Perimenopausal and Menopausal Mammary Glands In A 4-Vinylcyclohexene Diepoxide Mouse Model.

As both perimenopausal and menopausal periods are recognized critical windows of susceptibility for breast carcinogenesis, development of a physiologically relevant model has been warranted. The traditional ovariectomy model causes instant removal of the entire hormonal repertoire produced by the ovary, which does not accurately approximate human natural menopause with gradual transition. Here, we characterized the mammary glands of 4-vinylcyclohexene diepoxide (VCD)-treated animals at different time points, revealing that the model can provide the mammary glands with both perimenopausal and menopausal states. The perimenopausal gland showed moderate regression in ductal structure with no responsiveness to external hormones, while the menopausal gland showed severe regression with hypersensitivity to hormones. Leveraging the findings on the VCD model, effects of a major endocrine disruptor (polybrominated diphenyl ethers, PBDEs) on the mammary gland were examined during and after menopausal transition, with the two exposure modes; low-dose, chronic (environmental) and high-dose, subacute (experimental). All conditions of PBDE exposure did not augment or compromise the macroscopic ductal reorganization resulting from menopausal transition and/or hormonal treatments. Single-cell RNA sequencing revealed that the experimental PBDE exposure during the post-menopausal period caused specific transcriptomic changes in the non-epithelial compartment such as Errfi1 upregulation in fibroblasts. The environmental PBDE exposure resulted in similar transcriptomic changes to a lesser extent. In summary, the VCD mouse model provides both perimenopausal and menopausal windows of susceptibility for the breast cancer research community. PBDEs, including all tested models, may affect the post-menopausal gland including impacts on the non-epithelial compartments.

Impact of family caregivers' awareness of the prognosis on their quality of life/depression and those of patients with advanced cancer: a prospective cohort study.

PURPOSE: A caregiver's prognostic awareness can affect clinical decisions for the patient. The purpose of this study was to examine the impact of family caregivers' prognostic awareness on the quality of life (QOL) and emotional state of both patients with advanced cancer and their caregivers. METHODS: This prospective cohort study was conducted from December of 2016 to January of 2018. A total of 159 patients with advanced cancer and an equal number of caregivers participated. The investigation tools used include the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C15-Palliative, the McGill Quality of Life Questionnaire, and the Patient Health Questionnaire-9, and evaluation was performed at baseline, 3 months, and 6 months. Covariance analysis with a general linear modeling was used to compare changes in quality of life scores according to the caregivers' awareness of the prognosis. RESULTS: Mean patient overall QOL score increased in the group of caregivers who were aware of prognosis and decreased in the caregivers who were not aware of the prognosis (p = 0.018). The changes over time in the patients' QOL scores associated with symptoms improved with caregiver awareness (pain, p = 0.017; dyspnea, p = 0.048; appetite loss, p = 0.045). The percentage of depressed patients was smaller after 3 months in the group with caregivers aware of the prognosis (baseline to 3 months p = 0.028). Caregivers who did not understand their patients' prognosis exhibited better existential well-being (p = 0.036), and the incidence of depression was lower in this group at 3 months (p = 0.024). CONCLUSION: Caregivers' prognostic awareness may improve the quality of life and mood in patients with advanced cancer; however, this awareness may harm the quality of life and mood of the caregivers. These results may aid in developing in-depth interventions regarding prognosis for both patients and their caregivers.

Fibroblast growth factor receptor 4 increases epidermal growth factor receptor (EGFR) signaling by inducing amphiregulin expression and attenuates response to EGFR inhibitors in colon cancer.

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross-talk between FGFR4 and EGFR, and the effect of anti-EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab-induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti-EGFR therapy in colon cancer.

Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study.

The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).

Association of illness understanding with advance care planning and end-of-life care preferences for advanced cancer patients and their family members.

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 Attitudes of Physicians and the General Public toward Prognostic Disclosure of Different Serious Illnesses: a Korean Nationwide Study.

BACKGROUND: Although international guidelines recommend palliative care approaches for many serious illnesses, the palliative needs of patients with serious illnesses other than cancer are often unmet, mainly due to insufficient prognosis-related discussion. We investigated physicians' and the general public's respective attitudes toward prognostic disclosure for several serious illnesses. METHODS: We conducted a cross-sectional survey of 928 physicians, sourced from 12 hospitals and the Korean Medical Association, and 1,005 members of the general public, sourced from all 17 administrative divisions in Korea. RESULTS: For most illnesses, most physicians (adjusted proportions - end-organ failure, 99.0%; incurable genetic or neurologic disease, 98.5%; acquired immune deficiency syndrome [AIDS], 98.4%; stroke or Parkinson's disease, 96.0%; and dementia, 89.6%) and members of the general public (end-organ failure, 92.0%; incurable genetic or neurologic disease, 92.5%; AIDS, 91.5%; stroke or Parkinson's disease, 92.1%; and dementia, 86.9%) wanted to be informed if they had a terminal prognosis. For physicians and the general public, the primary factor to consider when disclosing terminal status was "the patient's right to know his/her condition" (31.0%). Yet, the general public was less likely to prefer prognostic disclosure than physicians. Particularly, when their family members were patients, more than 10% of the general public did not want patients to be informed of their terminal prognosis. For the general public, the main reason for not disclosing prognosis was "psychological burden such as anxiety and depression" (35.8%), while for the physicians it was "disclosure would have no beneficial effect" (42.4%). CONCLUSION: Most Physicians and the general public agreed that disclosure of a terminal prognosis respects patient autonomy for several serious illnesses. The low response rate of physicians might limit the generalizability of the results.

Correction to: Priorities of a "good death" according to cancer patients, their family caregivers, physicians, and the general population: a nationwide survey.

While recently extending that research, however, we discovered that 236 members of the general population were mistakenly duplicated by the investigating agency (Word Research) and 1241 were reported rather than 1005. Here, we present corrections and discuss the relevant data.

Prevalence and predictors of major depressive disorder in bereaved caregivers at 6 and 13 months.

OBJECTIVE: Depressive symptoms are common in bereaved caregivers; however, there have been few prospective studies using a structured interview. This study investigated the prevalence and preloss predictors of major depressive disorder (MDD) in bereaved caregivers of patients in a palliative care unit. METHOD: This prospective cohort study collected caregiver sociodemographic and psychological data before the death of a palliative care unit patient, including MDD, care-burden, coping style, and hopeful attitude. Postloss MDD was assessed 6 and 13 months after death, and a multivariate logistic regression analysis was conducted to identify its predictors.ResultOf 305 caregivers contacted, 92 participated in this study. The prevalence of preloss MDD was 21.8%; the prevalences of postloss MDD were 34.8% and 24.7% at 6 and 13 months, respectively. Preloss MDD predicted postloss MDD at 6 months (odds ratio [OR] = 5.38, 95% confidence interval [CI95%] = 1.29, 22.43); preloss nonhopeful attitude and unemployment status of caregivers predicted postloss MDD at 13 months (OR = 8.77, CI95% = 1.87, 41.13 and OR = 7.10, CI95% = 1.28, 39.36, respectively).Significance of resultsApproximately 35% of caregivers suffered from MDD at 6 months postloss, but the prevalence of MDD decreased to about 25% at 13 months. Preloss MDD significantly predicted postloss MDD at 6 months, whereas hopeful attitude and unemployment at baseline were significantly associated with postloss MDD at 13 months.

The role of interim FDG PET-CT after induction chemotherapy as a predictor of concurrent chemoradiotherapy efficacy and prognosis for head and neck cancer.

PURPOSE: Induction chemotherapy (ICT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CCRT) has the advantages of organ preservation and systemic control in head and neck cancer (HNC). Early prediction of CCRT efficacy may help identify patients who will benefit more from surgery than from CCRT. We investigated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) after ICT to predict the efficacy of CCRT and clinical outcomes. METHODS: Tumor responses were retrospectively reviewed after CCRT based on the Response Evaluation Criteria in Solid Tumors. FDG PET-CT imaging was performed before and after three cycles of TPF. We examined the associations between the metabolic response (percentage decrease in the maximum standardized uptake value [SUVmax] and total metabolic tumor volume [MTV]) after ICT and complete response (CR) to CCRT, progression-free survival (PFS), and overall survival (OS). RESULTS: We studied 43 HNC patients with a median follow-up of 32.7 months. Lymph node (LN) SUVmax and total MTV decreases from baseline after ICT were greater in patients with a CR to CCRT than in non-CR patients (LN SUVmax, 88.8% vs. 62.5%, respectively; total MTV, 99.7% vs. 89.9%, respectively). Decreases in total MTV ≥ 78% and LN SUVmax ≥73% after ICT predicted CR to CCRT and longer OS and PFS. CONCLUSIONS: Using interim FDG PET-CT to measure SUVmax and total MTV after three cycles of ICT may be a useful technique for identifying HNC patients who will benefit from CCRT and predicting survival outcomes.

Priorities of a "good death" according to cancer patients, their family caregivers, physicians, and the general population: a nationwide survey.

PURPOSE: Understanding the concept of a "good death" is crucial to end-of-life care, but our current understanding of what constitutes a good death is insufficient. Here, we investigated the components of a good death that are important to the general population, cancer patients, their families, and physicians. METHODS: We conducted a stratified nationwide cross-sectional survey of cancer patients and their families from 12 hospitals, physicians from 12 hospitals and the Korean Medical Association, and the general population, investigating their attitudes toward 10 good-death components. FINDINGS: Three components-"not be a burden to the family," "presence of family," and "resolve unfinished business"-were considered the most important components by more than 2/3 of each of the three groups, and an additional three components-"freedom from pain," "feel that life was meaningful," and "at peace with God"-were considered important by all but the physicians group. Physicians considered "feel life was meaningful," "presence of family," and "not be a burden to family" as the core components of a good death, with "freedom from pain" as an additional component. "Treatment choices' followed, "finances in order," "mentally aware," and "die at home" were found to be the least important components among all four groups. CONCLUSION: While families strongly agreed that "presence of family" and "not be a burden to family" were important to a good death, the importance of other factors differed between the groups. Health care providers should attempt to discern each patient's view of a good death.

Other primary systemic cancers in patients with melanoma: Analysis of balanced acral and nonacral melanomas.

BACKGROUND: Although other primary systemic cancers in patients with melanoma have been studied, there have been few focusing on acral melanomas. OBJECTIVES: We assessed other primary systemic cancers in patients with acral and nonacral melanomas. METHODS: We analyzed other primary cancers in 452 patients with melanoma from 1994 to 2013. Metachronous cancers were defined as those given a diagnosis more than 2 months after diagnosis of melanoma. The others were considered prechronous or synchronous cancers. RESULTS: Among 51 cases of other primary cancers, gastrointestinal cancer (35.3%, n = 18/51) was the most common, followed by thyroid (17.6%), lung (11.8%), and breast (5.9%). Those were more prevalent in the acral melanoma group (12.8%, n = 31/243) compared with the nonacral melanoma group (9.6%, n = 20/209). Of 23 cases of metachronous cancer, the risk was the highest in bone marrow, followed by oral cavity, bladder, colon, lung, and thyroid. Among 28 cases of prechronous or synchronous cancers, gastrointestinal tract (35.7%, n = 10/28) was the most common site, followed by thyroid (17.9%), breast (10.7%), and lung (7.1%). LIMITATIONS: The study is limited by a small number of patients. CONCLUSION: Careful follow-up and imaging studies are necessary for early detection of other primary cancers and metastatic lesions in patients with melanoma.

Four New Dicaffeoylquinic Acid Derivatives from Glasswort (Salicornia herbacea L.) and Their Antioxidative Activity.

Four new dicaffeoylquinic acid derivatives and two known 3-caffeoylquinic acid derivatives were isolated from methanol extracts using the aerial parts of Salicornia herbacea. The four new dicaffeoylquinic acid derivatives were established as 3-caffeoyl-5-dihydrocaffeoylquinic acid, 3-caffeoyl-5-dihydrocaffeoylquinic acid methyl ester, 3-caffeoyl-4-dihydrocaffeoylquinic acid methyl ester, and 3,5-di-dihydrocaffeoylquinic acid methyl ester. Their chemical structures were determined by nuclear magnetic resonance and electrospray ionization-mass spectroscopy (LC-ESI-MS). In addition, the presence of dicaffeoylquinic acid derivatives in this plant was reconfirmed by LC-ESI-MS/MS analysis. The isolated compounds strongly scavenged 1,1-diphenyl-2-picrylhydrazyl radicals and inhibited cholesteryl ester hydroperoxide formation during rat blood plasma oxidation induced by copper ions. These results indicate that the caffeoylquinic acid derivatives may partially contribute to the antioxidative effect of S. herbacea.

Influence of caregiver personality on the burden of family caregivers of terminally ill cancer patients.

OBJECTIVE: To determine the influence of caregiver personality and other factors on the burden of family caregivers of terminally ill cancer patients. METHOD: We investigated a wide range of factors related to the patient-family caregiver dyad in a palliative care setting using a cross-sectional design. Caregiver burden was assessed using the seven-item short version of the Zarit Burden Interview (ZBI-7). Caregiver personality was assessed using the 10-item short version of the Big Five Inventory (BFI-10), which measures the following five personality dimensions: extroversion, agreeableness, conscientiousness, neuroticism, and openness. Patient- and caregiver-related sociodemographic and psychological factors were included in the analysis because of their potential association with caregiver burden. Clinical patient data were obtained from medical charts or by using other measures. Multivariate linear regression analysis was performed to identify the independent factors associated with caregiver burden. RESULTS: We analyzed 227 patient-family caregiver dyads. The multivariate analysis revealed that caregiver extroversion was protective against caregiver burden, whereas depressive symptoms in caregivers were related to increased burden. Neuroticism was positively correlated with caregiver burden, but this relationship was nonsignificant following adjustment for depressive symptoms. Patient-related factors were not significantly associated with caregiver burden. SIGNIFICANCE OF RESULTS: Evaluating caregiver personality traits could facilitate identification of individuals at greater risk of high burden. Furthermore, depression screening and treatment programs for caregivers in palliative care settings are required to decrease caregiver burden.

A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean South West Oncology Group Study.

BACKGROUND: In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. METHODS: Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded. RESULTS: Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001). CONCLUSION: This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate.

Differential Associations Between Delirium and Mortality According to Delirium Subtype and Age: A Prospective Cohort Study.

OBJECTIVE: This study investigated the differential associations between delirium and mortality in terminally ill patients according to delirium subtype and age. METHODS: This was a prospective cohort study of terminally ill patients. Delirium was diagnosed using the confusion assessment method. Delirium subtypes were defined based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria and the Delirium Rating Scale-98-R. A multivariate Cox proportional hazards regression analysis was used to examine predictors of mortality. RESULTS: Of the 322 cases, 98 patients (30.4%) were diagnosed as having delirium. The median (interquartile range) number of survival days after admission was 17.0 (10.0-36.0) days for patients with delirium and 28.0 (16.0-57.0) days for patients without delirium (p = .002). A multivariate analysis revealed that patients with hypoactive and mixed subtypes of delirium survived for shorter periods compared with patients without delirium (hazard ratio [HR] = 1.65 [95% confidence interval {CI} = 1.05-2.59, p = .029] and HR = 2.30 [95% CI = 1.44-3.69, p = .001], respectively). The hypoactive and mixed delirium subtypes exhibited significant interactions with age: younger age was associated with shorter periods of survival in patients with hypoactive and mixed subtype delirium (HR = 0.95 [95% CI = 0.93-0.98, p < .001] and HR = 0.97 [95% CI = 0.93-1.00, p = .038], respectively). CONCLUSIONS: The hypoactive and mixed subtypes of delirium were associated with shorter survival periods in terminally ill patients, and these associations interacted significantly with age. These findings support the clinical and academic value of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition specifiers that differentiate the diagnoses of delirium subtypes.

Prognostic significance of the concomitant existence of lymphovascular and perineural invasion in locally advanced gastric cancer patients who underwent curative gastrectomy and adjuvant chemotherapy.

OBJECTIVE: In this study, we evaluated the prognostic significance of the concomitant existence of lymphovascular invasion and perineural invasion in patients with advanced gastric cancer. METHODS: A total of 206 consecutive patients with Stage II or III gastric cancer who underwent curative D2 gastrectomy and adjuvant chemotherapy from April 2004 to December 2011 were analyzed. Patients were classified into four groups according to the presence (+) or absence (-) of lymphovascular invasion and perineural invasion: lymphovascular invasion-/perineural invasion- (n = 33), lymphovascular invasion+/perineural invasion- (n = 31), lymphovascular invasion-/perineural invasion+ (n = 54) and lymphovascular invasion+/perineural invasion+ (n = 88). RESULTS: A total of 136 patients (66.0%) received 5-fluorouracil plus cisplatin adjuvant chemotherapy and 70 patients (34.0%) received TS-1. During the median follow-up period of 35.18 months, the median disease-free survival times for lymphovascular invasion-/perineural invasion-, lymphovascular invasion+/perineural invasion- and lymphovascular invasion-/perineural invasion+ were not reached at the time of analysis; however, median disease-free survival for lymphovascular invasion+/perineural invasion+ was the worst (36.73 months, P = 0.001). The median overall survival in the four groups was also not reached at the time of analysis; however, median overall survival with lymphovascular invasion+/perineural invasion+ was the poorest (P = 0.002). In a multivariate analysis, lymphovascular invasion+/perineural invasion+ was an independent prognostic factor for both disease-free survival (hazard ratio = 1.940, 95% confidence interval 1.157-3.252, P = 0.012) and overall survival (hazard ratio = 2.973, 95% confidence interval 1.561-5.662, P = 0.001). CONCLUSIONS: The concomitant existence of lymphovascular and perineural invasion has a significant prognostic impact on disease-free survival and overall survival in patients with Stage II or III gastric cancer.

Common genetic variants at 1q22 and 10q23 and gastric cancer susceptibility in a Korean population.

Genetic variants at 1q22 and 10q23 were identified as genetic markers of both gastric cancer and esophageal squamous cell carcinoma susceptibility by two genome-wide association studies. The aim of this study was to determine whether rs4072037A > G in MUC1 at 1q22 and rs2274223A > G in PLCE1 at 10q23 are associated with a risk of gastric cancer in a Korean population. We conducted a large-scale case-control study of 3,245 patients with gastric cancer and 1,700 controls. The allele frequencies of rs4072037G and rs2274223G were 11.2 and 25.5% among patients with gastric cancer, compared with 12.8 and 26.4%, respectively, among controls. We found that the rs4072037 AG genotype was significantly associated with a reduced risk of gastric cancer [odds ratios (OR) = 0.78; 95% confidence interval (CI) = 0.67-0.91 for AG vs AA]. Compared with the rs2274223 AA genotype, we found a significant association between the rs2274223 AG genotype and a weakly reduced risk of gastric cancer (OR = 0.87; 95% CI = 0.76-0.99 for AG vs AA). Our data suggest that genetic variants at 1q22 and 10q23 play a role in gastric carcinogenesis.

Different protein expression associated with chemotherapy response in oropharyngeal cancer according to HPV status.

BACKGOUND: Oropharyngeal cancer (OPC) associated with human papilloma virus (HPV OPC) shows better treatment outcomes than non-HPV OPC. We investigated the expression of p53, ß-tubulin, bcl-2 and ERCC 1, which are well-known biomarkers to predict the chemotherapy response, according to HPV status in OPC patients. METHODS: Patients who treated with at least 2 cycles of induction chemotherapy followed by concurrent chemoradiotherapy for locally advanced oropharyngeal cancer were reviewed. HPV PCR and immunohistochemical stain was done in paraffin embedded tumor tissue and evaluated the relation with the chemotherapy response and survival outcomes according to HPV status. RESULTS: Seventy-four patients were enrolled for this study and all patients received induction chemotherapy with docetaxel, 5-FU and cisplatin. After induction chemotherapy, complete response (CR) was shown in 22 patients (30%) and partial response (PR) in 46 patients (62%). HPV + was detected in 21 patients (28%), while 35 patients (47%) showed p16+ expression by IHC analysis. p16 positive patients showed better overall response, PFS and OS than p16 negative patients. p53 and class III beta-tubulin expression were significantly higher in HPV- and p16- than HPV + and p16+ patients. Conversely, bcl-2 expression was greater in HPV + or p16+ than HPV- or p16- patients. ERCC1 expression did not differ significantly according to HPV status. In multivariate analyses, early T stage (p = 0.036) and good PS (PS 0) (p = 0.029) showed a better 3Y-PFS rate, and low p53 expression (p = 0.012) and complete response after induction chemotherapy (p = 0.026) were highly associated with 3Y-OS rate. Low expression of p53 and p16 positive patients showed significantly prolonged OS than others (p = 0.010). CONCLUSION: P53, class III beta-tubulin and bcl-2 were differently expressed in OPC according to HPV status and present study suggested the underlying mechanism of better response to chemotherapy in case of HPV OPC than non-HPV OPC. Among these biomarkers, p53 is the strongest prognostic marker in OPC and p53 in addition to p16 support the rationale to study of de-escalation strategy for OPC.

Comparative Whole-Genome Sequencing Analysis of In-situ and Invasive Acral Lentiginous Melanoma: Markedly Increased Copy Number Gains of GAB2, PAK1, UCP2, and CCND1 are Associated with Melanoma Invasion.

Acral lentiginous melanoma (ALM) is the most common subtype of acral melanoma. Even though recent genetic studies are reported in acral melanomas, the genetic differences between in-situ and invasive ALM remain unclear. We aimed to analyze specific genetic changes in ALM and compare genetic differences between in-situ and invasive lesions to identify genetic changes associated with the pathogenesis and progression of ALM. We performed whole genome sequencing of 71 tissue samples from 29 patients with ALM. Comparative analyses were performed, pairing in-situ ALMs with normal tissues and, furthermore, invasive ALMs with normal and in-situ tissues. Among 21 patients with in-situ ALMs, 3 patients (14.3%) had SMIM14, SLC9B1, FRG1, FAM205A, ESRRA, and ESPN mutations, and copy number (CN) gains were identified in only 2 patients (9.5%). Comparing 13 invasive ALMs with in-situ tissues, CN gains were identified in GAB2 in 8 patients (61.5%), PAK1 in 6 patients (46.2%), and UCP2 and CCND1 in 5 patients (38.5%). Structural variants were frequent in in-situ and invasive ALM lesions. Both in-situ and invasive ALMs had very low frequencies of common driver mutations. Structural variants were common in both in-situ and invasive ALMs. Invasive ALMs had markedly increased CN gains, such as GAB2, PAK1, UCP2, and CCND1, compared with in-situ lesions. These results suggest that they are associated with melanoma invasion.

Clinical prognostic factors to guide treatment strategy for HPV­positive oropharyngeal cancer using treatment outcomes of induction chemotherapy: A real­world experience.

The role of induction chemotherapy (IC) in locally advanced oropharyngeal cancer (OPC) remains debatable, and suitable candidates for de-escalation treatment in these patients have not been fully identified. Therefore, the present study aimed to identify high-risk candidates for human papillomavirus (HPV)-positive OPC by analyzing patients who underwent IC followed by chemoradiotherapy (CRT) to guide optimal treatment strategies. Patients diagnosed with stage III-IVA OPC and treated with a minimum of two cycles of IC followed by CRT, between 2004 and 2020, were retrospectively reviewed. All the patients were restaged according to the American Joint Committee on Cancer, 8th edition. The overall response rate and survival outcomes associated with clinical factors based on HPV status were analyzed using univariate and multivariate analyses. The present study analyzed 105 patients with a median age of 60 years (range, 40-76 years). Among 105 patients, 40 (38.1%) were HPV-negative and 65 (61.9%) HPV-positive. In all patients, survival outcomes were notably poorer in patients aged ≥60 years (P=0.006) and those who did not achieve complete response post-CRT (P<0.001), irrespective of the HPV status. The median relative dose intensity of IC was ≥80%, indicating adequate treatment, regardless of age. In contrast to patients with HPV-negative OPC, age ≥60 years (P=0.011) and T4 stage (P=0.019) emerged as substantial poor prognostic factors for survival outcomes in patients with HPV-positive OPC. Patients with HPV-positive OPC were categorized into three groups based on the number of clinical factors at diagnosis (such as age and T4 stage). The progression-free and overall survival showed significant stratification across each group as the number of high-risk factors increased despite IC and CRT. The findings indicated that patients with these high-risk factors require a cautious therapeutic strategy even when they are diagnosed with HPV-positive OPC, and the role of combined modality, including IC, will need to be investigated in a randomized trial to be routinely incorporated into clinical practice.