The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy.

BACKGROUND: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. RESULTS: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. CONCLUSIONS: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Polypharmacy, Inappropriate Medication Use, and Drug Interactions in Older Korean Patients with Cancer Receiving First-Line Palliative Chemotherapy.

BACKGROUND: Polypharmacy is an important issue in the care of older patients with cancer, as it increases the risk of unfavorable outcomes. We estimated the prevalence of polypharmacy, potentially inappropriate medication (PIM) use, and drug-drug interactions (DDIs) in older patients with cancer in Korea and their associations with clinical outcomes. SUBJECTS, MATERIALS, AND METHODS: This was a secondary analysis of a prospective observational study of geriatric patients with cancer undergoing first-line palliative chemotherapy. Eligible patients were older adults (≥70 years) with histologically diagnosed solid cancer who were candidates for first-line palliative chemotherapy. All patients enrolled in this study received a geriatric assessment (GA) at baseline. We reviewed the daily medications taken by patients at the time of GA before starting chemotherapy. PIMs were assessed according to the 2015 Beers criteria, and DDIs were assessed by a clinical pharmacist using Lexi-comp Drug Interactions. We evaluated the association between polypharmacy and clinical outcomes including treatment-related toxicity, and hospitalization using logistic regression and Cox regression analyses. RESULTS: In total, 301 patients (median age 75 years; range, 70-93) were enrolled; the most common cancer types were colorectal cancer (28.9%) and lung cancer (24.6%). Mean number of daily medications was 4.7 (±3.1; range, 0-14). The prevalence of polypharmacy (≥5 medications) was 45.2% and that of excessive polypharmacy (≥10 medications) was 8.6%. PIM use was detected in 137 (45.5%) patients. Clinically significant DDIs were detected in 92 (30.6%) patients. Polypharmacy was significantly associated with hospitalization or emergency room (ER) visits (odds ratio: 1.73 [1.18-2.55], p < .01). Neither polypharmacy nor PIM use showed association with treatment-related toxicity. CONCLUSION: Polypharmacy, PIM use, and potential major DDIs were prevalent in Korean geriatric patients with cancer. Polypharmacy was associated with a higher risk of hospitalization or ER visits during the chemotherapy period. IMPLICATIONS FOR PRACTICE: This study, which included 301 older Korean patients with cancer, highlights the increased prevalence of polypharmacy in this population planning to receive palliative chemotherapy. The prevalence of polypharmacy and excessive polypharmacy was 45.2% and 8.6%, respectively. The prescription of potentially inappropriate medications (PIMs) was detected in 45.5% and clinically significant drug-drug interaction in 30.6% of patients. Given the association of polypharmacy with increased hospitalization or emergency room visits, this study points to the need for increased awareness and intervention to minimize polypharmacy in the geriatric cancer population undergoing chemotherapy. Moreover, specific criteria for establishing PIMs should be adopted for the treatment of older adults with cancer.

Predicting cumulative incidence of adverse events in older patients with cancer undergoing first-line palliative chemotherapy: Korean Cancer Study Group (KCSG) multicentre prospective study.

BACKGROUND: Older patients have increased risk of toxicity from chemotherapy. Current prediction tools do not provide information on cumulative risk. METHODS: Patients aged ≥ 70 years with solid cancer were prospectively enrolled. A prediction model was developed for adverse events (AEs) ≥ Grade 3 (G3), based on geriatric assessment (GA), laboratory, and clinical variables. RESULTS: 301 patients were enrolled (median age, 75 years). Median number of chemotherapy cycles was 4. During first-line chemotherapy, 53.8% of patients experienced AEs ≥ G3. Serum protein < 6.7 g/dL, initial full-dose chemotherapy, psychological stress or acute disease in the past 3 months, water consumption < 3 cups/day, unable to obey a simple command, and self-perception of poor health were significantly related with AEs ≥ G3. A predicting model with these six variables ranging 0-8 points was selected with the highest discriminatory ability (c-statistic= 0.646), which could classify patients into four risk groups. Predicted cumulative incidence of AEs ≥ G3 was discriminated according to risk groups. CONCLUSIONS: This prediction tool could identify the risk of AEs ≥ G3 after chemotherapy and provide information on the cumulative incidence of AEs in each cycle. CLINICAL TRIAL ID: WHO ICTRP number, KCT0001071.

Phase II study of gemcitabine and vinorelbine as second- or third-line therapy in patients with primary refractory or platinum-resistant recurrent ovarian and primary peritoneal cancer by the Korean Cancer Study Group (KCSG)_KCSG GY10-10.

OBJECTIVE: The main aim of this study was to evaluate the antitumor activity and safety of vinorelbine and gemcitabine combination chemotherapy in patients with primary refractory or recurrent platinum-resistant epithelial ovarian and primary peritoneal cancers. METHODS: Patients with platinum-resistant or primary refractory disease were eligible. Patients were allowed one prior chemotherapy for the treatment of platinum-resistant or refractory disease. Vinorelbine 25mg/m(2), followed by gemcitabine 1000mg/m(2), was administered intravenously on days 1 and 8 every 3weeks. Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and cancer antigen 125 test (CA-125 criteria) were adopted to classify responses. RESULTS: 44 patients received the median of 4 (range, 1-24) treatments with fifteen (34.1%) receiving six or more cycles. The overall objective response rate was 22.7%. One patient (2.3%) had complete while 9 patients (20.4%) had partial responses with median duration of response of 5.9months. 17 patients (38.6%) had stable disease for a median of 3.3months. Median progression-free survival (PFS) was 3.4months and overall survival (OS) was 14.5months. Four (9.1%) patients were not assessable. Neutropenia was the most frequently encountered toxicity, with grade 3 or 4 observed in 22 patients (50.0%). Fifteen patients (34.1%) needed immediate dose reduction. No treatment related death was reported. CONCLUSIONS: The combination chemotherapy with gemcitabine and vinorelbine achieved the primary end point of our clinical trial in management of platinum resistant recurrent ovarian cancer. However, further sophisticated dosing and scheduling of combination chemotherapy are needed because of a significant proportion of dose reduction.

Metronomic chemotherapy as a potential partner of immune checkpoint inhibitors for metastatic colorectal cancer treatment.

The use of immune checkpoint inhibitors (ICIs) in clinical practice for the treatment of metastatic colorectal cancer (mCRC) is currently limited to patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), which comprise less than 5% of all mCRC cases. Combining ICIs with anti-angiogenic inhibitors, which modulate the tumor microenvironment, may reinforce and synergize the anti-tumor immune responses of ICIs. In mCRCs, combinations of pembrolizumab and lenvatinib have shown good efficacy in early phase trials. These results suggest the potential utility of immune modulators as partners in combination treatment with ICIs in immunologically cold microsatellite stable, as well as hot dMMR/MSI-H tumors. Unlike conventional pulsatile maximum tolerated dose chemotherapy, low-dose metronomic (LDM) chemotherapy recruits immune cells and normalizes vascular-immune crosstalk, similar to anti-angiogenic drugs. LDM chemotherapy mostly modulates the tumor stroma rather than directly killing tumor cells. Here, we review the mechanism of LDM chemotherapy in terms of immune modulation and its potential as a combination partner with ICIs for the treatment of patients with mCRC tumors, most of which are immunologically cold.

Association of Metabolic Syndrome Components and Nutritional Status with Kidney Cancer in Young Adult Population: A Nationwide Population-Based Cohort Study in Korea.

The aim of this study was to determine the association of metabolic syndrome (MetS) with kidney cancer and the impact of age and gender on such an association. Using the Korean National Health Insurance Service database, 9,932,670 subjects who had check-ups in 2009 were followed up until the diagnosis of kidney cancer or death or until 2019. Kidney cancer was significantly associated with MetS (HR 1.56). This association was higher in the younger age group (HR: 1.82, 1.5, and 1.37 in 20-39 years, 40-64 years, and ≥65 years, respectively). In terms of the association of kidney cancer with obesity and central obesity, young-aged males showed higher HR for kidney cancer than old-aged ones (HR of obesity: 1.96, 1.52, and 1.25; HR of central obesity: 1.94, 1.53, and 1.3 in 20-39 years, 40-64 years, ≥65 years, respectively), while young-aged females showed lower HR. Kidney cancer was associated with obesity and MetS. The association was higher in younger populations than in older ones. Regarding gender, MetS, obesity, and central obesity showed higher associations with kidney cancer in younger aged male population, while there was no significant difference in such associations according to age in the female population.

Efficacy of the granisetron transdermal system for the control of nausea and vomiting induced by highly emetogenic chemotherapy: a multicenter, randomized, controlled trial.

BACKGROUND/AIMS: We compared the efficacy of the granisetron transdermal system (GTS) with that of ondansetron for controlling chemotherapy-induced nausea and vomiting (CINV) in patients treated with highly emetogenic chemotherapy (HEC). METHODS: We randomized a total of 389 patients to groups treated by GTS and ondansetron before HEC. The primary endpoint was the percentage of patients achieving complete response (CR; no retching/vomiting/rescue medication) of CINV from the time of chemotherapy initiation to 24 hours after the last administration of chemotherapy (prespecified non-inferiority margin of 15%). Quality of life (QoL) was also assessed using the Functional Living Index-Emesis (FLIE). RESULTS: The per protocol analysis included 152 (47.80%) and 166 patients (52.20%) in the GTS and ondansetron groups, respectively. In the full analysis set, the most common diagnosis, regimen, and period of chemotherapy were lung cancer (149 patients, 40.27%), cisplatin-based regimen (297 patients, 80.27%), and 1 day chemotherapy (221 patients, 59.73%). The CR rates were 86.84% and 90.36% in the GTS and ondansetron groups, respectively; the treatment difference was -3.52% (95% confidence interval, -10.52 to 3.48) and met the primary endpoint, indicating that GTS was not inferior to ondansetron. Patient satisfaction, assessed on the FLIE, showed significantly higher scores in the GTS group compared to the ondansetron group (mean ± standard deviation, 1,547.38 ± 306.00 and 1,494.07 ± 312.05 mm, respectively; p = 0.0449). CONCLUSION: GTS provided effective, safe, and well-tolerated control of CINV and improved the QoL in HEC.

A Randomized Phase III Study of Patients With Advanced Gastric Adenocarcinoma Without Progression After Six Cycles of XELOX (Capecitabine Plus Oxaliplatin) Followed by Capecitabine Maintenance or Clinical Observation.

PURPOSE: Oxaliplatin, a component of the capecitabine plus oxaliplatin (XELOX) regimen, has a more favorable toxicity profile than cisplatin in patients with advanced gastric cancer (GC). However, oxaliplatin can induce sensory neuropathy and cumulative, dose-related toxicities. Thus, the capecitabine maintenance regimen may achieve the maximum treatment effect while reducing the cumulative neurotoxicity of oxaliplatin. This study aimed to compare the survival of patients with advanced GC between capecitabine maintenance and observation after 1st line XELOX chemotherapy. MATERIALS AND METHODS: Sixty-three patients treated with six cycles of XELOX for advanced GC in six hospitals of the Catholic University of Korea were randomized 1:1 to receive capecitabine maintenance or observation. The primary endpoint was progression-free survival (PFS), analyzed using a two-sided log-rank test stratified at a 5% significance level. RESULTS: Between 2015 and 2020, 32 and 31 patients were randomized into the maintenance and observation groups, respectively. After randomization, the median number of capecitabine maintenance cycles was 6. The PFS was significantly higher in the maintenance group than the observation group (6.3 vs. 4.1 months, P=0.010). Overall survival was not significantly different between the 2 groups (18.2 vs. 16.5 months, P=0.624). Toxicities, such as hand-foot syndrome, were reported in some maintenance group patients. Maintenance treatment was a significant factor associated with PFS in multivariate analysis (hazard ratio, 0.472; 95% confidence interval, 0.250-0.890; P=0.020). CONCLUSIONS: After 6 cycles of XELOX chemotherapy, capecitabine maintenance significantly prolonged PFS compared with observation, and toxicity was manageable. Maintenance treatment was a significant prognostic factor associated with PFS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02289547.

Impacts of Subtype on Clinical Feature and Outcome of Male Breast Cancer: Multicenter Study in Korea (KCSG BR16-09).

PURPOSE: The treatment of male breast cancer (MBC) has been extrapolated from female breast cancer (FBC) because of its rarity despite their different clinicopathologic characteristics. We aimed to investigate the distribution of intrinsic subtypes based on immunohistochemistry, their clinical impact, and treatment pattern in clinical practice through a multicenter study in Korea. MATERIALS AND METHODS: We retrospectively analyzed clinical data of 248 MBC patients from 18 institutions across the country from January 1995 to July 2016. RESULTS: The median age of MBC patients was 63 years (range, 25 to 102 years). Among 148 intrinsic subtype classified patients, 61 (41.2%), 44 (29.7%), 29 (19.5%), and 14 (9.5%) were luminal A, luminal B, human epidermal growth factor receptor 2, and triple-negative breast cancer, respectively. Luminal A subtype showed trends for superior survival compared to other subtypes. Most hormone receptor-positive patients (166 patients, 82.6%) received adjuvant endocrine treatment. Five-year completion of adjuvant endocrine treatment was associated with superior disease-free survival (DFS) in patients classified with an intrinsic subtype (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 to 0.49; p=0.002) and in all patients (HR, 0.16; 95% CI, 0.05 to 0.54; p=0.003). CONCLUSION: Distribution of subtypes of MBC was similar to FBC and luminal type A was most common. Overall survival tended to be improved for luminal A subtype, although there was no statistical significance. Completion of adjuvant endocrine treatment was associated with prolonged DFS in intrinsic subtype classified patients. MBC patients tended to receive less treatment. MBC patients should receive standard treatment according to guidelines as FBC patients.

Comprehensive Comparison of 22C3 and SP263 PD-L1 Expression in Non-Small-Cell Lung Cancer Using Routine Clinical and Conditioned Archives.

PD-L1 harmonization studies revealed a strong correlation between the 22C3 and SP263 assays in non-small-cell lung cancer (NSCLC). However, the assays' characteristics have yet to be validated in a variety of clinical and analytical settings. The results of 431 NSCLC samples tested concurrently in routine clinical practice with the PD-L1 22C3 and SP263 assays were reviewed, and both assays were performed on 314 archives of surgically resected NSCLCs to assess PD-L1 expression in relation to variables such as FFPE block age and FFPE section storage condition. In routine clinical samples, 22C3 showed the highest concordance rate with 94.5% of SP263 tumor proportion score (TPS) ≥50% and 92.3% of SP263 TPS ≥1%, while SP263 showed a concordance rate with 79.6% of 22C3 TPS ≥50% and 89.9% of 22C3 TPS ≥1%. In the archival analysis, the high TPS of 22C3 and SP263 (versus TPS 1%) were significantly associated with a more recent block (<3 years versus ≥3 years) (p = 0.007 and p = 0.009, respectively). Only the TPS of 22C3 was reduced when FFPE sections were stored at room temperature compared to SP263. However, when stored at 4 °C, the storage duration had no effect on expression in either assay. For 22C3 TPS 1−49 percent and ≥50 percent (OR = 1.73, p = 0.006 and OR = 1.98, p = 0.002, respectively). There was a considerably larger chance of preserved 22C3 expression in recent room-temperature paraffin section storage, although SP263 demonstrated preserved expression in prolonged room-temperature section storage. Despite the good association between PD-L1 22C3 and SP263 in routine clinical samples, FFPE blocks older than 3 years and sections held at room temperature for more than 1 week may result in an underestimation of PD-L1 status, particularly for the 22C3 test. However, the SP263 assay was more sensitive under these conditions.

Real-world experience of safety and effectiveness of regorafenib for treatment of metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and hepatocellular carcinoma: a post-marketing surveillance study in Korea.

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.

Perioperative Systemic Chemotherapy for Colorectal Liver Metastasis: Recent Updates.

The liver is the most common site of metastases for colorectal cancer. Complete resection in some patients with resectable liver metastases (LM) can lead to long-term survival and cure. Adjuvant systemic chemotherapy after complete resection of LM improves recurrence-free survival; however, the overall survival benefit is not clear. In selected patients, preoperative systemic treatment for metastatic colorectal cancer can convert unresectable to resectable cancer. This review will focus on patient selection, and integration of perioperative and postoperative systemic treatment to surgery in resectable and initially unresectable LM. Additionally, new drugs and biomarkers will be discussed.

Surtuin 1 as a potential prognostic biomarker in very elderly patients with colorectal cancer.

BACKGROUND/AIMS: Colorectal cancer (CRC) rate increases with aging. Aging-related proteins, such as sirtuins (SIRTs) may be a potential therapeutic target in the elderly patients with CRC. The clinical implications of SIRT1 and SIRT2 have not been reported for elderly patients with cancer. The aim of this study was to evaluate the impact of expression of SIRT1 and SIRT2 on clinical outcome in two extreme age groups of patients with CRC. METHODS: The expression of SIRT1 and SIRT2 were evaluated in CRC tissues of 101 patients aged ≥ 80 years and 29 patients aged ≤ 40 years by immunohistochemistry. We defined the patients aged ≥ 80 years as the very elderly and patients aged ≤ 40 years as the young patients. Correlations between the expression of these proteins and clinicopathological features were analyzed. RESULTS: The prognosis for the very elderly patients with high expressions of SIRT1 was significantly worse than that for patients showing low expression (median survival, 24.9 months vs. 38.6 months, p = 0.027) whereas high expression of SIRT2 better prognosis (median survival, 37.9 months vs. 17.3 months, p = 0.006). However, the young patients did not show any difference in prognosis according to expression of SIRT1 and SIRT2. In multivariate analysis, high SIRT1 expression retained statistical significance as a poor prognostic factor in the very elderly patients with CRC. CONCLUSION: The results suggest that high SIRT1 expression could be predictive of a poor outcome for very elderly patients with CRC.

Real-World Clinical Data of Palbociclib in Asian Metastatic Breast Cancer Patients: Experiences from Eight Institutions.

PURPOSE: Use of cyclin-dependent kinase 4/6 inhibitors improved survival outcome of hormone receptor (HR) positive metastatic breast cancer (MBC) patients, including Asian population. However, Asian real-world data of palbociclib is limited. We analyzed the real-world clinical practice patterns and outcome in HR-positive, MBC Asian patients treated with palbociclib. MATERIALS AND METHODS: Between April 2017 to November 2019, 169 HR-positive, human epidermal growth factor-2-negative MBC patients treated with letrozole or fulvestrant plus palbocilib were enrolled from eight institutions. Survival outcome (progression-free survival [PFS]), treatment response and toxicity profiles were analyzed. RESULTS: Median age of letrozole plus palbociclib (145 patients, 85.8%) and fulvestrant plus palbociclib (24 patients, 14.2%) was 58 and 53.5 years, with median follow-up duration of 14.63 months (range 0.2 to 33.9 months). Median PFS (mPFS) of letrozole plus palbociclib and fulvestrant plus palbociclib was 25.6 (95% confidence interval [CI], 19.1 to not reached) and 6.37 months (95% CI, 5.33 to not reached), comparable to previous phase 3 trials. In letrozole plus palbociclib arm, luminal A (hazard ratio, 2.86; 95% CI, 1.20 to 6.80; p=0.017) and patients with good performance (Eastern Cooperative Oncology Group 0-1 [hazard ratio, 3.68; 95% CI, 1.70 to 7.96]) showed better mPFS. In fulvestrant plus palbociclib group, chemotherapy naïve patients showed better mPFS (hazard ratio, 12.51, 95% CI, 1.59 to 99.17; p=0.017). The most common grade 3 or 4 adverse event was neutropenia (letrozole 86.3%, fulvestrant 88.3%). CONCLUSION: To our knowledge, this is the first real-world data of palbociclib reported in Asia. Palbociclib showed comparable benefit to previous phase 3 trials in Asian patients during daily clinical practice.

Prevalence and Predictive Factors for Upfront Dose Reduction of the First Cycle of First-Line Chemotherapy in Older Adults with Metastatic Solid Cancer: Korean Cancer Study Group (KCSG) Multicenter Study.

Old age alone does not reflect an intolerability to chemotherapy. However, upfront dose reduction (UDR) of the first cycle of first-line palliative chemotherapy has sometimes been chosen by physicians for older adults with metastatic cancer due to concerns regarding adverse events. The development of predictive factors for UDR of palliative chemotherapy would be helpful for treatment planning among older adults. This was a secondary analysis of a study on predicting adverse events of first-line palliative chemotherapy in 296 patients (≥70 years) with solid cancer. We assessed the prevalence of UDR of the first cycle of first-line chemotherapy and the association of UDR with the variables of geriatric assessment (GA) and chemotherapy compliance. Among the 296 patients, 177 (59.8%) patients were treated with UDR. The mean percentage of UDR for the total patient group was 19.2% (range: 4-47%) of the standard dose. In a multivariate analysis, poor performance status (PS) and living without a spouse were independent predictive factors of UDR of first-line palliative chemotherapy in older adults. Patients with UDR showed fewer grade 3-5 adverse events versus the standard dose group. Study completion as planned was significantly higher in the UDR group versus the standard dose group. Older adults with UDR better tolerated chemotherapy than patients with a standard dose.

Prognostic relevance of collagen XVIII expression in metastatic gastric carcinoma.

Collagen XVIII is a component of vascular and epithelial basement membranes. The C-terminal fragment of the protein is termed endostatin, and is a potent inhibitor of angiogenesis. No reports on the clinical implications of collagen XVIII expression in human gastric cancer are currently available. Here, we investigate the clinical significance of collagen XVIII expression in gastric cancer. Seven gastric cancer cell lines were subjected to Western blotting. Collagen XVIII expression was examined in 118 gastric carcinoma tissues via immunohistochemistry. Western blotting revealed the presence of the 22-kDa collagen XVIII protein in four of seven gastric cancer cell lines. Immunohistochemistry detected collagen XVIII expression in the tumor cytoplasm in 115 of 118 gastric carcinoma patients (97%). No correlation was evident between collagen XVIII expression score and clinicopathologic findings when all patients were considered together. However, on subgroup analysis, 42 of 70 patients with distant metastasis were classified into low or moderate collagen XVIII expression groups, whereas the remaining 28 patients were grouped as showing high collagen XVIII expression. The prognosis for patients with high collagen XVIII-expressing gastric carcinoma was significantly worse than that for patients displaying low or moderate collagen XVIII expression (median survival time, 7.8 months vs. 18.3 months [log-rank, p = 0.01]; median time to progression, 3 months vs. 8 months [log-rank, p = 0.01]). High expression of collagen XVIII is associated with poor prognosis in patients with metastatic gastric carcinoma. Further studies on larger patient populations are warranted to validate the utility of collagen XVIII as a prognostic biomarker in gastric carcinoma.

DeepBTS: Prediction of Recurrence-free Survival of Non-small Cell Lung Cancer Using a Time-binned Deep Neural Network.

Accurate prediction of non-small cell lung cancer (NSCLC) prognosis after surgery remains challenging. The Cox proportional hazard (PH) model is widely used, however, there are some limitations associated with it. In this study, we developed novel neural network models called binned time survival analysis (DeepBTS) models using 30 clinico-pathological features of surgically resected NSCLC patients (training cohort, n = 1,022; external validation cohort, n = 298). We employed the root-mean-square error (in the supervised learning model, s- DeepBTS) or negative log-likelihood (in the semi-unsupervised learning model, su-DeepBTS) as the loss function. The su-DeepBTS algorithm achieved better performance (C-index = 0.7306; AUC = 0.7677) than the other models (Cox PH: C-index = 0.7048 and AUC = 0.7390; s-DeepBTS: C-index = 0.7126 and AUC = 0.7420). The top 14 features were selected using su-DeepBTS model as a selector and could distinguish the low- and high-risk groups in the training cohort (p = 1.86 × 10-11) and validation cohort (p = 1.04 × 10-10). When trained with the optimal feature set for each model, the su-DeepBTS model could predict the prognoses of NSCLC better than the traditional model, especially in stage I patients. Follow-up studies using combined radiological, pathological imaging, and genomic data to enhance the performance of our model are ongoing.

Preliminary experience using high intensity focused ultrasound for treating liver metastasis from colon and stomach cancer.

PURPOSE: To determine the efficacy and safety from our preliminary results of using high intensity focused ultrasound (HIFU) to treat liver metastasis from colon and stomach cancer. MATERIALS AND METHODS: Ten patients with liver metastasis from colon cancer and three from stomach cancer underwent HIFU under general anesthesia. HIFU was performed using an extracorporeal, ultrasound-guided focused system. Complications during the study, extent of coagulative necrosis at two-week follow up, and evidence of tumor on further follow up were analyzed. Patients were divided into four categories: (I) complete ablation with no evidence of recurrence on follow up; (II) apparent complete ablation of target mass with new foci of disease in the target organ or distant malignancy and no local tumor progression; (III) local tumor progression after apparent complete ablation; (IV) partial ablation. RESULTS: Mean follow-up period was 22 weeks in the colon cancer group and 58 weeks in the stomach cancer group. The sum of total lesion size was between 1.8 cm and 21.4 cm (mean: 8.4 cm +/- 6.7 cm) for the colon cancer group and between 1.7 and 16.3 cm (mean: 8.8 cm +/- 7.3 cm) for the stomach cancer group. In the colon cancer group, one patient was categorized as category I, one as category II, three as category III, and the remaining five as category IV. The stomach cancer group showed two patients as category I, and one as category II. CONCLUSION: For treating liver metastasis from colon and stomach cancer HIFU seems safe but its efficacy is questionable. Further research is warranted.

High expression level of SOX2 is significantly associated with shorter survival in patients with thymic epithelial tumors.

OBJECTIVES: Thymic epithelial tumors (TET) are heterogenous tumors which are composed of thymoma (TM) and thymic carcinoma (TC). We attempted to determine differences in gene expression between TM and TC, and to determine the effect of such genes on the prognosis of patients with TET. MATERIALS AND METHODS: Gene expression profiles of SOX2, OCT-4, IGF-1, IGF-1R and IR mRNA transcripts in tumor tissues of TM and TC were determined using real-time PCR (RT-PCR). We constructed tissue microarray with 140 paraffin-embedded tumor tissues and performed immunohistochemistry (IHC) for IGF-1R-related signaling molecules, including SOX2, IGF-1, IGF-1R and pAKT. RESULTS: SOX2 mRNA expression was notably higher (216-fold) in TCs than in TMs. However, there was no significant difference in expression of IGF-1, IGF-1R, OCT-4 or IR between the two tumor types. In IHC results, SOX2 (HR: 7.57, P = 0.001) and IGF-1 (HR: 9.43, P = 0.001) expression levels in TC were significantly higher than those in TM. There was a significant correlation in expression of SOX2 with IGF-1 (P = 0.021) and pAKT (P = 0.026). In univariate analysis, clinical TNM stage, WHO classification, serum LDH, expression of SOX2, IGF-1R, IGF-1 and pAKT, were significantly correlated with overall survival (OS). Multivariate analysis using a forward-selection procedure revealed that clinical N stage (HR: 4.08, P < 0.001), M stage (HR: 3.37, P = 0.001) and SOX2 expression (HR: 4.53, P = 0.010) were significantly associated with OS. CONCLUSIONS: SOX2 is expressed significantly higher in TC than in TM. SOX2 expression is also closely related to IGF-1 and pAKT expression. The higher expression of SOX2 is significantly associated with shorter survival in patients with TET.

PD-L1 expression in ROS1-rearranged non-small cell lung cancer: A study using simultaneous genotypic screening of EGFR, ALK, and ROS1.

BACKGROUND: The aim of the current study was to investigate the prevalence and clinicopathologic characteristics of ROS1-rearranged non-small cell lung cancer (NSCLC) in routine genotypic screening in conjunction with the study of PD-L1 expression, a biomarker for first-line treatment decisions. METHODS: Reflex simultaneous genotypic screening for EGFR by peptide nucleic acid clamping, and ALK and ROS1 by fluorescence in situ hybridization (FISH) was performed on consecutive NSCLC cases at the time of initial pathologic diagnosis. We evaluated genetic aberrations, clinicopathologic characteristics, and PD-L1 tumor proportion score (TPS) using a PD-L1 22C3 assay kit. RESULTS: In 407 consecutive NSCLC patients, simultaneous genotyping identified 14 (3.4%) ROS1 and 19 (4.7%) ALK rearrangements, as well as 106 (26%) EGFR mutations. These mutations were mutually exclusive and were found in patients with similar clinical features, including younger age, a prevalence in women, adenocarcinoma, and advanced stage. The PD-L1 assay was performed on 130 consecutive NSCLC samples. High PD-L1 expression (TPS ≥ 50%) was observed in 29 (22.3%) tumors. PD-L1 expression (TPS ≥ 1%) was significantly associated with wild type EGFR, while ROS1 rearrangement was associated with high PD-L1 expression. Of the 14 cases with ROS1 rearrangement, 12 (85.7%) showed PD-L1 expression and 5 (35.7%) showed high PD-L1 expression. CONCLUSION: In the largest consecutive routine Asian NSCLC cohort analyzed to date, we found that high PD-L1 expression frequently overlapped with ROS1 rearrangement, while it negatively correlated with EGFR mutations.