Clinical outcomes of Epstein-Barr virus (EBV)-associated metastatic and locally advanced unresectable gastric cancers (GCs) in patients receiving first-line fluoropyrimidine and platinum (FP) doublet chemotherapy.

BACKGROUND: Epstein-Barr virus-associated gastric cancer (EBVaGC) is a distinct molecular subgroup showing excellent outcomes after surgery for localized disease. Prominent immune cell infiltration in EBVaGC reflects the immunogenicity of Epstein-Barr virus (EBV) and, as suggested by some investigators, responsiveness to immune checkpoint inhibitors in the palliative setting. However, few data are available on the prevalence, clinical characteristics, and prognosis of EBVaGC patients receiving palliative cytotoxic chemotherapy. METHODS: In this retrospective study, we identified 1061 patients with metastatic, recurrent, or locally advanced unresectable gastric cancer (GC) who started first-line fluoropyrimidine/platinum (FP) doublet chemotherapy with or without trastuzumab from January 2015 to August 2018. For 766 patients with available tumor tissue, the presence of EBV in cancer cells was evaluated by EBV-encoded RNA in situ hybridization and correlated with clinical characteristics and treatment outcomes. RESULTS: Among the patients evaluated (n = 766), 40 (5.0%) were EBV-positive. EBVaGC was associated with male sex (p = 0.009) and lower neutrophil-lymphocyte ratio (NLR < 2.46, p = 0.03). Efficacy of first-line FP chemotherapy, in terms of response rate ad progression-free survival (PFS), did not differ between EBVaGC and EBV-negative GC (overall response rate: 53.8% vs. 51.8%, p = 0.99; median PFS: 6.4 vs. 6.7 months, p = 0.90). However, overall survival tended to be better with EBVaGC than EBV-negative GC (16.4 vs. 14.0 months, p = 0.07). CONCLUSIONS: EBVaGC accounted for 5% of metastatic/unresectable GCs. While EBVaGC was not associated with better response to or PFS following first-line cytotoxic chemotherapy, it showed a trend toward better overall survival.

Prognostic value of mismatch repair deficiency in patients receiving first-line fluoropyrimidine plus platinum for metastatic, recurrent, or unresectable gastric cancer.

BACKGROUND: We examined the impact of mismatch repair (MMR) status on efficacy of first-line fluoropyrimidine plus platinum (FP) chemotherapy in patients with HER2-negative metastatic, recurrent, or unresectable gastric cancer (mGC). METHODS: Patients with mGC receiving first-line FP between 2015 and 2018 at Asan Medical Center, Korea, were reviewed. We evaluated the clinical characteristics and the efficacy of chemotherapy according to MMR status in patients with available immunohistochemistry results. RESULTS: Of 895 patients, we analyzed 543 with available MMR protein expression results, and deficient MMR (dMMR) was detected in 4.4% (n = 24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p = 0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR. Objective response rate was 27.3% in dMMR and 34.3% in pMMR (p = 0.556). No difference in progression-free survival was noted between patients with dMMR and pMMR (median, 5.6 vs. 5.8 months, p = 0.266). Patients with dMMR tended to have better overall survival than those with pMMR although this difference was not statistically significant (median, 17.9 vs. 12.2 months, p = 0.183). CONCLUSIONS: Efficacy of first-line FP was not different by MMR status in mGC patients.

Prostate cancer risk prediction based on clinical factors and prostate-specific antigen.

INTRODUCTION: The incidence rate of prostate cancer (PCa) has continued to rise in Korea. This study aimed to construct and evaluate a 5-year PCa risk prediction model using a cohort with PSA < 10 ng/mL by incorporating PSA levels and individual factors. METHODS: The PCa risk prediction model including PSA levels and individual risk factors was constructed using a cohort of 69,319 participants from the Kangbuk Samsung Health Study. 201 registered PCa incidences were observed. A Cox proportional hazards regression model was used to generate the 5-year risk of PCa. The performance of the model was assessed using standards of discrimination and calibration. RESULTS: The risk prediction model included age, smoking status, alcohol consumption, family history of PCa, past medical history of dyslipidemia, cholesterol levels, and PSA level. Especially, an elevated PSA level was a significant risk factor of PCa (hazard ratio [HR]: 1.77, 95% confidence interval [CI]: [1.67-1.88]). This model performed well with sufficient discrimination ability and satisfactory calibration (C-statistic: 0.911, 0.874; Nam-D'Agostino test statistic:19.76, 4.21 in the development and validation cohort, respectively). CONCLUSIONS: Our risk prediction model was effective in predicting PCa in a population according to PSA levels. When PSA levels are inconclusive, an assessment of both PSA and specific individual risk factors (e.g., age, total cholesterol, and family history of PCa) could provide further information in predicting PCa.

Prediction and prevention of central nervous system relapse in patients with extranodal natural killer/T-cell lymphoma.

Because non-anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline-based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.

Clinical outcomes of systemic therapy in patients with unresectable or metastatic combined hepatocellular-cholangiocarcinoma.

BACKGROUND & AIMS: The optimal systemic chemotherapy for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) has not yet been defined. The definition and classification of cHCC-CCA has changed recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC-CCA. METHODS: Among 254 patients with histologically confirmed cHCC-CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were retrospectively evaluated. RESULTS: Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first-line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow-up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non-platinum containing first-line chemotherapy remained as significant prognostic factors for poorer OS. CONCLUSIONS: The efficacy outcomes according to first-line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.

Systemic Steroid Treatment for Imatinib-Associated Severe Skin Rash in Patients with Gastrointestinal Stromal Tumor: A Phase II Study.

BACKGROUND: To achieve optimal clinical outcomes in patients with gastrointestinal stromal tumor (GIST), it is crucial to maintain sufficient dosing of imatinib. Skin rash is a common imatinib-associated adverse event and may affect compliance. This phase II study was conducted to evaluate whether imatinib-associated severe skin rash can be managed with systemic steroids without dose reduction or interruption of imatinib. This study is registered at ClinicalTrials.gov, number NCT03440515. PATIENTS AND METHODS: Between 2014 and 2016, 29 patients with imatinib-associated severe skin rash were enrolled. Skin rash of grade 2 with grade ≥2 pruritus or of grade 3 was considered severe. Oral prednisolone was administered 30 mg/day for 3 weeks, then tapered off over 12 weeks. The primary endpoint was treatment success rate (TSR). Treatment success was defined as maintaining imatinib for more than 15 weeks after completion of the steroid administration schedule without skin rash that led to additional steroid treatment or dose reduction or interruption of imatinib. RESULTS: Of the 29 patients enrolled, 22 patients with skin rash were treated successfully (TSR, 75.8%), 2 (6.9%) were evaluated as treatment failures, and 5 (17.2%) were not evaluable. The 2-year rash-free and imatinib reduction-free interval rate was 67.2% with median follow-up of 22.0 months (range, 0.4-30.3). Recurrence of severe skin rash occurred in seven patients (24.1%). Systemic steroids were well tolerated except in one patient who experienced pneumocystis pneumonia. CONCLUSION: This study demonstrated that imatinib-associated severe skin rash can be effectively controlled by systemic steroid treatment without interruption or dose reduction of imatinib in patients with GIST. IMPLICATIONS FOR PRACTICE: Imatinib has been the standard treatment of gastrointestinal stromal tumor in both adjuvant and palliative settings. It is crucial to maintain sufficient dosing of imatinib to achieve optimal clinical outcomes. Imatinib commonly causes imatinib-associated skin rash, which may worsen drug compliance. This phase II study demonstrated that systemic steroids could help maintaining the efficacy of imatinib by preventing interruption or dose reduction of imatinib. The present study provides a new administration strategy of systemic steroids and its efficacy and safety data. Thus, this study can be a cornerstone to establish treatment guidelines for imatinib-associated skin rash.

Anti-N-methyl-D-aspartate Receptor Encephalitis: a Rare Complication of Ovarian Teratoma.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a potentially life-threatening but reversible autoimmune disorder characterized by psychiatric symptoms, cognitive dysfunction, speech dysfunction, seizures, movement disorder, decreased level of consciousness, and autonomic dysfunction or central hypoventilation. It occurs predominantly in young women and approximately half of them have underlying tumors, mainly ovarian teratoma. A 24-year old woman was admitted because of fever, headache, abnormal movement and decreased mental status. Five cycles of plasmapheresis improved her neurological and mental status. Anti-NMDAR antibodies in her CSF and serum were positive, and computed tomography revealed a 1-cm sized mass suggestive of mature cystic teratoma arising from the right ovary. We promptly performed laparoscopic right ovarian cystectomy. She was discharged after 2 weeks with mild memory deficit. Prompt removal of ovarian teratoma and multidisciplinary care are particularly important for good outcome.

Association between Five Common Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms and Colorectal Cancer Susceptibility.

The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and modulates cancer growth, invasion, and angiogenesis. The present study investigated the association between five PAI-1 gene polymorphisms and colorectal cancer (CRC) risk. Five PAI-1 polymorphisms (-844G > A [rs2227631], -675 4G > 5G [rs1799889], +43G > A [rs6092], +9785G > A [rs2227694], and +11053T > G [rs7242]) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay in 459 CRC cases and 416 controls. Increased CRC risk was more frequently associated with PAI-1 -675 5G5G polymorphism than with 4G4G (adjusted odds ratio (AOR) = 1.556; 95% confidence interval (CI): 1.012-2.391; p = 0.04). In contrast, for the PAI-1 +11053 polymorphism, we found a lower risk of CRC with the GG genotype (AOR = 0.620; 95% CI: 0.413-0.932; p = 0.02) than with the TT genotype, as well as for recessive carriers (TT + TG vs. GG, AOR = 0.662; 95% CI: 0.469-0.933; p = 0.02). The +43AA genotype was associated with lower overall survival (OS) than the +43GG genotype. Our results suggest that the PAI-1 genotype plays a role in CRC risk. This is the first study to identify an association between five PAI-1 polymorphisms and CRC incidence worldwide.

Analysis of the Association Between MicroRNA Biogenesis Gene Polymorphisms and Venous Thromboembolism in Koreans.

Venous thromboembolism (VTE) involves the formation of a blood clot, typically in the deep veins of the leg or arm (deep vein thrombosis), which then travels via the circulatory system and ultimately lodges in the lungs, resulting in pulmonary embolism. A number of microRNAs (miRNAs) are well-known regulators of thrombosis and thrombolysis, and mutations in miRNA biogenesis genes, such as DICER1, DROSHA have been implicated in miRNA synthesis and function. We investigated the genetic association between polymorphisms in four miRNA biogenesis genes, DICER1 rs3742330A > G, DROSHA rs10719T > C, RAN rs14035C > T and XPO5 rs11077A > C, and VTE in 503 Koreans: 300 controls and 203 patients. Genotyping was assessed with polymerase chain reaction-restriction fragment length polymorphism assays. We detected associations between polymorphisms in RAN and XPO5 and VTE prevalence (RAN rs14035CC + CT versus TT: p = 0.018; XPO5 rs11077AA + AC versus CC: p < 0.001). Analysis of allele combinations of all four polymorphisms (DICER1, DROSHA, RAN, XPO5) revealed that A-T-T-A was associated with decreased VTE prevalence (p = 0.0002), and A-T-C-C was associated with increased VTE prevalence (p = 0.027). Moreover, in subjects with provoked VTE, the DROSHA rs10719T > C, polymorphism was associated with increased disease prevalence (TT versus TC + CC: p < 0.039). Our study demonstrates that RAN and XPO5 polymorphisms are associated with risk for VTE in Korean subjects.

Foot and Ankle Radiographic Parameters in Korean Adults Vary by Sex and Age.

Although many radiographic measurements of the foot and ankle have been used, reference values for normal functional groups are rarely reported. These can change according to sex and age; therefore, this study aimed to: (1) determine reference values for radiographic foot and ankle angles in an asymptomatic healthy Korean population, and (2) compare differences in the measurements according to sex and age. A total of 200 healthy volunteers were recruited, including 100 young adults (50 males, 50 females) aged 20 to 35 years, and 100 older adults (50 males, 50 females) aged 60 to 69 years. Weightbearing ankle anteroposterior views, talar tilt, and tibiotalar angles were measured. On the weightbearing foot anteroposterior views, the hallux valgus, hallux interphalangeal, and talo-first metatarsal angles were measured. On the weightbearing lateral foot views, the calcaneal pitch, lateral talo-calcaneal, lateral talo-first metatarsal, and lateral calcaneo-first metatarsal angles were measured. Values were stratified by sex and age, and statistically compared. The hallux valgus, calcaneal pitch, and lateral calcaneo-first metatarsal angles were affected by both sex and age; the hallux interphalangeal angle was affected by age and the lateral talo-first metatarsal angle by sex. We presented reference values for foot and ankle radiographic measurements in a healthy Korean population; several radiographic indices varied significantly by sex or age, which were grossly similar to previous studies based on white race. The study data can serve as a basis for evaluation of foot and ankle disorders.

Spontaneous spinal epidural hematoma of the thoracic spine after herbal medicine: a case report.

BACKGROUND: Spontaneous spinal epidural hematoma (SSEH) is an uncommon disease, but it can lead to acute cord compression with disabling consequences. Identifiable reasons for spontaneous hemorrhage are vascular malformations and bleeding disorders. However, SSEH after taking herbal medicines has not been described yet. CASE PRESENTATION: A 60-year-old female experienced sudden back pain combined with numbness and weakness in the lower limbs for several hours with no trauma, drug use, family history or any disease history. Her deep tendon reflexes were normoactive, and Babinski was negative. An emergent MRI showed a spinal epidural hematoma extending from T3 to T5. She was taken to surgery after immediate clinical and laboratory evaluations had been completed. Emergency decompression with laminectomy was performed and the patient recovered immediately after the surgery. Additional history taken from the patient at outpatient clinic after discharge revealed that she had been continuously taking herbal medicine containing black garlic for 8 weeks. CONCLUSION: To our knowledge, no report has been previously issued on SSEH after taking herbal medicines. Although contradictory evidence is present on bleeding risks with herbal uses, we believe that it's reasonable to ascertain if patients with SSEP are taking herbal medication before or during spinal surgery.

Quantitative Imaging of Cerebral Thromboemboli In Vivo: The Effects of Tissue-Type Plasminogen Activator.

BACKGROUND AND PURPOSE: Quantitative imaging for the noninvasive assessment of thrombolysis is needed to advance basic and clinical thrombosis-related research and tailor tissue-type plasminogen activator (tPA) treatment for stroke patients. We quantified the evolution of cerebral thromboemboli using fibrin-targeted glycol chitosan-coated gold nanoparticles and microcomputed tomography, with/without tPA therapy. METHODS: We injected thrombi into the distal internal carotid artery in mice (n=50). Fifty-five minutes later, we injected fibrin-targeted glycol chitosan-coated gold nanoparticles, and 5 minutes after that, we treated animals with tPA or not (25 mg/kg). We acquired serial microcomputed tomography images for 24 hours posttreatment. RESULTS: Thrombus burden at baseline was 784×103±59×103 µm2 for the tPA group (n=42) and 655×103±103×103 µm2 for the saline group (n=8; P=0.37). Thrombus shrinkage began at 0.5 to 1 hour after tPA therapy, with a maximum initial rate of change at 4603±957 µm2/min. The rate of change lowered to ≈61% level of the initial in hours 1 to 2, followed by ≈29% and ≈1% in hours 2 to 3 and 3 to 24, respectively. Thus, 85% of total thrombolysis over 24 hours (≈500 µm2, equivalent to 64% of the baseline thrombus burden) occurred within the first 3 hours of treatment. Thrombus burden at 24 hours could be predicted at around 1.5 to 2 hours. Saline treatment was not associated with significant changes in the thrombus burden. Infarct size was smaller in the tPA group versus saline group (18.1±2.3 versus 45.8±3.3 mm2; P<0.01). Infarct size correlated to final thrombus burden (r=0.71; P<0.01). Time to thrombolysis, completeness of thrombolysis, and tPA therapy were independent predictors of infarct size. CONCLUSIONS: Thromboembolic burden and the efficacy of tPA therapy can be assessed serially, noninvasively, and quantitatively using high-resolution microcomputed tomography and a fibrin-binding nanoparticle imaging agent.

Nonpigmented hair removal using photodynamic therapy in animal model.

BACKGROUND AND OBJECTIVE: Lasers have been successfully used for decades to remove dark hair. However, laser removal of nonpigmented hair is challenging due to the lack of chromophores. The aim of this study was to use photodynamic therapy (PDT) to remove nonpigmented hair. STUDY DESIGN/MATERIAL AND METHODS: We compared the efficacy of permanent hair reduction in white BALB/c and black C57BL/6 mice treated with PDT or an 800-nm diode laser. We collected skin biopsy specimens and investigated post-PDT histologic changes and molecular changes. RESULTS: We observed keratin 15 staining in the bulge area and alkaline phosphatase staining in the dermal papilla following PDT. We observed a temporary, catagen-like transformation in nonpigmented hair follicles after PDT. We observed apoptotic cells in the hair matrix after PDT. Irradiation with an 800-nm diode laser did not achieve nonpigmented hair removal. Multiple PDT sessions achieved permanent reduction of nonpigmented hair. Interestingly, removal of black hair using PDT was less efficient. CONCLUSION: Our results suggest that PDT can damage the nonpigmented hair matrix, but not stem cells or dermal papillae. Repeated PDT may impair the hair-regeneration capacity via a bystander effect on bulge stem cells or dermal papillae. In this study, we found it was possible to remove nonpigmented hair using PDT. Lasers Surg. Med. 48:748-762, 2016. © 2016 Wiley Periodicals, Inc.

Inter-segmental motions of the foot in healthy adults: Gender difference.

BACKGROUND: Multi-segment Foot Models (MFM) have increased in use for both clinical and research applications; however, little is known about the gender differences of inter-segmental motions within the foot and ankle during gait. The objectives of this study were to analyze the gender differences of inter-segmental foot motion during gait in healthy young adults using a MFM with a 15-marker set. METHODS: One hundred healthy adults (50 males, 50 females) between 20 and 35 years of age who had normal function and no radiographic abnormality, were evaluated. Inter-segmental angles (ISA) (hindfoot, forefoot, and hallux) were calculated at each time point. The ISAs at specific phases of the gait cycle, the change in ISAs between the phases, and the range of motion for each ISA across the entire gait cycle were compared between genders. RESULTS: The kinematic curve of the inter-segmental foot motions showed a characteristic pattern during the whole gait cycle. Although the hallux of female was aligned in a more valgus angulation during gait, the overall patterns of the inter-segmental foot motions were quite similar for both genders. Most differences in the inter-segmental foot motions between men and women were observed in the range of motion. Considering the stance phase of gait-cycle, the range of motion in the sagittal and transverse plane of the hindfoot was greater in females than in males. The sagittal range of motion of the hallux was also greater in females, mainly due to higher plantar flexion. CONCLUSIONS: The gender differences of the inter-segmental foot motion were investigated during gait in healthy young adults using a MFM with a 15-marker set. Females had a larger range of motion in the sagittal plane of the hallux and in the sagittal and transverse plane of the hindfoot.

Quantifying rotator cuff atrophy and fatty degeneration at the supraspinatus origin in the scapular fossa.

PURPOSE: The aim of this study was to evaluate the location difference (distance) between the conventional Y-view (CYV) and the bony origin of the supraspinatus, and therefore, to suggest hypotrophy measurement in the CYV could be highly influenced by retraction of a torn tendon. METHODS: Ninety five arthroscopically repaired rotator cuff tears were retrospectively enrolled in this study. The most lateral portion of the osseous origin of the supraspinatus muscle [the Y-view at the level was newly defined as the supraspinatus origin-view (SOV)] and the CYV were determined on the MRI, and location discrepancy between the two levels was measured. Fatty degeneration and cross-sectional areas of rotator cuff muscles were measured on both views. Subgroup analyses were performed in partial-thickness tears and full-thickness tears with tendon retraction. RESULTS: Distance between the SOV and CYV was 11.2 ± 3.7 mm. Discrepancy of the supraspinatus areas at the two views was greater in full-thickness tears than it was in partial-thickness tears without retraction. In the full-thickness tear group, correlation analysis between retraction and cross-sectional areas of the supraspinatus in both views exhibited statistical significance [Pearson's correlation coefficients = 0.500 (P < 0.001) in the CYV and 0.283 (P = 0.017) in the SOV]; however, the correlation was stronger in the CYV. Ratings of fatty degeneration were similar in both views. CONCLUSIONS: There is considerable location discrepancy between the osseous origin of the supraspinatus at the suprascapular fossa and the CYV in which fatty degeneration and hypotrophy are routinely measured. LEVEL OF EVIDENCE: Case series, Level IV.

Interplay between 3'-UTR polymorphisms in the vascular endothelial growth factor (VEGF) gene and metabolic syndrome in determining the risk of colorectal cancer in Koreans.

BACKGROUND: Polymorphisms in angiogenesis-related genes and metabolic syndrome (MetS) risk factors play important roles in cancer development. Moreover, recent studies have reported associations between a number of 3'-UTR polymorphisms and a variety of cancers. The aim of this study was to investigate the associations of three VEGF 3'-UTR polymorphisms (1451C > T [rs3025040], 1612G > A [rs10434], and 1725G > A [rs3025053]) and MetS with colorectal cancer (CRC) susceptibility in Koreans. METHODS: A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of VEGF polymorphisms was performed by TaqMan allelic discrimination assays. Cancer risks of genetic variations and gene-environment interactions were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of multivariate logistic regression analyses. RESULTS: VEGF 1451C > T was significantly associated with rectal cancer risk (Dominant model; AOR =1.58; 95% CI = 1.09 - 2.28; p = 0.015) whereas VEGF 1725G > A correlated with MetS risk (Dominant model; AOR =1.61; 95% CI =1.06 - 2.46; p = 0.026). Of the gene-environment combined effects, the interaction of VEGF 1451C > T and MetS contributed to increased rectal cancer risk (AOR = 3.15; 95% CI = 1.74 - 5.70; p < .001) whereas the combination of VEGF 1725G > A and MetS was involved with elevated colon cancer risk (AOR = 2.68; 95% CI = 1.30 - 1.55; p =0.008). CONCLUSIONS: Our results implicate that VEGF 1451C > T and 1725G > A may predispose to CRC susceptibility and the genetic contributions may be varied with the presence of MetS.

Predicting tolerability of high-dose fentanyl buccal tablets in cancer patients.

BACKGROUND & AIMS: Fentanyl buccal tablets (FBTs) are a rapid-onset opioid indicated for breakthrough cancer pain (BTcP) and FBT titration is needed to optimize BTcP management. We aimed to predict which patients could tolerate a high dose of FBT (400 µg or more at a time). METHODS: A retrospective analysis was performed to assess the final FBT dose. The final FBT doses were compared according to the clinical features. The prediction accuracy of patients tolerant of 400 µg or higher FBT was compared using the area under the receiver operating characteristic (ROC) curves. A risk scoring model based on the odds ratio (OR) was developed from the final multivariable model, and patients were assigned into two groups: low tolerance (0-1 point) and high tolerance (2-3 points). RESULTS: Among 131 patients, the most frequently effective dose of FBT was 200 µg (54%), followed by 100 µg (30%). The median value of morphine equivalent daily doses (MEDD) was 60 mg/day, and the most common daily use was 3-4 times/day. In multivariable analysis, male sex, younger age, and use of FBTs three or more times per day were independently associated with high-dose FBT. According to the risk scoring model, the patients with a final FBT of 400 µg or higher were significantly more in the high tolerance group (17%) compared to the low tolerance group (3%; p = 0.023). CONCLUSIONS: According to the dose relationship between the final FBT dose and the clinical features, three factors (sex, age, daily use of FBT) were independently associated with the final dose of FBT. Our risk score model could help predict tolerance to high-dose FBT and guide the titration plan for BTcP.

Detection and evaluation of signals for immune-related adverse events: a nationwide, population-based study.

Background: Immune checkpoint inhibitors (ICIs) are one of the main pillars of cancer therapy. Since other studies such as clinical trial and retrospective study have limitations for detecting the immune-related adverse events (irAEs) characterized by unpredictable onset, nonspecific symptoms and wide clinical spectrum, we aimed to identify the incidence of irAEs and to detect and evaluate the signals using real-world data. Methods: Cancer patients treated with anticancer medications were analyzed using the nationwide health insurance claims database of South Korea from 2017 to 2019, and Clinical Data Warehouse (CDW) database of Asan Medical Center (AMC), a tertiary referral hospital, from 2012 to 2019. AEs of ICI users were compared with those of non-ICI anticancer medication users. PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab) were evaluated. We defined an AE as a newly added diagnosis after the ICI prescription using an ICD-10 diagnostic code. A signal was defined as an AE that was detected by any one of the four indices of data mining: hazard ratio (HR), proportional claims ratio (PCR), claims odds ratio (COR), or information component (IC). All detected signals were reviewed and classified into well-known or potential irAEs. Signal verification was performed for targeted AEs using CDW of AMC using diagnostic codes and text mining. Results: We identified 118 significant signals related to ICI use. We detected 31 well-known irAEs, most of which were endocrine diseases and skin diseases. We also detected 33 potential irAEs related to disorders in the nervous system, eye, circulatory system, digestive system, skin and subcutaneous tissues, and bones. Especially, portal vein thrombosis and bone disorders such as osteoporosis with pathological fracture and fracture of shoulder, upper arm, femur, and lower leg showed high HR in ICI users than in non-ICI users. The signals from hospital database were verified using diagnostic codes and text mining. Conclusion: This real-world data analysis demonstrated an efficient approach for signal detection and evaluation of ICI use. An effective real-world pharmacovigilance system of the nationwide claims database and the EMR could complement each other in detecting significant AE signals.

Genetic variants of MUC4 are associated with susceptibility to and mortality of colorectal cancer and exhibit synergistic effects with LDL-C levels.

As a disease with high mortality and prevalence rates worldwide, colorectal cancer (CRC) has been thoroughly investigated. Mucins are involved in the induction of CRC and the regulation of intestinal homeostasis but a member of the mucin gene family MUC4 has a controversial role in CRC. MUC4 has been associated with either decreased susceptibility to or a worse prognosis of CRC. In our study, the multifunctional aspects of MUC4 were elucidated by genetic polymorphism analysis in a case-control study of 420 controls and 464 CRC patients. MUC4 rs1104760 A>G polymorphism had a protective effect on CRC risk (AG, AOR = 0.537; GG, AOR = 0.297; dominant model, AOR = 0.493; recessive model, AOR = 0.382) and MUC4 rs2688513 A>G was associated with an increased mortality rate of CRC (5 years, GG, adjusted HR = 6.496; recessive model, adjusted HR = 5.848). In addition, MUC4 rs1104760 A>G showed a high probability of being a potential biomarker for CRC patients with low-density lipoprotein cholesterol (LDL-C) in the risk range while showing a significant synergistic effect with the LDL-C level. This is the first study to indicate a significant association between MUC4 genetic polymorphisms and CRC prevalence, suggesting a functional genetic variant with the LDL-C level, for CRC prevention.

Clinical outcomes of immune checkpoint inhibitors in unresectable or metastatic combined hepatocellular-cholangiocarcinoma.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been demonstrated to be effective for unresectable or metastatic hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCA) in prior prospective trials. However, the clinical outcomes of ICIs in patients with combined HCC-CCA (cHCC-CCA) have not been investigated. Accordingly, we retrospectively evaluated the effectiveness and safety of ICIs in patients with unresectable or metastatic cHCC-CCA. METHODS: Among 101 patients with histologically documented cHCC-CCA who received systemic therapy, 25 received ICIs between January 2015 and September 2021 and were included in the current analysis. Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were retrospectively evaluated. RESULTS: The median age was 64 years (range 38-83) and 84% (n = 21) of patients were males. Most patients had Child-Pugh A liver function (n = 22, 88%) and hepatitis B virus infection (17, 68%). Nivolumab (n = 17, 68%) was the most frequently used ICI, followed by pembrolizumab (n = 5, 20%), atezolizumab plus bevacizumab (n = 2, 8%), and ipilimumab plus nivolumab (n = 1, 4%). All patients, except one, had previously received systemic therapy; median two lines (1-5 lines) of systemic therapy were administered prior to ICIs. With a median follow-up duration of 20.1 months (95% CI 4.9-35.2 months), the median PFS was 3.5 months (95% CI 2.4-4.8 months), and the median OS was 8.3 months (95% CI 6.8-9.8 months). The ORR was 20.0% (n = 5, nivolumab for 2 patients, pembrolizumab for 1, atezolizumab plus bevacizumab for 1, and ipilimumab plus nivolumab for 1) and the duration of response was 11.6 months (95% CI 11.2-12.0 months). CONCLUSIONS: ICIs displayed clinical anti-cancer effectiveness, aligning with the results of prior prospective studies for HCC or CCA. Further international studies are required to define the optimal strategies for managing unresectable or metastatic cHCC-CCA.