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We prospectively investigated the potential of tumor-informed circulating tumor DNA (ctDNA) for detecting minimal residual disease (MRD) in surgically resected biliary tract cancer (BTC). Personalized panels were developed using individual variants identified from the whole-exome sequencing of surgical specimens from each patient. Two sequential blood samples, collected preoperatively and within 6 weeks after surgery, were analyzed. A positive ctDNA result was defined as the identification of two or more patient-specific mutations. A total of 18 patients were enrolled. However, 1 patient was excluded due to inoperability detected during surgery, and personalized target panels could not be created for 3 patients due to a low number of target variants, resulting in the analysis of 14 patients. There was a tendency for a higher preoperative ctDNA positivity rate in an advanced overall stage (100% in stage III-IV vs. 44.4% in stage I-II, p = 0.126) and node-positive disease (100% in node-positive vs. 60% in node-negative, p = 0.210). After a median follow-up of 17.4 months (range, 11.4-31.1), the 1-year and 2-year progression-free survival (PFS) rates were 78.6% and 58.2%, respectively. Changes in ctDNA positivity status were negative to negative in 3 patients (25.0%), positive to negative in 3 patients (25.0%), and positive to positive in 6 patients (50%). Additionally, there was a trend for an association between poorer PFS and both preoperative and postoperative ctDNA positivity. Among ctDNA-negative patients before surgery, no progression was observed; however, 5 out of 10 ctDNA-positive patients experienced progression. Postoperatively, only 1 out of 6 ctDNA-negative patients experienced progression, in contrast to 3 out of 6 patients with a positive ctDNA result. Although limited by the small sample size, our results may indicate a possible role for tumor-informed ctDNA analysis in detecting MRD in surgically resected BTC and warrant further validation in larger studies.

Purpose Little has been determined regarding the association between patients’ and families’ illness understanding and preferences for medical care. We aimed to evaluate the association of illness understanding with advance care planning (ACP) and preferences for end-of-life care, such as aggressive care, early palliative care (EPC), and hospice care, among advanced cancer patients and their family caregivers. Methods Patients were recruited for a prospective cohort study at outpatient and inpatient facilities in nine university hospitals in Korea (n = 150), and their primary family caregivers were also asked to participate (n = 101). Data on ACP and end-of-life care preferences were collected only at baseline in the cohort study with optional questions and were used to analyze these study results. Results Patients with illness understanding were more likely to have documented physician orders for life-sustaining treatment (POLSTs) (adjusted odds ratio [aOR] of 4.94) and to have discussed ACP with their families (aOR 2.15) than those who did not. Being expected to live for several months, they were unlikely to prefer active treatment. Caregivers understanding patients’ illness were more likely to write advance directives (ADs) and to discuss ACP; furthermore, they had already discussed ACP with family members. They did not prefer active treatment or life-sustaining treatments when their family members were expected to die within a few weeks. There was no significant association between illness understanding and preferences for EPC. Conclusion Accurately recognizing an incurable disease is associated with preferences for more ACP and less aggressive care but not with preferences for EPC or hospice care among both advanced cancer patients and their family caregivers.

The β-catenin signaling is important in cell growth and differentiation and is frequently dysregulated in various cancers. The most well-known mechanism of endocrine resistance is cross-talk between the estrogen receptor (ER) and other growth factor signaling, such as phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway. In the present study, we investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer. We established tamoxifen-resistant (TamR) cell line via long-term exposure of MCF-7 breast cancer cells to gradually increasing concentrations of tamoxifen. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay. TamR cells showed a mesenchymal phenotype, and exhibited a relatively decreased expression of ER and increased expression of human epidermal growth factor receptor 2 and the epidermal growth factor receptor. We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells. The expression and transcriptional activity of β-catenin were inhibited by β-catenin small-molecule inhibitor, ICG-001 or β-catenin siRNA. The viability of TamR cells, which showed no change after treatment with tamoxifen, was reduced by ICG-001 or β-catenin siRNA. The combination of ICG-001 and mTOR inhibitor, rapamycin, yielded an additive effect on the inhibition of viability in TamR cells. These results suggest that β-catenin plays a role in tamoxifen-resistant breast cancer, and the inhibition of β-catenin may be a potential target in tamoxifen-resistant breast cancer.

Background For locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC. Methods This is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m 2 , once a day] on day 1 and capecitabine [1,000 mg/m 2 , twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m 2 twice a day). After preoperative treatment, total mesorectal excision was performed 2–4 weeks in the TNT group and 6–10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate. Discussion The TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients. Trial registration Cris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

Background Comorbid depression and poor performance status are associated with increased mortality and reduced quality of life in patients with advanced cancer. Coping strategies based on “proactive positivity” may facilitate adaptation to functional decline and limited life expectancy. However, few studies have examined the impact of the interaction between depressive symptoms and coping strategies on survival outcomes in this population. This study investigated the associations of 1-year survival with the interaction between comorbid depression and proactive coping strategies, and performance status, in patients with advanced cancer. Methods This was a secondary analysis of data from a multicentre randomized clinical trial of patients with advanced cancer (ClinicalTrials.gov Identifier: NCT03181854). A total of 144 patients who were aware of their cancer diagnosis were recruited from 12 tertiary hospitals across South Korea between October 2017 and October 2018. In this prospective cohort design, participants were stratified into subgroups with higher versus lower levels of baseline proactive coping (proactive positivity) and followed for 1 year to assess survival status. Demographic and socioeconomic data were collected via self-report questionnaires, while cancer diagnosis and treatment information was obtained from attending oncologists. Cancer-related physical functioning, depressive symptoms, and coping strategies were assessed at baseline and at 12 weeks using the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scale, the Patient Health Questionnaire-9 (PHQ-9), and the Smart Management Strategy for Health Assessment Tool– short form (SAT-SF), respectively. Univariate Cox regression analyses were conducted to identify factors associated with 1-year survival, and a multivariate Cox proportional hazards model was developed to evaluate the predictive impact of performance status, depression, and the interaction between depression and proactive positivity. Results In univariate Cox regression models, lower performance status (ECOG-PS = 2; hazard ratio [HR] = 2.33, 95% confidence interval [CI]: 1.25–4.34) and comorbid depression (PHQ-9 ≥ 10; HR = 2.76, 95% CI: 1.72–4.42) were associated with increased risk of not surviving for 1 year. In the multivariate model, among patients with lower proactive positivity (SAT-SF Core strategies score ≤ 66.66/100), comorbid depression was associated with a 363% higher risk of 1-year mortality compared to those without depression (adjusted HR = 4.63, 95% CI: 2.54–8.43). Conversely, the association between depression and 1-year survival was not statistically significant among patients with higher proactive positivity (SAT-SF score > 66.66/100). Conclusions Comorbid depression is associated with a significantly higher risk of 1-year mortality in patients with advanced cancer who exhibit lower levels of proactive positivity, but not in those with higher levels of proactive coping. These findings highlight the importance of incorporating assessments of psychological resilience and coping strategies into the clinical management of advanced cancer. Trial registration Registry (ClinicalTrials.gov); registration number (NCT03181854); study registration dates [first submitted (2017-06-07), first submitted that met QC criteria (2017-06-07), first posted (2017-06-09)]

ObjectivesThis study determined attitudes of four groups—Korean patients with cancer, their family caregivers, physicians and the general Korean population—towards five critical end-of-life (EOL) interventions—active pain control, withdrawal of futile life-sustaining treatment (LST), passive euthanasia, active euthanasia and physician-assisted suicide.Design and settingWe enrolled 1001 patients with cancer and 1006 caregivers from 12 large hospitals in Korea, 1241 members of the general population and 928 physicians from each of the 12 hospitals and the Korean Medical Association. We analysed the associations of demographic factors, attitudes towards death and the important components of a ‘good death’ with critical interventions at EoL care.ResultsAll participant groups strongly favoured active pain control and withdrawal of futile LST but differed in attitudes towards the other four EoL interventions. Physicians (98.9%) favoured passive euthanasia more than the other three groups. Lower proportions of the four groups favoured active euthanasia or PAS. Multiple logistic regression showed that education (adjusted OR (aOR) 1.77, 95% CI 1.33 to 2.36), caregiver role (aOR 1.67, 95% CI 1.34 to 2.08) and considering death as the ending of life (aOR 1.66, 95% CI 1.05 to 1.61) were associated with preference for active pain control. Attitudes towards death, including belief in being remembered (aOR 2.03, 95% CI 1.48 to 2.79) and feeling ‘life was meaningful’ (aOR 2.56, 95% CI 1.58 to 4.15) were both strong correlates of withdrawal of LST with the level of monthly income (aOR 2.56, 95% CI 1.58 to 4.15). Believing ‘freedom from pain’ negatively predicted preference for passive euthanasia (aOR 0.69, 95% CI 0.55 to 0.85). In addition, ‘not being a burden to the family’ was positively related to preferences for active euthanasia (aOR 1.62, 95% CI 1.39 to 1.90) and PAS (aOR 1.61, 95% CI 1.37 to 1.89).ConclusionGroups differed in their attitudes towards the five EoL interventions, and those attitudes were significantly associated with various attitudes towards death.

Background Statins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer. Methods Patients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP). Results Between December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4 months (95 % CI 0.7–4.1 months) and 3.6 months (95 % CI 3.1–4.1 months) in the GS and GP arms, respectively ( P  = 0.903). The overall disease control rate was 39.7 % (95 % CI 12.2–33.8 %) and 57.1 % (95 % CI 19.8–44.2 %) in the GS and GP arms, respectively ( P  = 0.09). The 1-year expected survival rates were similar (27.7 and 31.7 % in the GS and GP arms, respectively; P  = 0.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis. Conclusions Adding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.

Purpose To investigate the significance of carbohydrate antigen 19-9 (CA19-9) levels for survival in locally advanced pancreatic cancer (LAPC) treated with concurrent chemoradiotherapy (CCRT). Methods/patients We retrospectively reviewed data from 97 LAPC patients treated with CCRT between 2000 and 2013. CA19-9 levels (initial and post-CCRT) and their changes [{(post-CCRT CA19-9 level − initial CA19-9 level)/(initial CA19-9 level)} × 100] were analyzed for overall survival. A cut-off point of 37 U/mL was used to analyze initial and post-CCRT CA19-9 levels. In order to define an optimal cut-off point for change in CA19-9 level, the maxstat package of R was applied. Results Median overall survival was 14.7 months (95% CI 13.4–16.0), and the 2-year survival rate was 16.5%. The estimated optimal cut-off point of CA19-9 level change was 94.4%. On univariate analyses, CA19-9 level change between initial and post-CCRT was significantly correlated with overall survival (median survival time 9.7 vs 16.3 months, p < 0.001). Multivariate analyses confirmed that CA19-9 level change from initial to post-CCRT was the only prognostic factor (p < 0.001). Conclusions Change in CA19-9 level between initial and post-CCRT was a significant prognostic marker for overall survival in LAPC treated with CCRT. A CA19-9 level increase >94.4% might serve as a surrogate marker for poor survival in patients with LAPC undergoing CCRT, and the prognostic power surpassed other CA19-9 variables including initial and post-CCRT values.

Background Combination therapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) chemotherapy drastically improves survival of advanced pancreatic cancer patients. However, the efficacy of FOLFIRINOX as a second-line treatment after gemcitabine failure has not been tested prospectively. We investigated the feasibility and safety of attenuated FOLFIRINOX in patients with gemcitabine-refractory advanced pancreatic cancer. Methods A multicenter phase II prospective open-label, single-arm study was conducted at 14 hospitals. Patients with histologically proven invasive ductal pancreatic adenocarcinoma, a measurable or evaluable lesion, Eastern Cooperative Oncology Group performance status 0 or 1, adequate organ function, and aged 19 years or older were eligible. Attenuated FOLFIRINOX consisted of oxaliplatin 65 mg/m 2 , irinotecan 135 mg/m 2 , and leucovorin 400 mg/m 2 injected intravenously on day 1 and 5-fluorouracil 2000 mg/m 2 continuously infused intravenously over 46 h on days 1–2, repeated every 2 weeks. The primary endpoint was progression-free survival from the initiation of FOLFIRINOX. Secondary endpoints were the objective response rate, disease control rate, overall survival, safety, and tolerability. We estimated overall survival and progression-free survival using the Kaplan–Meier methods. Results We enrolled 39 patients from 14 institutions. The objective response rate was 10.3%, while the disease control rate was 64.1%. The 6-month and 1-year overall survival rates were 59.0% and 15.4%, respectively. Median progression-free survival and overall survival were 3.8 months (95% confidence interval [CI] 1.5–6.0 months) and 8.5 months (95% CI 5.6–11.4 months), respectively. Grade 3 or 4 adverse events were neutropenia (41.0%), nausea (10.3%), anorexia (10.3%), anemia (7.7%), mucositis (7.7%), pneumonia/pleural effusion (5.1%), and fatigue (5.1%). One treatment-related death attributable to septic shock occurred. Conclusion Attenuated FOLFIRINOX may be promising as a second-line therapy for gemcitabine-refractory pancreatic cancer.

Purpose ABC-02 trial of gemcitabine plus cisplatin combination showed prolongation of overall survival in biliary tract cancer (BTC) patients. In this multicenter retrospective study, we evaluated the treatment outcome of gemcitabine combined with platinum (GP) compared to that of gemcitabine (G) alone in Korean BTC patients. Methods One hundred and fifty-one patients with histologically confirmed biliary tract adenocarcinoma were enrolled at nine institutions between July 2003 and May 2011, including 100 treated with GP and 51 treated with G. Results With a median follow-up of 7.7 months (range 0.4–38.3 months), the median overall survival (OS) was 12.4 months [95 % confidence interval (CI) 9.4–15.6 months] of the G group, which was not significantly different for the median OS of 11.0 months (95 % CI 9.7–12.3 months) of the GP group ( p  = 0.599). The median progression-free survival (PFS) was 3.9 months (95 % CI 0.8–7.0 months) in the G group and 3.3 months (95 % CI 2.6–4.0 months) in the GP group ( p  = 0.504). Overall response rates (ORR) were 18.8 % in G group and 23.9 % in GP group ( p  = 0.485). Conclusions There was no significant difference in ORR, PFS, or OS for patients between the G group and the GP group, which was different from the ABC-02 trial. Therefore, gemcitabine monotherapy and GP combination are both effective regimens for Korean BTC patients.