pinecone/core-2020-05-10-deduplication huggingface dataset:
Nationwide trends in chemotherapy use and survival of elderly patients with metastatic pancreatic cancer

Despite an aging population and underrepresentation of elderly patients in clinical trials, studies on elderly patients with metastatic pancreatic cancer are scarce. This study investigated the use of chemotherapy and survival in elderly patients with metastatic pancreatic cancer. From the Netherlands Cancer Registry, all 9407 patients diagnosed with primary metastatic pancreatic adenocarcinoma in 2005–2013 were selected to investigate chemotherapy use and overall survival (OS), using Kaplan–Meier and Cox proportional hazard regression analyses. Over time, chemotherapy use increased in all age groups (<70 years: from 26 to 43%, 70–74 years: 14 to 25%, 75–79 years: 5 to 13%, all P < 0.001, and ≥80 years: 2 to 3% P = 0.56). Median age of 2,180 patients who received chemotherapy was 63 years (range 21–86 years, 1.6% was ≥80 years). In chemotherapy-treated patients, with rising age (<70, 70–74, 75–79, ≥80 years), microscopic tumor verification occurred less frequently (91-88-87-77%, respectively, P = 0.009) and OS diminished (median 25-26-19-16 weeks, P = 0.003). After adjustment for confounding factors, worse survival of treated patients ≥75 years persisted. Despite limited chemotherapy use in elderly age, suggestive of strong selection, elderly patients (≥75 years) who received chemotherapy for metastatic pancreatic cancer exhibited a worse survival compared to younger patients receiving chemotherapy
5-Chloro-2,4-dihydroxypyridine, CDHP, prevents lung metastasis of basal-like breast cancer cells by reducing nascent adhesion formation

A drug for metastasis prevention is necessary. The orally administered anticancer drug S‐1 contributes to cancer therapy. In a mouse xenograft model of metastatic breast cancer from our previous study, the administration of S‐1 inhibited lung metastasis. However, the mechanism of inhibition remains elusive. S‐1 contains 5‐chloro‐2, 4‐dihydroxypyridine (CDHP), which does not have the antigrowth activity, but prevents the degradation of 5‐fluorouracil, an anticancer reagent. In this study, we found that CDHP treatment shrinks cell morphology in metastatic basal‐like breast cancer cell lines. Wound healing assays showed reduced cell migration in CDHP‐treated cells. At the molecular level, CDHP treatment reduced the number of nascent adhesions, whereas the number of mature focal adhesions was not changed. These findings indicate that CDHP impairs focal adhesion formation, which results in a reduction in cell migration. For the in vivo metastasis assay, we used a highly lung‐metastatic cell line. We xenografted them into immunodeficient mice, and administered CDHP. To determine whether CDHP prevents metastasis, we measured the weights of harvested lungs. The results showed that the lung weights of the CDHP‐treated animals were not significantly different compared to the no‐tumor controls, whereas the vehicle group showed a number of metastatic foci and an increase in lung weight. These observations indicate that CDHP administration prevents metastasis. This study reveals a novel effect of CDHP for lung metastasis prevention. Our findings may facilitate the establishment of future metastasis prevention therapies
The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non–small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB‐resistant (VR) lung cancer cells (NCI‐H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP‐binding Cassette Sub‐family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB‐resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies
SALL4 - KHDRBS3 network enhances stemness by modulating CD44 splicing in basal-like breast cancer

Understanding the mechanism by which cancer cells enhance stemness facilitates cancer therapies. Here, we revealed that a stem cell transcription factor, SALL4, functions to enhance stemness in basal‐like breast cancer cells. We used shRNA‐mediated knockdown and gene overexpression systems to analyze gene functions. To evaluate stemness, we performed a sphere formation assay. In SALL4 knockdown cells, the sphere formation ability was reduced, indicating that SALL4 enhances stemness. CD44 is a membrane protein and is known as a stemness factor in cancer. CD44 splicing variants are involved in cancer stemness. We discovered that SALL4 modulates CD44 alternative splicing through the upregulation of KHDRBS3, a splicing factor for CD44. We cloned the KHDRBS3‐regulated CD44 splicing isoform (CD44v), which lacks exons 8 and 9. CD44v overexpression prevented a reduction in the sphere formation ability by KHDRBS3 knockdown, indicating that CD44v is positively involved in cancer stemness. In addition, CD44v enhanced anoikis resistance under the control of the SALL4 ‐ KHDRBS3 network. Basal‐like breast cancer is an aggressive subtype among breast cancers, and there is no effective therapy so far. Our findings provide molecular targets for basal‐like breast cancer therapy. In the future, this study may contribute to the establishment of drugs targeting cancer stemness
Long‐term outcomes of proton therapy for prostate cancer in Japan: a multi‐institutional survey of the Japanese Radiation Oncology Study Group

This is the first multi‐institutional retrospective survey of the long‐term outcomes of proton therapy (PT) for prostate cancer in Japan. This retrospective analysis comprised prostate cancer patients treated with PT at seven centers between January 2008 and December 2011 and was approved by each Institutional Review Board. The NCCN classification was used. Biochemical relapse was based on the Phoenix definition (nadir + 2.0 ng/mL). Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. There were 215, 520, and 556 patients in the low‐risk, intermediate‐risk, and high‐risk groups, respectively. The median follow‐up period of surviving patients was 69 months (range: 7–107). Among all patients, 98.8% were treated using a conventional fractionation schedule and 1.2% with a hypofractionation schedule; 58.5% and 21.5% received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The 5‐year biochemical relapse‐free survival (bRFS) and overall survival rates in the low‐risk, intermediate‐risk, and high‐risk groups were 97.0%, 91.1%, and 83.1%, and 98.4%, 96.8%, and 95.2%, respectively. In the multivariate analysis, the NCCN classification was a significant prognostic factor for bRFS, but not overall survival. The incidence rates of grade 2 or more severe late gastrointestinal and genitourinary toxicities were 4.1% and 4.0%, retrospectively. This retrospective analysis of a multi‐institutional survey suggested that PT is effective and well‐tolerated for prostate cancer. Based on this result, a multi‐institutional prospective clinical trial (UMIN000025453) on PT for prostate cancer has just been initiated in order to define its role in Japan
Socioeconomic and demographic inequalities in stage at diagnosis and survival among colorectal cancer patients: evidence from a Swiss population-based study.

Socioeconomic inequalities in cancer stage at diagnosis and survival are important public health issues. This study investigates the association between socioeconomic position (SEP) and colorectal cancer (CRC) stage at diagnosis and survival in Switzerland, a European country with highest level of medical facilities and life expectancy. We used population-based CRC data from seven Swiss cantonal cancer registries 2001-2008 (N = 10,088) linked to the Swiss National Cohort (SNC). Follow-up information was available until the end of 2013. SEP was estimated based on education. The association between cancer stage and SEP was assessed using logistic regression models including cancer localization (colon/rectum), sex, age, civil status, urbanity of residence, language region, and nationality (Swiss/non-Swiss). Survival was analyzed using competing risk regressions reporting subhazard ratios (SHRs) for the risk of dying due to CRC. We observed a social gradient for later stage CRC with adjusted odds ratios (ORs) of 1.11 (95% CI: 0.97-1.19) and 1.28 (95% CI: 1.08-1.50) for middle and low SEP compared to high SEP. Further, single compared to married people had elevated odds of being diagnosed at later stages. Survival was lower in patients with CRC with low SEP in the unadjusted model (SHR: 1.18, 95% CI: 1.07-1.30). After adjustment for stage at diagnosis and further sociodemographic characteristics, significant survival inequalities by SEP disappeared but remained for non-Swiss compared to Swiss citizens and for patients living in nonurban areas compared to their urban counterparts. Swiss public health strategies should facilitate equal access to CRC screening and optimal CRC care for all social groups and in all regions of Switzerland
Ipilimumab and radiation therapy for melanoma brain metastases

Ipilimumab, an antibody that enhances T‐cell activation, may augment immunogenicity of tumor cells that are injured by radiation therapy. We hypothesized that patients with melanoma brain metastasis treated with both ipilimumab and radiotherapy would have improved overall survival, and that the sequence of treatments may affect disease control in the brain. We analyzed the clinical and radiographic records of melanoma patients with brain metastases who were treated with whole brain radiation therapy or stereotactic radiosurgery between 2005 and 2012. The hazard ratios for survival were estimated to assess outcomes as a function of ipilimumab use and radiation type. Seventy patients were identified, 33 of whom received ipilimumab and 37 who did not. The patients who received ipilimumab had a censored median survival of 18.3 months (95% confidence interval 8.1–25.5), compared with 5.3 months (95% confidence interval 4.0–7.6) for patients who did not receive ipilimumab. Ipilimumab and stereotactic radiosurgery were each significant predictors of improved overall survival (hazard ratio = 0.43 and 0.45, with  P  = 0.005 and 0.008, respectively). Four of 10 evaluable patients (40.0%) who received ipilimumab prior to radiotherapy demonstrated a partial response to radiotherapy, compared with two of 22 evaluable patients (9.1%) who did not receive ipilimumab. Ipilimumab is associated with a significantly reduced risk of death in patients with melanoma brain metastases who underwent radiotherapy, and this finding supports the need for multimodality therapy to optimize patient outcomes. Prospective studies are needed and are underway.    Treatment with ipilimumab significantly reduced the risk of death by 57% in patients with brain metastases due to melanoma who underwent whole brain radiation therapy or stereotactic radiosurgery ( SRS ). Patients who were treated with  SRS  and ipilimumab had a 16‐month improvement in survival as compared to those who received  SRS  alone
Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses

Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (r = 0.23, P = 9.3 × 10 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10 ) and concordance in effect direction (P = 2.0 × 10 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.status: accepte
BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1

The bromodomain and extra terminal (BET) family protein bromodomain containing protein 4 (BRD4) is an epigenetic regulator recently identified as a therapeutic target for several hematological cancers, notably mixed lineage leukemia-fusion acute myeloid leukemia (MLL-AML). Here, we show that the BRD4 bromodomain inhibitor JQ1 is highly active against the p53-wild-type Ontario Cancer Institute (OCI)-AML3 cell line which carries mutations in nucleophosmin (NPM1) and DNA methyltransferase 3 (DNMT3A) genes commonly associated with poor prognostic disease. We find that JQ1 causes caspase 3/7-mediated apoptosis and DNA damage response in these cells. In combination studies, we show that histone deacetylase (HDAC) inhibitors, the HDM2 inhibitor Nutlin-3, and the anthracycline daunorubicin all enhance the apoptotic response of JQ1. These compounds all induce activation of p53 suggesting that JQ1 might sensitize AML cells to p53-mediated cell death. In further experiments, we show that BRD4 associates with acetylated p53 but that this association is not inhibited by JQ1 indicating that the protein-protein interaction does not involve bromodomain binding of acetylated lysines. Instead, we propose that JQ1 acts to prevent BRD4-mediated recruitment of p53 to chromatin targets following its activation in OCI-AML3 cells resulting in cell cycle arrest and apoptosis in a c-MYC-independent manner. Our data suggest that BET bromodomain inhibition might enhance current chemotherapy strategies in AML, notably in poor-risk DNMT3A/NPM1-mutated disease
Preliminary results of proton radiotherapy for pediatric rhabdomyosarcoma: a multi-institutional study in Japan

To evaluate preliminary results of proton radiotherapy (PRT) for pediatric patients with rhabdomyosarcoma (RMS). From 1987 to 2014, PRT was conducted as initial radiotherapy in 55 patients (35 males, 20 females, median age 5 years, range 0–19) with RMS at four institutes in Japan. Thirty‐one, 18, and six patients had embryonal, alveolar, and other RMS, respectively. One, 11, 37, and six patients were in IRSG groups I, II, III, and IV, respectively, and the COG risk group was low, intermediate, and high for nine, 39, and seven patients, respectively. The irradiation dose was 36–60 GyE (median: 50.4 GyE). The median follow‐up period was 24.5 months (range: 1.5–320.3). The 1‐ and 2‐year overall survival rates were 91.9% (95% CI: 84.3–99.5%) and 84.8% (95% CI 75.2–94.3%), respectively, and these rates were 100% and 100%, 97.1% and 90.1%, and 57.1% and 42.9% for COG low‐, intermediate‐, and high‐risk groups, respectively. There were 153 adverse events of Grade ≥3, including 141 hematologic toxicities in 48 patients (87%) and 12 radiation‐induced toxicities in nine patients (16%). Proton‐specific toxicity was not observed. PRT has the same treatment effect as photon radiotherapy with tolerable acute radiation‐induced toxicity
ADAM 17‐mediated  CD 44 cleavage promotes orasphere formation or stemness and tumorigenesis in  HNSCC

CD 44, an extracellular matrix ( ECM ) receptor, has been described as a cancer stem cell marker in multiple cancers, including head and neck squamous cell carcinoma ( HNSCC ).  HNSCC  orasphere formation or stemness was characterized by cleavage of  CD 44, and thus we hypothesized that this proteolytic processing may be critical to stemness and tumorigenesis. We tested this hypothesis by examining the mechanisms that regulate this process in vitro and in vivo, and by exploring its clinical relevance in human specimens. Sphere assays have been used to evaluate stemness in vitro. Spheres comprised of  HNSCC  cells or oraspheres and an oral cancer mouse model were used to examine the significance of  CD 44 cleavage using stable suppression and inhibition approaches. These mechanisms were also examined in  HNSCC  specimens. Oraspheres exhibited increased levels of  CD 44 cleavage compared to their adherent counterparts. Given that disintegrin and metalloproteinase domain‐containing protein 17 (ADAM17) is a major matrix metalloproteinase known to cleave  CD 44, we chemically inhibited and stably suppressed  ADAM 17 expression in  HNSCC  cells and found that these treatments blocked  CD 44 cleavage and abrogated orasphere formation. Furthermore, stable suppression of  ADAM 17 in  HNSCC  cells also diminished tumorigenesis in an oral cancer mouse model. Consistently, stable suppression of  CD 44 in  HNSCC  cells abrogated orasphere formation and inhibited tumorigenesis in vivo. The clinical relevance of these findings was confirmed in matched primary and metastatic human  HNSCC  specimens, which exhibited increased levels of  ADAM 17 expression and concomitant  CD 44 cleavage compared to controls.  CD 44 cleavage by  ADAM 17 is critical to orasphere formation or stemness and  HNSCC  tumorigenesis.    Our data demonstrate, for the first time that CD44 cleavage by ADAM17 is a critical determinant of orasphere formation or stemness and tumorigenesis in oral cancer. Our data support the concept that therapeutics that target CD44 cleavage mechanisms within the stem cell compartment can impair stemness and thus hold promise for treating aggressive oral cancer
A multicenter phase II trial of neoadjuvant letrozole plus low-dose cyclophosphamide in postmenopausal patients with estrogen receptor-positive breast cancer (JBCRG-07): therapeutic efficacy and clinical implications of circulating endothelial cells

Neoadjuvant endocrine therapy has been reported to decrease tumor size, which leads to increased breast conservation rates. To improve the clinical response, metronomic chemotherapy with endocrine therapy is a promising strategy. A multicenter phase II single‐arm neoadjuvant trial with letrozole and cyclophosphamide was conducted. Eligibility criteria included postmenopausal status, T2–4 N0–1, and estrogen receptor‐positive breast carcinoma. Letrozole (2.5 mg) plus cyclophosphamide (50 mg) was given orally once a day for 24 weeks. The primary endpoint was the clinical response rate (CRR). To investigate anti‐angiogenic effects, circulating endothelial cells (CECs) were quantified using the CellSearch system. From October 2007 to March 2010, 41 patients were enrolled. The CRR was 67.5% (52.0–80.0%), which was above the prespecified threshold (65%). The conversion rate from total mastectomy to breast‐conserving surgery was 64% (18/28). Grade 3 or greater nonhematological toxicity was not reported. Clinical response was associated with improved disease‐free survival (DFS) (P = 0.020). The increase in CEC counts at 8 weeks was observed in nonresponders (P = 0.004) but not in responders. Patients with higher CEC counts at baseline or post‐treatment showed worse DFS than those with lower counts (P < 0.001 at baseline and = 0.014 post‐treatment). Multivariate analysis showed that post‐treatment CEC counts but not pretreatment counts were independently correlated with DFS (P = 0.046). In conclusion, neoadjuvant letrozole plus cyclophosphamide showed a good clinical response for postmenopausal patients with estrogen receptor‐positive breast cancer. CEC quantification is a promising tool for treatment monitoring and prognostic stratification for metronomic therapy following validation of our results in larger studies. Clinical trial registration number: UMIN000001331 Phase II study of neoadjuvant letrozole combined with low‐dose metronomic cyclophosphamide for postmenopausal women with endocrine‐responsive breast cancer (JBCRG‐07
Expression profiling of cervical cancers in  I ndian women at different stages to identify gene signatures during progression of the disease

Cervical cancer is the second most common cancer among women worldwide, with developing countries accounting for >80% of the disease burden. Although in the West, active screening has been instrumental in reducing the incidence of cervical cancer, disease management is hampered due to lack of biomarkers for disease progression and defined therapeutic targets. Here we carried out gene expression profiling of 29 cervical cancer tissues from  I ndian women, spanning International Federation of Gynaecology and Obstetrics ( FIGO ) stages of the disease from early lesion (IA and IIA) to progressive stages (IIB and IIIA–B), and identified distinct gene expression signatures. Overall, metabolic pathways, pathways in cancer and signaling pathways were found to be significantly upregulated, while focal adhesion, cytokine–cytokine receptor interaction and  WNT  signaling were downregulated. Additionally, we identified candidate biomarkers of disease progression such as  SPP 1, proliferating cell nuclear antigen ( PCNA ),  STK 17A, and  DUSP 1 among others that were validated by quantitative real‐time polymerase chain reaction ( qRT ‐ PCR ) in the samples used for microarray studies as well in an independent set of 34 additional samples. Integrative analysis of our results with other cervical cancer profiling studies could facilitate the development of multiplex diagnostic markers of cervical cancer progression.    Cervical cancer is the leading cause of cancer deaths among women in  I ndia, yet it remains poorly characterized at molecular level. This study provides one of the largest molecular profiling efforts from this region involving cervical cancer tissues from well‐defined clinical stages to identify molecular signatures of disease progression, as well as identify novel biomarkers distinguishing early and advanced disease. We expect this study to serve as a template for larger studies, including those based on high‐throughput sequencing, to help develop robust biomarkers of disease progression and potentially identify actionable therapeutic targets