Abstract Introduction Gene amplification is an important mechanism for activating oncogenes in malignant tumors. Although amplification of HER2 , C-MYC , CCND1 and FGFR1 has been reported in breast cancers, their role in the progression of in situ to invasive breast carcinoma is unclear. To investigate this question we compared the amplification frequencies of these genes in pure ductal carcinoma in situ (DCIS), DCIS associated with invasive carcinoma, and invasive carcinoma. Methods We performed fluorescence in situ hybridization of the selected genes on tissue microarrays composed of 179 pure DCIS and 438 invasive carcinomas. Two hundred and sixteen of the latter had DCIS components, and in those cases we compared gene amplification in the intraductal and invasive components of each carcinoma. Results The rate of amplification of FGFR1 was higher in invasive carcinomas than in the pure DCIS, but the opposite was true for HER2 amplification. These findings applied consistently to high-grade tumors, but not to low/intermediate-grade tumors. The amplification status of HER2 , C-MYC , CCND1 and FGFR1 was generally similar in the matched invasive and DCIS components of the same tumors. However, FGFR1 amplification was more common in the invasive components than in the DCIS components. In survival analyses, FGFR1 amplification was found to be an independent prognostic factor for poor disease-free survival for all patients with invasive carcinoma and for the hormone receptor-positive subgroup. Conclusion Amplification of HER2 , C-MYC and CCND1 seems to play a role in the early development of breast cancer, but not in its progression. However, the increased frequency of FGFR1 amplification in invasive carcinomas compared with pure DCIS and in the invasive components of individual tumors, and its association with decreased disease-free survival, suggests a role for FGFR1 amplification in the progression of breast cancer including in situ -to-invasive transition, as well as initiation.
Abstract Background. KIT has been suggested to be a potential therapeutic target for malignant melanoma. We evaluated the antitumor activity and safety of the KIT inhibitor nilotinib in metastatic melanoma patients harboring KIT gene mutations or amplifications. Methods. We conducted a phase II multicenter trial of nilotinib in metastatic malignant melanoma with KIT mutations or amplifications. Patients received 400 mg oral nilotinib twice daily. The primary endpoint was response rate, and if seven or more responders were observed from the cumulative 36 patients, nilotinib would be considered worthy of further testing in this study population. Results. Between October 2009 and June 2013, 176 patients underwent molecular screening for KIT gene aberrations, and 42 patients harboring KIT gene mutations and/or amplification were enrolled in the study. Overall, 25 (59.5%), 15 (35.7%), and 2 (4.8%) patients had KIT mutations, KIT amplifications, and both KIT mutations and amplification, respectively. Of the 42 enrolled patients, 1 patient achieved complete response, 6 patients achieved partial response, and 17 patients achieved stable disease, resulting in an overall response rate of 16.7% (95% confidence interval [CI]: 5.4%−28.0%) and a disease control rate of 57.1% (95% CI: 42.1%−72.1%). The median duration of response was 34 weeks (range: 5–55 weeks). Of the 7 responders, 6 patients had KIT mutations (exon 11: 5 patients; exon 17: 1 patient), and 1 patient had KIT amplification only. Conclusion. Although this study did not meet its primary endpoint of response rate, nilotinib showed durable response in a subset of metastatic melanoma patients with specific KIT mutations. Implications for Practice: KIT aberration can be detected in a subset of metastatic melanoma patients. This phase II trial showed that nilotinib demonstrates durable response in a subset of patients with KIT mutations. The safety profile was very tolerable. This study suggests that a KIT inhibitor may benefit a small subset of metastatic melanoma patients with KIT mutations.
Temsirolimus is effective in the treatment for metastatic non-clear cell renal cell carcinoma (nccRCC) with poor prognosis. We aim to investigate the efficacy and tolerability of temsirolimus in treatment of naïve Asian patients with metastatic/recurrent nccRCC.From January 2008 to July 2017, data of treatment-naïve, metastatic/recurrent nccRCC patients, who were treated with temsirolimus according to the standard protocol, were collected. The primary end-point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate (ORR), and tolerability of temsirolimus.Forty-four metastatic/recurrent nccRCC patients, 10 from prospective and 34 from retrospective groups, were enrolled; 24 patients (54%) were papillary type, and other histology subtypes included 11 chromophobes (25%), two collecting ducts (5%), one Xp11.2 translocation (2%), and six others (14%). The median PFS and OS were 7.6 months and 17.6 months, res-pectively. ORR was 11% and disease control rate was 83%. Patients with prior nephrectomy had longer PFS (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.06 to 0.42; p < 0.001) and OS (HR, 0.15; 95% CI, 0.05 to 0.45; p < 0.001). Compared to favorable/intermediate prognosis group, poor prognosis group had shorter median PFS (4.7 months vs. 7.6 months [HR, 2.91; 95% CI, 1.39 to 6.12; p=0.005]) and median OS (9.2 months vs. 17.6 months [HR, 2.84; 95% CI, 1.23 to 6.56; p=0.015]).Temsirolimus not only benefits poor-risk nccRCC patients, but it is also effective in favorable or intermediate-risk group in Asians. Temsirolimus was well-tolerated with manageable adverse events.
Abstract Background Despite recent advances in treating non‐small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK‐positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK‐positive NSCLC. Methods Between 2011 and 2018, a total of 14 ALK‐positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD‐L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets. Results A total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2–8) courses of therapy. The study included nine patients (64.3%) who were PD‐L1‐high (>50%) and four (28.6%) who were PD‐L1‐low (<50%). The objective response rate was 14.3% (2/14). The median progression‐free survival time was 2.18 months (95% confidence interval [CI] 1.13 months‐not reached [NR]). The median overall survival time was 5.67 months (95% CI 3.00 months‐NR). RNA expression levels of CD274 were similar between the ALK‐positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK‐positive group. Cytolytic activity scores including interferon‐γ‐related response were lower in the ALK‐positive group in the NCCRI but not TCGA dataset. Conclusions Despite high PD‐L1‐positive rates, ICIs show limited efficacy in ALK‐positive NSCLC. Decreased interferon‐γ‐related response may underlie these findings.
Abstract Objective Spirituality is what gives people meaning and purpose in life, and it has been recognized as a critical factor in patients’ well-being, particularly at the ends of their lives. Studies have demonstrated relationships between spirituality and patient-reported outcomes such as quality of life and mental health. Although a number of studies have suggested that spiritual belief can be associated with mortality, the results are inconsistent. We aimed to determine whether spirituality was related to survival in advanced cancer inpatients in Korea. Method For this multicenter study, we recruited adult advanced cancer inpatients who had been admitted to seven palliative care units with estimated survival of <3 months. We measured spirituality at admission using the Korean version of the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-sp), which comprises two subscales: meaning/peace and faith. We calculated a Kaplan-Meier curve for spirituality, dichotomized at the predefined cutoffs and medians for the total scale and each of the two subscales, and performed univariate regression with a Cox proportional hazard model. Result We enrolled a total of 204 adults (mean age: 64.5 ± 13.0; 48.5% female) in the study. The most common primary cancer diagnoses were lung (21.6%), colorectal (18.6%), and liver/biliary tract (13.0%). Median survival was 19.5 days (95% confidence interval [ CI 95% ]: 23.5, 30.6). Total FACIT-sp score was not related to survival time (hazard ratio [HR] = 0.981, CI 95% = 0.957, 1.007), and neither were the scores for its two subscales, meaning/peace (HR = 0.969, CI 95% = 0.932, 1.008) and faith (HR = 0.981, CI 95% = 0.938, 1.026). Significance of results Spirituality was not related to survival in advanced cancer inpatients in Korea. Plausible mechanisms merit further investigation.
Abstract BackgroundHigh-dose chemotherapy followed by autologous stem-cell transplantation (HDC–ASCT) as a consolidation treatment is a promising approach in eligible patients with newly diagnosed primary central nervous system lymphoma (PCNSL). This study sought to assess the safety and efficacy of initial methotrexate-based chemotherapy followed by consolidation HDC-ASCT with a thiotepa-based conditioning regimen in patients with newly diagnosed PCNSL. MethodsIn this retrospective analysis, 22 patients with newly diagnosed PCNSL received chemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV). Those who showed a complete or partial response subsequently received consolidation HDC-ASCT with a thiotepa-based conditioning regimen and no radiotherapy. ResultsCharacteristics of the PCNSL patients included a median age of 57 years (range: 49–67 years), Eastern Cooperative Oncology Group performance status of grade 2 or more in 9.1%, elevated lactate dehydrogenase level in 26.3%, and involvement of multiple lesions in 72.1%. About 82% of patients received six cycles of induction chemotherapy, which was well-tolerated with excellent disease control. The rate of confirmed/or unconfirmed complete response increased from 45.5% in the interim to 81.8% before HDC-ASCT. With a median follow-up of 19.6 months (range: 7.5–56.5 months), the 2-year progression-free survival and overall survival estimates were 84% and 88%, respectively. There were no treatment-related deaths. Grade 3 toxicity was recorded in 90.9% after HDC-ASCT, and the most common grade 3 adverse event was febrile neutropenia without sepsis. ConclusionsThe discussed treatment approach appears feasible in patients with newly diagnosed PCNSL, yielding encouraging results.
This study evaluated the toxicity profiles of temozolomide in the treatment of malignant glioma as either concurrent or adjuvant chemotherapy. We retrospectively reviewed the medical records of 300 malignant glioma patients treated with temozolomide in two medical institutions in Korea between 2004 and 2010. Two hundred nine patients experienced a total of 618 toxicities during temozolomide therapy. A total of 84.8% of the 618 toxicities were Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or 2, while 15.2% were grade 3 or 4. Among the hematologic toxicities, thrombocytopenia (13.7%), anemia (11.0%), and AST/ALT increases (7.0%) were common. Among the non-hematologic toxicities, nausea (44.3%), vomiting (37.0%), and anorexia (14.3%) were the three most common toxicities. There was no mortality due to temozolomide. Although temozolomide showed many types of toxicities, the majority of the toxicities were tolerable and of lower grade. Gastrointestinal troubles are the most common toxicities in Korean patients treated with temozolomide.
99 Background: Understanding about young adults with advanced cancer in palliative care was still insufficient. The purpose of this study was to identify the differences in symptom distress between young (20-39 years) and older (≥ 40 years) adults with advanced cancer who were admitted to acute palliative care unit. Methods: We retrospectively analyzed 502 consecutive patients admitted to acute palliative care unit between April 2015 and March 2016 in two tertiary cancer centers. Descriptive statistics, analysis of Edmonton Symptom Assessment Scale (ESAS), and Symptom Distress Scale (SDS) were performed. Results: Among 502 patients, 33 (7%) were aged 20-39 years, and 469 (93%) were aged ≥ 40 years. The most common malignancies among the young adult patients were stomach and colorectal cancers. SDS was similar between young adult (38.7 ± 15.1) and old adult (41.5 ± 13.7) patients. However, pain, nausea, poor feeling of well-being sense, sleep disturbance, and financial distress were numerically higher in young adult group than older adult group. Especially, sleep disturbance (5.72 vs. 4.56, p = 0.030) and financial distress (4.44 vs. 2.87, p = 0.008) showed statistically significant difference. Conclusions: Young adult advanced cancer patients appear to show different symptom profiles. Further research is needed to identify determinants and to provide timely integration of palliative care services for this unique patient cohort.
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