Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Risk factors for delirium among patients with advanced cancer in palliative care: a multicenter, patient-based registry cohort in South Korea.

OBJECTIVE: Previous studies have comprehensively investigated the prevalence and various potential risk factors for delirium among patients with advanced cancer admitted to the acute palliative care unit (APCU). Our objective was to evaluate the comprehensive association between delirium and various risk factors among patients with advanced cancer in an acute palliative care setting using a patient-based multicenter registry cohort. PATIENTS AND METHODS: We performed a multicenter, patient-based registry cohort study collected in South Korea between January 1, 2019, and December 31, 2020. Delirium was identified using a medical record review based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. RESULTS: In total, 2,124 eligible patients with advanced cancer in the APCU met the inclusion criteria. There were 127 out of 2,124 patients (prevalence, 6.0%; 95% CI, 5.0 to 7.1) with delirium during admission. Delirium in patients with advanced cancer was associated with age >70 years (OR, 1.793; 95% CI, 1.246 to 2.581), male sex (OR, 1.675; 95% CI, 1.131 to 2.479), no chemotherapy during hospitalization (OR, 2.019; 95% CI, 1.236 to 3.298), hearing impairment (OR, 3.566; 95% CI, 1.176 to 10.810), underweight (OR, 1.826; 95% CI, 1.067 to 3.124), current use of opioid medication (OR, 1.942; 95% CI, 1.264 to 2.982), previous history of delirium (OR, 12.497; 95% CI, 6.920 to 22.568), and mental illness (OR, 2.333; 95% CI, 1.251 to 4.352). CONCLUSIONS: In a large-scale multicenter patient-based registry cohort, delirium was associated with old age, male sex, no chemotherapy during hospitalization, hearing impairment, underweight, current use of opioid medication, and a history of delirium and mental illness. Our findings suggest physicians should pay attention to delirium in patients with advanced cancer admitted to the APCU with the above risk factors.

Pemetrexed plus cisplatin in patients with previously treated advanced sarcoma: a multicenter, single-arm, phase II trial.

BACKGROUND: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. We assessed the efficacy and tolerability of pemetrexed and cisplatin combination therapy in patients with refractory bone and soft tissue sarcoma (STS). PATIENTS AND METHODS: Patients were included in this multicenter, phase II study (ClinicalTrials.gov identifier NCT03809637) if they progressed after receiving one or more chemotherapy regimens containing an anthracycline and/or ifosfamide. Pemetrexed was first administered intravenously, followed by cisplatin, over a cycle of 21 days, for a maximum of six cycles. The primary endpoint was a progression-free rate (PFR) at 3 months (3-month PFR). RESULTS: From January 2017 to September 2019, we enrolled 37 patients; of these, 73% had previously undergone three or more rounds of chemotherapy. Five patients (13.5%) exhibited objective responses, including two patients (2/6, 33.3%) with malignant peripheral nerve sheath tumors, one patient (1/4, 25%) with synovial sarcoma, one patient (1/4, 25%) with undifferentiated pleomorphic sarcoma, and one patient (1/4, 25%) with angiosarcoma. The median progression-free survival was 2.6 months, and the 3-month PFR was 45.9% (n = 17). None of the four patients with osteosarcoma exhibited objective responses or were progression free at 3 months. The most frequent treatment-related grade 3-4 toxicities included neutropenia (16.2%), anemia (13.5%), thrombocytopenia (13.5%), and fatigue (8.1%). Among 26 patients (70.3%) available for immunohistochemical assessments, patients in the low-excision repair cross-complementation group 1 (ERCC1) and low-thymidylate synthase expression groups showed a tendency for longer overall survival. CONCLUSIONS: Combination therapy with pemetrexed and cisplatin was associated with clinically meaningful and sustained responses among patients with advanced and refractory STS. The combination therapy met its predefined primary study endpoint.

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy.

Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773.

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

Integration of radiotherapy and chemotherapy for abdominal lymph node recurrence in gastric cancer.

PURPOSE: Abdominal lymph node (ALN) recurrence in gastric cancer (GC) is rare and usually unresectable. We investigated the effects of integration of radiotherapy (RT) and chemotherapy against ALN recurrence in GC. METHODS: We retrospectively categorized GC patients with ALN recurrence treated between 2005 and 2013 into two groups: those treated with integration of RT and chemotherapy (RCT) and those who received systemic chemotherapy only (CT). The median follow-up period after ALN recurrence for all patients was 20 months. RESULTS: Of 53 patients, 31 and 22 were in the RCT and CT groups, respectively. Isolated distant failure (DF; 35.5%) without local progression (LP) was the dominant pattern of failure (POF) in the RCT group (median DF-free period, 26 months). LP followed by DF (31.8%) was the dominant POF in the CT group; LP (median LP-free period, 8 months) occurred 10 months earlier than DF (median DF-free period, 18 months). RCT patients had significantly longer median progression-free survival (PFS) compared to CT patients (25 vs. 8 months; P = 0.021). On multivariate analysis, treatment (CT vs. RCT) was an independent prognostic factor for PFS (hazard ratio 2.085; 95% confidence interval 1.073-4.050; P = 0.013). CONCLUSIONS: Integration of RT and chemotherapy achieved long-term local control and prolonged PFS in GC patients with ALN recurrence. Local RT is feasible for treating isolated ALN recurrences.

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Locoregional relapse after gastrectomy with D2 lymphadenectomy for gastric cancer.

BACKGROUND: Risk for and site of locoregional relapse have not been well studied in patients undergoing gastrectomy with D2 lymphadenectomy for gastric cancer. METHODS: Patients who had undergone gastrectomy with D2 lymphadenectomy for gastric cancer between 2004 and 2007 were identified from an institutional database. The locoregional relapse rate was estimated by competing risk analysis, and risk groups were derived according to locoregional relapse risk using recursive partitioning analysis (RPA). The locations of nodal relapses were evaluated according to Japanese Classification of Gastric Carcinoma criteria. RESULTS: Some 2618 patients were included. With a median follow-up of 78·0 (range 28·5-122·6) months, relapse was diagnosed in 471 of 2618 patients (18·0 per cent). The cumulative incidence of locoregional relapse at 5 years was 8·5 (95 per cent c.i. 7·4 to 9·6) per cent. The 5-year locoregional recurrence rates for high-risk (N3), intermediate-risk (N1-2) and low-risk (N0) groups were 32·4, 12·3 and 1·7 per cent respectively (P < 0·001). Among patients with regional relapse, 90·4 per cent had involvement outside the D2 dissected area, and the most commonly involved site was station 16b1. This pattern was maintained in the RPA risk groups (P = 0·329). CONCLUSION: Locoregional relapse at 5 years after gastrectomy with D2 lymphadenectomy was 8·5 per cent, and was most often seen outside the D2 dissected area.

hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness.

Stress hormones have been implicated in both tumor initiation and progression. Human telomerase reverse transcriptase (hTERT) is overexpressed in cancer cells and associated with malignant tumor progression and poor outcome. We thus sought to determine whether the stress hormone norepinephrine (NE) could induce hTERT expression and subsequently ovarian cancer progression. Unexpectedly, NE induced hTERT transcript and protein expression, and subsequently ovarian cancer cell invasion. Pharmacologic inhibition of ß2-adrenergic receptor 2 and protein kinase A, as well as silencing of hypoxia-inducible factor-1α and c-Myc expression, profoundly attenuated NE-induced hTERT expression. Strikingly, stimulation of the cells with NE or ectopic expression of hTERT induced expression of Slug, ovarian cancer cell epithelial-mesenchymal transition (EMT) and invasion. Silencing of hTERT expression abrogated NE-induced ovarian cancer cell invasion, EMT and Slug expression. In addition, silencing of Slug expression significantly inhibited NE- and hTERT-induced ovarian cancer cell EMT and invasion. Moreover, continuous exposure to NE was sufficient to enhance in vivo hTERT expression and metastasis of ovarian cancer cells to the lung. Finally, we provide evidence that hTERT links Src to Slug expression in NE-induced ovarian cancer EMT and metastasis. We thus demonstrate a novel role of hTERT in stress hormone-induced ovarian cancer aggressiveness through inducing Slug, providing novel biomarkers and potential therapeutic targets for ovarian cancer.

A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer.

BACKGROUND: Pertuzumab plus trastuzumab provides a more comprehensive blockade of HER2 signalling than trastuzumab alone. Therefore, we conducted a phase IIa study of the pharmacokinetics and safety of pertuzumab plus trastuzumab and chemotherapy in advanced gastric cancer (aGC). METHODS: Patients received pertuzumab 840 mg for cycle 1 and 420 mg q3w for cycles 2-6 (Arm A) or pertuzumab 840 mg q3w for six cycles (Arm B). Trastuzumab, cisplatin and capecitabine were also given for six cycles, then trastuzumab q3w until disease progression or unmanageable toxicity. The co-primary endpoints were day 43 pertuzumab serum trough concentration (Cmin) and safety. RESULTS: Thirty patients were randomised. Mean pertuzumab Cmin at day 43 was 40.0 µg ml(-1) (s.d.: 17.3) in Arm A and 62.7 µg ml(-1) (29.1) in Arm B. Mean day 43 Cmin in Arm A was ~37% lower than that seen in metastatic breast cancer. The safety profiles were similar between arms and treatment was well tolerated. Partial responses were achieved by 86% and 55% of patients in Arms A and B, respectively. CONCLUSIONS: On the basis of the pharmacokinetic and safety data, the 840 mg q3w pertuzumab dose has been selected for a phase III study of pertuzumab, trastuzumab and chemotherapy in HER2-positive aGC.

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC.

BACKGROUND: Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design. METHODS: Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria. RESULTS: In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months. CONCLUSIONS: Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

Anti-VEGF therapy in mRCC: differences between Asian and non-Asian patients.

BACKGROUND: Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised. METHODS: A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium. RESULTS: This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively). CONCLUSIONS: Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials.

BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Identifying genes related to radiation resistance in oral squamous cell carcinoma cell lines.

Radioresistance is one of the main determinants of treatment outcome in oral cancer, but the prediction of radioresistance is difficult. The authors aimed to establish radioresistant oral squamous cell carcinoma (OSCC) cell lines to identify genes with altered expression in response to radioresistance. To induce radioresistant cell lines, the authors treated OSCC cell lines with an accumulated dosage of 60Gy over 30 cycles of radiotherapy. They compared the results from cDNA arrays and proteomics between non-radiated and radioresistant cell lines in order to identify changes in gene expression. Western blot analysis was used to validate the results. The cDNA array revealed 265 commonly up-regulated genes and 268 commonly down-regulated genes in radioresistant cell lines, 30 of which were cancer-related genes. Proteomics identified 51 proteins with commonly altered expression in radioresistant cell lines, 18 of which were cancer-related proteins. Both the cDNA array and proteomics indicated that NM23-H1 and PA2G4 were over-expressed. Western blot analysis showed increased expression of NM23-H1, but not PA2G4, in radioresistant cell lines. The authors concluded that NM23-H1 may be a radioresistance-related gene and over-expression of NM23-H1 could serve as a biomarker to predict radioresistance in OSCC.

Phase II trial of everolimus for the treatment of nonclear-cell renal cell carcinoma.

BACKGROUND: We investigated the efficacy of everolimus against nonclear-cell renal cell carcinoma (nccRCC). Patients and methods Patients with nccRCC received 10-mg everolimus once daily until disease progression or unacceptable toxicity. PATIENTS: who had received a VEGF- tyrosine kinase inhibitor (TKI) previously were included. RESULTS: A total of 49 patients were enrolled. Twenty-three patients (46.9%) received prior anti-VEGF agents. A partial response was observed in five patients (10.2%) and stable disease in 25 patients (51.0%). The disease progressed in 16 patients (32.7%) despite the administration of everolimus. Two of the five patients who showed an objective response to everolimus had chromophobe carcinoma, whereas two had papillary carcinoma and one had unclassifiable carcinoma. Thirty-six patients experienced disease progression during follow-up, and the median progression-free survival (PFS) was 5.2 months. Chromophobe RCC patients seemed to have longer PFS than nccRCC patients with the other histological subtypes (P = 0.084). Previous VEGF-TKI treatment did not influence the efficacy of everolimus, and the toxicity profiles were in line with previous reports. CONCLUSION: Everolimus shows certain efficacy against nccRCC, particularly in patients with chromophobe RCC, and prior treatment with a VEGF-TKI appears not influencing the outcome of everolimus therapy in nccRCC patients. ClinicalTrials.gov number NCT00830895.

Evaluation of survival benefits by platinums and taxanes for an unfavourable subset of carcinoma of unknown primary: a systematic review and meta-analysis.

BACKGROUND: Although chemotherapeutic regimens containing a taxane or platinum agent have been widely recommended for unfavourable carcinoma of unknown primary (CUP), no evidence exists for the superiority of any administered regimens. To date, the efficacy has been mostly assessed in the limited setting of phase II trials, and few attempts have been made to synthesise all available data for survival outcomes. METHODS: Electronic databases were searched from 1980 to 2011. Survival results were combined for each pre-specified category of regimens using a random-effects model, and meta-regression models were used to adjust for heterogeneity in some known prognostic factors. RESULTS: A total of 32 studies were included for meta-analysis. Tendency towards better survival outcome by platinums or taxanes was indicated. After adjustment for important prognostic factors, however, the difference between the platinum-based and non-platinum regimens became no longer significant. Survival benefits by the taxane-based regimens remained significant, with a prolonged median survival time of 1.52 months (P=0.03) and a higher 1-year survival rate of 6.25% (P=0.05), but the benefit did not sustain for 2 years. CONCLUSION: Although no effective therapies have been established, this meta-analysis helps to fill an important gap of evidence. However, caution should still be taken because of the potential unmeasured confounding.

External validation of nomogram for the prediction of recurrence after curative resection in early gastric cancer.

BACKGROUND: Nomograms are statistics-based tools that provide the overall probability of a specific outcome. In our previous study, we developed a nomogram that predicts recurrence of early gastric cancer (EGC) after curative resection. We carried out this study to externally validate our EGC nomogram. PATIENTS AND METHODS: The EGC nomogram was established from a retrospective EGC database that included 2923 consecutive patients. This nomogram was independently externally validated for a cohort of 1058 consecutive patients. For the EGC nomogram validation, we assessed both discrimination and calibration. RESULTS: Within the follow-up period (median 37 months), a total of 11 patients (1.1%) experienced recurrence. The concordance index (c-index) was 0.7 (P = 0.02) and the result of the overall C index was 0.82 [P = 0.006, 95% confidence interval (CI) 0.59-1.00]. The goodness of fit test showed that the EGC nomogram had significantly good fit for 1- and 2-year survival intervals (P = 0.998 and 0.879, respectively). The actual and predicted survival outcomes showed good agreement, suggesting that the survival predictions from the nomogram are well calibrated externally. CONCLUSIONS: A preexisting nomogram for predicting disease-free survival (DFS) of EGC after surgery was externally validated. The nomogram is useful for accurate and individual prediction of DFS, patient prognostication, counseling, and follow-up planning.

Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer.

Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2'-deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.

DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers.

Promoter CpG methylation of tumour suppressor genes (TSGs) is an epigenetic biomarker for TSG identification and molecular diagnosis. We screened genome wide for novel methylated genes through methylation subtraction of a genetic demethylation model of colon cancer (double knockout of DNMT1 and DNMT3B in HCT116) and identified DLEC1 (Deleted in lung and oesophageal cancer 1), a major 3p22.3 TSG, as one of the methylated targets. We further found that DLEC1 was downregulated or silenced in most colorectal and gastric cell lines due to promoter methylation, whereas broadly expressed in normal tissues including colon and stomach, and unmethylated in expressing cell lines and immortalised normal colon epithelial cells. DLEC1 expression was reactivated through pharmacologic or genetic demethylation, indicating a DNMT1/DNMT3B-mediated methylation silencing. Aberrant methylation was further detected in primary colorectal (10 out of 34, 29%) and gastric tumours (30 out of 89, 34%), but seldom in paired normal colon (0 out of 17) and gastric (1 out of 20, 5%) samples. No correlation between DLEC1 methylation and clinical parameters of gastric cancers was found. Ectopic expression of DLEC1 in silenced HCT116 and MKN45 cells strongly inhibited their clonogenicity. Thus, DLEC1 is a functional tumour suppressor, being frequently silenced by epigenetic mechanism in gastrointestinal tumours.