR/B844. Traducción- Dr. Francisco M. Abarca-Rendon).

First-line pembrolizumab versus dabrafenib/trametinib treatment for BRAF V600-mutant advanced melanoma.

BACKGROUND: Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma. OBJECTIVE: To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation. METHODS: Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n = 40) or dabrafenib/trametinib (n = 32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed. RESULTS: A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio = 2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P = .375) and response rate (P = .123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8+ T cells. LIMITATIONS: Analysis was conducted in a retrospective manner. CONCLUSION: Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer.

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).

Synthesis of novel 1H-Pyrazolo[3,4-b]pyridine derivatives as DYRK 1A/1B inhibitors.

As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8 and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC50 Values of 3-287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory enzymatic activity (IC50 = 3 nM) and cell proliferation inhibitory activity (IC50 = 1.6 µM) towards HCT116 colon cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic interactions.

Autonomy is not but competence and relatedness are associated with physical activity among colorectal cancer survivors.

PURPOSE: The main objective of this study was to use the framework of the self-determination theory, incorporating both internal and external sources of motivation, to identify factors influencing physical activity among colorectal cancer survivors (CRC-S) in Korea. METHOD: In total, 242 patients at a university-affiliated hospital in Seoul, Korea, responded to a descriptive survey, which comprised questionnaire sets including the Global Physical Activity Questionnaire and the Patient Health Questionnaire. Motivation was then assessed on three scales: the Treatment Self-Regulation (autonomy), Perceived Competence (competence), and the multidimensional Scale of Perceived Social Support (relatedness). Logistic regression analysis was then used to identify factors associated with physical activity. RESULT: The mean physical activity score was 16.07 metabolic equivalent hours per week, and only 23.3% of patients had an appropriate level of exercise. In the logistic regression analysis, physical activity was associated with competence (odds ratio (OR) = 1.36, 95% confidence interval (CI): 1.06-1.74), relatedness (OR = 1.11, 95% CI: 1.04-1.18), depression (OR = 0.84, 95% CI: 0.75-0.94), and stage I or II disease (OR = 3.33, 95% CI: 1.28-1.86). This study indicated that competence, relatedness, depression, and the disease stage contributed to physical activity among these subjects while autonomy did not. CONCLUSION: Future interventions to achieve the recommended levels of physical activity among CRC-S could benefit from taking into account the disease stage as well as psychosocial factors including motivation and depression.

Clinical Significance of Preoperative Serum Carcinoembryonic Antigen Within the Normal Range in Colorectal Cancer Patients Undergoing Curative Resection.

BACKGROUND: Serum carcinoembryonic antigen (CEA) is a widely used tumor marker in colorectal cancer (CRC), but within normal range of preoperative CEA levels the clinical significance of CEA is unknown. OBJECTIVE: The aim of this study was to evaluate the usefulness of CEA within the normal range as a prognosticator of non-metastatic CRC. METHODS: This retrospective cohort study included 2021 CRC patients with normal preoperative CEA who underwent elective curative surgery (discovery group). We determined the optimal cut-off value for disease-free survival (DFS) discrimination using the Contal and O'Quigley method. We also assessed the prognostic significance of the cut-off value in a prospective cohort of 171 stage III colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (validation group). RESULTS: The optimal cut-off CEA value was 2.1 ng/mL in the discovery group. The DFS rates were significantly poorer in patients with high-normal preoperative CEA levels (2.1-5.0 ng/mL) than in those with low-normal CEA levels (< 2.1 ng/mL) in both groups. A high-normal CEA level was an independent risk factor for DFS in both groups, and was associated with inferior DFS in patients with stage II and III disease and in never or former smokers. The correlation between DFS and CEA levels was more distinct in left-sided colon and rectal cancer. CONCLUSIONS: A high-normal preoperative CEA level (≥ 2.1 ng/mL), even within the normal range, was an independent prognosticator for poor DFS in CRC. The usefulness of CEA was influenced by smoking status and tumor location in addition to tumor stage.

Male sex and Breslow thickness are important risk factors for recurrence of localized melanoma in Korean populations.

BACKGROUND: Predicting the recurrence of localized melanoma is important; however, studies investigating risk factors for recurrence of localized melanoma are lacking in Asian populations. OBJECTIVE: To identify risk factors for recurrence of localized melanoma in Korean patients. METHODS: We retrospectively reviewed patients with cutaneous melanoma without evidence of metastasis from 2000 to 2017. Logistic and Cox regression analyses were conducted for recurrence. The average follow-up time was 46.2 months. RESULTS: We reviewed the data of 340 patients diagnosed with cutaneous melanoma and staged as melanoma in situ, stages I and II. Acral melanoma (70.3%, 239/340) was the predominant subtype. Ninety-two patients (27.1%) had a recurrence after primary melanoma removal (29 local recurrences, 49 regional metastases, and 28 distant metastases). Some patients had multiple types of recurrence at the same time. Male sex (P = .030) and Breslow thickness greater than 1 mm (P = .008) correlated with an increased risk of recurrence. Breslow thickness greater than 2.5 mm in males and greater than 4 mm in females showed a higher predictive value for recurrence than traditional stages IIB and IIC (hazard ratio 3.743 vs 2.972). LIMITATIONS: This was a single-center retrospective study. CONCLUSION: In patients with localized cutaneous melanoma, male sex and Breslow thickness are the most important prognostic factors for recurrence in Korean populations. Different cutoff values of Breslow thickness may better predict recurrence according to sex.

Objectively measured physical activity during chemotherapy in colon cancer patients.

PURPOSE: Although adjuvant chemotherapy can have an impact on physical activity (PA), PA level has not been studied in patients with stage II-III colon cancer. This study investigated PA levels during and between chemotherapy cycles. METHODS: We objectively measured PA levels for 2 weeks during the 2nd and 11th chemotherapy cycles. In addition, self-reported PA levels were assessed before chemotherapy initiation, during 2nd, 6th, and 12th chemotherapy cycles. This study included 22 men and 33 women with stage II-III colon cancer patients (57 ± 9 years). RESULTS: Before the initiation of chemotherapy, most cancer patients were minimally active. Compared with the 1st week of chemotherapy, moderate- and light-intensity PA levels significantly increased during the 2nd week of chemotherapy. Patients increased moderate- and light-intensity PA from 217.4 to 290.3 min per week and from 585.7 to 657.8 min per week, respectively (p < 0.01). PA levels did not show any difference between the 2nd and 12th cycles when objectively measured, or between baseline and 2nd, 6th, and 12th cycles when self-reported. CONCLUSION: PA levels during chemotherapy cycles are initially low, and then increase towards the end of the cycle; however, PA levels do not change between chemotherapy cycles. Future work with broader and larger samples size is recommended.

The role of endoscopic evaluation for radiation proctitis in patients receiving intermediate-dose postoperative radiotherapy for rectal cancer.

OBJECTIVES: High-dose pelvic radiotherapy (RT) is known to be associated with chronic radiation proctitis (RP). However, the effects of intermediate radiation doses are unknown. We assessed the incidence of late clinical RP among patients with rectal cancer receiving intermediate-dose postoperative RT, as well as the role of early endoscopic abnormalities in predicting RP development. METHODS: We retrospectively reviewed 153 patients with rectal cancer who received postoperative RT at a median dose of 54 Gy between 2005 and 2009 and who underwent endoscopic examination within 12 months thereafter. Endoscopic RP was assessed using the Vienna rectoscopy score (VRS). Late clinical RP toxicity was evaluated, as was its correlation with endoscopic RP. RESULTS: All patients underwent an endoscopic examination at a median of 9 months after postoperative pelvic RT. Endoscopic RP was detected in 45 patients (29.4%); the predominant patterns were telangiectasia and congested mucosa. During the median 88-month follow-up period, 29 patients (19.0%) experienced late clinical RP; only 3 (2.0%) had Grade 3 or above. The VRS predicted the development of late clinical RP as well as its cumulative incidence (P < 0.001). Endoscopic evidence of telangiectasia was significantly associated with the development of late clinical RP (P < 0.001). CONCLUSIONS: Early endoscopic findings using VRS are useful for predicting the possibility of late clinical RP, although the incidences of severe cases were low. Patients with endoscopic abnormalities should be followed closely owing to their susceptibility to clinical RP.

Preoperative Serum Carcinoembryonic Antigen Level as a Prognostic Factor for Recurrence and Survival After Curative Resection Followed by Adjuvant Chemotherapy in Stage III Colon Cancer.

BACKGROUND: Carcinoembryonic antigen (CEA) is the most widely used tumor marker in colon cancer; however, there has been controversy regarding the significance of preoperative serum CEA level as a prognostic factor for recurrence. In this study, we evaluated the optimal cutoff value and prognostic significance of preoperative serum CEA level in stage III colon cancer. METHODS: Based on a retrospective cohort of 965 patients with stage III colon cancer who underwent elective curative surgery and adjuvant chemotherapy with fluoropyrimidine and oxaliplatin (training set), we determined the optimal cutoff value of CEA for recurrence using the Contal and O'Quigley method. We assessed the prognostic value of this cutoff value in terms of disease-free survival (DFS) and overall survival (OS) in a prospective cohort of 268 patients with stage III colon cancer (validation set). A Cox proportional hazards model was used to explore the association of prognostic variables with DFS and OS. RESULTS: The statistically determined best cutoff value for CEA was 3 ng/mL in the training set. A high CEA level (≥3 ng/mL) was associated with inferior DFS (hazard ratio [HR] 4.609, 95 % confidence interval [CI] 2.028-10.474) and OS (HR 3.956, 95 % CI 1.127-13.882) in the validation set, while multivariate analysis showed that a high CEA level was an independent risk factor for DFS and OS in both study subsets. CONCLUSION: Preoperative serum CEA level is an independent prognostic factor for DFS and OS in patients with stage III colon cancer after curative resection and adjuvant chemotherapy.

A phase 1, open label, dose escalation study to investigate the safety, tolerability, and pharmacokinetics of MG1102 (apolipoprotein(a) Kringle V) in patients with solid tumors.

Purpose MG1102 is a potent inhibitor of angiogenesis in both in vitro and in vivo models. The purpose of the study was to investigate the safety and tolerability, pharmacokinetic (PK) profile, and preliminary antitumor efficacy of MG1102. Methods Patients with refractory solid tumors were eligible. Each patient received 1 dose of MG1102 followed by a 6-day rest period, during which they underwent PK assessments and safety monitoring. If the initial dose was tolerated, the patient continued with the 21-day treatment of MG1102 (5 days on, 2 days off for 3 weeks). Dose escalation was planned in 6 cohorts (6, 12, 24, 48, 96, and 192 mg/m2). Primary objectives included safety and maximum tolerated dose (MTD) assessment. Secondary objectives included assessment of PK, pharmacodynamics, and efficacy. Results A total of 16 patients were enrolled and 12 (75%) completed the study. The most common cancer type was colorectal cancer (n = 10). There was no dose limiting toxicity and the MTD was not reached at 192 mg/m2. The most frequent treatment-emergent adverse events were gastrointestinal disorders, including nausea (30.8%), abdominal pain (23.1%), constipation (23.1%), and dyspepsia (23.1%). The PK of MG1102 was slightly less than dose proportional from Cohorts 3 to 6. Among 13 response-evaluable patients, 1 unconfirmed partial response (PR) was seen (in the 48 mg/m2 cohort) and 4 patients had stable disease. Conclusions The safety profile of MG1102 was generally manageable and the toxicities resolved quickly. Potential antitumor activity was observed with 1 unconfirmed PR (60% size reduction).

Role of adjuvant chemotherapy in locally advanced rectal cancer with ypT0-3N0 after preoperative chemoradiation therapy and surgery.

BACKGROUND: We aimed to explore the clinical benefit of adjuvant chemotherapy (AC) with fluoropyrimidine in patients with ypT0-3N0 rectal cancer after preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME). METHODS: Patients with ypT0-3N0 rectal cancer after preoperative CRT and TME were included using prospectively collected tumor registry cohort between January 2001 and December 2013. Patients were categorized into two groups according to the receipt of AC. Disease-free survival (DFS) and overall survival (OS) were compared between the adjuvant and observation groups. To control for potential confounding factors, we also calculated propensity scores and performed propensity score-matched analysis for DFS and OS. RESULTS: Of the 339 evaluated patients, 87 patients (25.7%) did not receive AC. There were no differences in DFS (hazard ratio [HR], 0.921; 95% confidence interval [CI], 0.562-1.507; P = 0.742) and OS (HR, 0.835; 95% CI, 0.423-1.648; P = 0.603) between the adjuvant and observation groups. After propensity score matching, DFS (HR, 1.129; 95% CI, 0.626-2.035; P = 0.688) and OS (HR, 1.200; 95% CI, 0.539-2.669; P = 0.655) did not differ between the adjuvant and observation groups. Advanced T stage and positive resection margin were independently associated with inferior DFS and OS on multivariate analysis. CONCLUSIONS: AC did not improve DFS and OS for patients with ypT0-3N0 rectal cancer after preoperative CRT followed by TME in this cohort study. The confirmative role of AC in locally advanced rectal cancer should be evaluated in prospective randomized trials with a larger sample size.

Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers.

BACKGROUND: Among colorectal cancers (CRCs), high-frequency microsatellite instability (MSI-H) is associated with a better prognosis, compared with low-frequency MSI or microsatellite stability (MSI-L/MSS). However, it is unclear whether MSI affects the prognosis of recurrent CRCs. METHODS: This study included 2940 patients with stage I-III CRC who underwent complete resection. The associations of MSI status with recurrence patterns, disease-free survival (DFS), overall survival from diagnosis to death (OS1), and overall survival from recurrence to death (OS2) were analysed. RESULTS: A total of 261 patients (8.9%) had MSI-H CRC. Patients with MSI-H CRC had better DFS, compared to patients with MSI-L/MSS CRC (hazard ratio (HR): 0.619, P<0.001). High-frequency microsatellite instability CRC was associated with more frequent local recurrence (30.0% vs 12.0%, P=0.032) or peritoneal metastasis (40.0% vs 12.3%, P=0.003), and less frequent lung (10.0% vs 42.5%, P=0.004) or liver metastases (15.0% vs 44.7%, P=0.01). Recurrent MSI-H CRC was associated with worse OS1 (HR: 1.363, P=0.035) and OS2 (HR: 2.667, P<0.001). An analysis of patients with colon cancer yielded similar results. CONCLUSIONS: Recurrence patterns differed between MSI-H CRC and MSI-L/MSS CRC, and recurrent MSI-H CRCs had a worse prognosis.

Benefit of Adjuvant Chemotherapy After Curative Resection of Lung Metastasis in Colorectal Cancer.

BACKGROUND: The survival benefit of adjuvant chemotherapy after colorectal cancer (CRC) lung metastasectomy is uncertain. METHODS: We enrolled 221 CRC patients who underwent pulmonary metastasectomy between October 2002 and July 2013, including those with previous liver metastasis that had been curatively resected. Disease-free survival (DFS) and overall survival (OS) were calculated from the day of lung metastasectomy. RESULTS: Among all patients, 176 (79.6%) received adjuvant chemotherapy after lung metastasectomy. Median follow-up was 34.7 months from the time of lung metastasectomy [95% confidence interval (95% CI), 7.4-90.9 months]. Patients treated with adjuvant chemotherapy had longer DFS compared with surgery alone (median 32.7 vs 11.2 months respectively, P = 0.076). Multivariate analysis revealed previous liver metastasis, preoperative carcinoembryonic antigen ≥5 ng/mL, disease-free interval <24 months, and surgery without adjuvant chemotherapy as independent risk factors for recurrence. Low-risk patients who had 0-1 risk factors received a significant survival benefit from adjuvant chemotherapy [hazard ratio (HR) 0.54; 95% CI 0.32-0.91, P = 0.020]; however, high-risk patients with ≥2 risk factors did not (HR 1.02; 95% CI 0.48-2.14, P = 0.964). Patients treated with adjuvant chemotherapy showed no OS benefit compared with patients who received surgery alone (median 89.6 vs 86.8 months respectively, P = 0.833). CONCLUSIONS: CRC patients received lung metastasectomy could have a DFS benefit from adjuvant chemotherapy, especially in low-risk patients. Larger, prospective studies are needed to evaluate the role of adjuvant chemotherapy after CRC lung metastasectomy.