tbuckley/cabot-search huggingface dataset:
Long-term progression-free survival (PFS) and overall survival (OS) to pemetrexed (P) as single agent in metastatic urothelial carcinoma (MUC): A Spanish Oncology Genitourinary Group (SOGUG) systematic review.
Authors: J. M. Cervera Grau, Enrique Gonzalez-Billalabeitia, Francisco Ayala, Inmaculada Ballester Navarro, Antonio Lopez, Javier Garde, Oscar Juan Vidal, Jose Manuel Satre, Enrique Barrajon, Gaspar Esquerdo, Carmen Molins, Sonia Maciá, Christian Diego Rolfo, Macarena Paz Espinoza Venegas
Journal: Journal of Clinical Oncology (2012)

4587 Background: The effect of pemetrexed in MUC is not well characterized. Vinflunine is the standar second-line in MUC with adjusted benefits and no more drugs have been aproved. SOGUG reports a systematic review of MUC patient series with high activity of P in monotherapy. Methods: Patients with locally advanced urothelial carcinoma and/or MUC whom received P 500 mg/m(2) every 21 days with folic acid and vitamin B12 supplementation, were elected. These patients received P in second, third or fourth-line of chemotherapy. Results: 44 patients have been reported (39males), median age 62 [41-82]. Of all 44 patients; 21, 22, and 1 patients received P as second-line, third and fourth-line respectively. A median of 4 courses were administered [1-12] and disease control (SD+PR+CR) was achieved in 19 patients for an overall control rate of 43.2%. Four groups with significant differences in PFS (p=.033) were established (1.bone-metastasis, 2.visceral-metastasis, 3. nodal-visceral-metastasis and 4.nodal-metastasis). OS was significant between 2 nd and 4 th group (p=.036) . Mean PFS and OS were 125days [17-606] and 219days [17-1168] respectively for all 44 patients. Mean PFS and OS of 8 patients with bone metastasis were 75 days and 134 days. Mean PFS and OS of 10 patients with visceral metastasis were 65 days and 144 days. Mean PFS and OS of 8 patiens with nodal+visceral metastasis were 154 and 228 days. Mean PFS and OS of 18 patients with nodal metastasis were 166 days and 299 days. Conclusions: Our longer and multicenter follow-up shows that single agent P in monotherapy as second, third and fourth line in MUC is associated with high activity and long-time survival specially in metastatic nodal MUC. These results suggest that P as monotherapy requires to be further studied, more patients are being collected.
Family history of lung cancer in never smokers with non-small cell lung cancer (NSCLC) and its association with tumors harboring epidermal growth factor receptor (<i>EGFR)</i> mutations.
Authors: Elizabeth Mary Gaughan, Sarah K Cryer, Beow Yong Yeap, David Michael Jackman, Daniel Botelho Costa
Journal: Journal of Clinical Oncology (2012)

7579 Background: Inherited susceptibility to lung cancer is an understudied subject, however it has been described among never smokers (&lt;100 cigarettes/lifetime). Never smokers with NSCLC comprise an important subgroup of patients enriched for tumors harboring oncogene aberrations in the EGFR and ALK genes. We aimed to better characterize the incidence of family history of lung cancer in the setting of routine tumor genotyping among never smokers with NSCLC. Methods: Clinicopathologic data plus tumor genotype (EGFR, KRAS, ALK) from 230 consecutive never smokers seen at Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute was compiled. We retrospectively analyzed the incidence of a family history of any cancer and lung cancer in these patients. Results: In our cohort, the average age was 56 years, 67% of the patients were women, 75% were white, 41% had advanced NSCLC and 87% had adenocarcinoma histology. In these tumors, 98/230 (43%) had an EGFR mutation, 16/155 (10%) had KRAS mutations and 27/127 (17%) had an ALK translocation. Family history of any cancer was common (57%) and specific family history of lung cancer was present in 42/230 cases (18%). Out of thecases with a family history of any cancer, 22/53 (41.5%) EGFR-mutated, 1/6 (17%) KRAS-mutated and 3/20 (15%) ALK-translocated cohorts had a family history of lung cancer. The rate of family history of lung cancer to family history of cancer was significantly higher in the EGFR-mutated cohort when compared to the ALK translocated plus KRAS-mutated cohorts (p=0.023). Conclusions: Family history of lung cancer is common in never smokers with NSCLC, and there seems to be a particular link in families in which the proband has an EGFR-mutated tumor. Further study of families with EGFR-mutated NSCLC may yield insights into the pathogenesis of this tumor type.
A multinational phase III randomized trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small cell lung cancer (CCheIN).
Authors: Keunchil Park, Yong Chan Ahn, Jin Seok Ahn, Myung-Ju Ahn, Joo-Hang Kim, Eun Kyung Cho, Kyu Chan Lee, Chang Geol Lee, Ming Chen, Dae Seog Heo, Hoon-Kyo Kim, Young Joo Min, Jin Hyoung Kang, Jin-Hyuk Choi, Sang-We Kim, Guangying Zhu, Yi-Long Wu, Sung Rok Kim, Kyung Hee Lee, Hong-Suk Song
Journal: Journal of Clinical Oncology (2014)

7500 Background: Currently, the recommended treatment for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT). The efficacy of consolidation chemotherapy after CCRT needs to be confirmed. The aim of this phase III randomized trial is to determine the efficacy of consolidation chemotherapy with docetaxel (D) and cisplatin (P) following definitive CCRT with the same agents in stage III inoperable NSCLC. Methods: Patients with inoperable stage III NSCLC were randomized to either CCRT alone (observation arm) or CCRT followed by consolidation chemotherapy (consolidation arm). N2 or N3 disease was confirmed by PET and/or pathology. CCRT with D (20 mg/m2) and P (20 mg/m2) was administered every week for 6 weeks with a total dose of 66 Gy of thoracic RT as 33 fractions. In the consolidation arm, patients were further treated with 3 cycles of D and P (35 mg/m2each on day 1 and 8, every 3 weeks). The primary endpoint is progression-free survival (PFS). The secondary endpoints are overall survival, response rate, pattern of failure, and safety. Total target number of patients is 434. Results: From Oct 2005 to Apr 2011, 437 patients were enrolled and randomized. 419 patients completed CCRT phase (intent-to-treat population; observation 208, consolidation 211). Patients’ characteristics were well-balanced in both arms. In the consolidation arm, 142 patients (67%) received consolidation chemotherapy, of whom 95 (67%) completed 3 planned cycles. The median PFS was 8.0 months (95% CI, 7.5 ~ 8.8) in the observation arm and 9.1 months (95% CI, 7.9 ~ 10.9) in the consolidation arm (P=0.38). Median overall survival was 20.6 (95% CI, 17.5 ~ 26.3) and 21.2 months (95% CI, 17.7 ~ 24.7), respectively (P=0.48). Exploratory biomarker study using tissue and blood is under way. Conclusions: This study suggests that consolidation chemotherapy with DP after CCRT with weekly DP in stage III NSCLC does not prolong PFS. Clinical trial information: NCT00326378.
The special needs of children and women
Authors: John Seaman, Sarah Maguire
Journal: BMJ (2005)

Children are more vulnerable to communicable diseases and environmental exposure than adults, have special dietary needs, and are generally dependent on their family for their material and emotional support.

Many of the most severe emergencies occur in poor countries. Poverty tends to exacerbate the impact of emergencies of all types: poor people live in low quality, damage-prone housing, often on marginal land at risk of landslide or flood. The children of the poor tend to have low nutritional status, increased exposure to communicable disease, low immunisation rates, high levels of intestinal parasites, and limited access to health care.

### Earthquakes, floods, and other physical shocks

Trauma in these events may affect children disproportionally. In the 1976 Guatemala earthquake child mortality was generally higher than that of adults, but low in those less than 1 year old, attributed to the fact infants slept with their mother and were thus protected. Serious injury increased steadily with age, an effect assumed to result from the greater susceptibility to injury with increasing age.

View this table:

Risk assessment for humanitarian emergencies



In the 1971 Bangladesh cyclone children aged less than 10 years made up about a third of the population but accounted for half of all deaths. Many people survived this storm by clinging to trees. Mortality was particularly high in young children and in women older than 15 years, probably because of women trying to protect small children, the relative physical weakness of these groups, and the effects of exposure as the cyclone continued for many hours.

### Economic consequences of disasters

The economic impact on families affected by disasters may be considerable. Houses, standing crops, domestic food stocks, livestock, and goods may be lost.

Crop failure and an increase in the price of food may lead to famine. The initial damage is often …
Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice
Authors: Chen-Ching Yuan, Katarzyna Kazmierczak, Jingsheng Liang, Rosemeire Kanashiro-Takeuchi, Thomas C. Irving, Aldrin V. Gomes, Yihua Wang, Thomas P. Burghardt, Danuta Szczesna-Cordary
Journal: Cardiovascular Research (2017)

The E143K (Glu → Lys) mutation in the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans, but the mechanisms that underlie the development of defective cardiac function are unknown. Using transgenic E143K-RCM mice, we sought to determine the molecular and cellular triggers of E143K-induced heart remodelling.The E143K-induced abnormalities in cardiac function and morphology observed by echocardiography and invasive haemodynamics were paralleled by augmented active and passive tension measured in skinned papillary muscle fibres compared with wild-type (WT)-generated force. In vitro, E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin, increased actin-activated ATPase activity and slower rates of ATP-dependent dissociation of the acto-myosin complex, indicating an E143K-induced myosin hypercontractility. E143K was also observed to reduce the level of myosin regulatory light chain phosphorylation while that of troponin-I remained unchanged. Small-angle X-ray diffraction data showed a decrease in the filament lattice spacing (d1,0) with no changes in the equatorial reflections intensity ratios (I1,1/I1,0) in E143K vs. WT skinned papillary muscles. The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals and these changes were hypothesized to contribute to diastolic disturbance and to mild systolic dysfunction. Gene expression profiles of E143K-hearts supported the histopathology results and showed an upregulation of stress-response and collagen genes. Finally, proteomic analysis evidenced RCM-dependent metabolic adaptations and higher energy demands in E143K vs. WT hearts.As a result of the E143K-induced myosin hypercontractility, the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles and physiological, morphologic, and metabolic remodelling consistent with the development of RCM. Future efforts should be directed toward normalization of myosin motor function and the use of myosin-specific therapeutics to avert the hypercontractile state of E143K-myosin and prevent pathological cardiac remodelling.
Molecular profiling of tumour budding to implicate TGF-β mediated epithelial-mesenchymal transition as a therapeutic target.
Authors: David Hebbelstrup Jensen, Erik Dabelsteen, Lena Specht, anne-Marie Kanstrup Fiehn, Marianne Hamilton Therkildsen, Finn Cilius Nielsen, Lars Joenson, Jonas Vikesaa, Christian von Buchwald
Journal: Journal of Clinical Oncology (2015)

6059 Background: Tumor budding is an adverse prognostic factor in many types of cancer and understanding of the molecular basis of this phenomenon may provide new therapeutic options. Methods: The number of tumor buds in 199 oral squamous cell carcinoma (OSCC) patients was correlated to metastases, disease-free and overall survival. Tumor buds and paired central-tumor areas were laser-capture-microdissected from 5 OSCC specimens and examined with RNA-sequencing and miRNA-qPCR arrays. Results were validated with immunohistochemistry in 199 and in situ hybridization (ISH) in 20 OSCC samples. Results: The number of tumor buds was predictive of the presence of lymph node metastasis at presentation, and was an independent predictor of overall survival. Compared to cells in the central parts of the tumors, budding cells exhibited a particular gene expression signature comprising factors involved in epithelial-to-mesenchymal transition (EMT) and activated TGF-β signaling. Transcription factors ZEB1 and PRRX1 were upregulated concomitantly with a decreased expression of mesenchymal-to-epithelial (MET) transcription factors such as OVOL1 in addition to Krüppel-like factors and Grainyhead-like factors. Moreover, the miR-200 family members, was identified to be down-regulated in budding tumor cells. Five markers of the EMT/MET process were validated with immunohistochemistry and ISH. Conclusions: Taken together the results imply that therapeutics based on the inhibition of TGF-β signaling may prove useful in the treatment of oral squamous cancers.
A productive NHS
Authors: Gareth Iacobucci
Journal: BMJ (2017)

As the NHS in England grapples with the longest funding squeeze in its history, the quest for greater productivity becomes ever more pressing.

Two new analyses published this week show that the productivity of consultants in NHS hospitals has fallen over the past six years. The authors reject any notion that this means doctors need to work harder but argue that we need to rethink how we seek and measure productivity in the NHS.

In his latest data briefing John Appleby crunches …
A prospective study of family conferences (FCs) in a palliative care unit (PCU) at a comprehensive cancer center.
Authors: Rony Dev, Luke C Coulson, Kalyan Pulivarthi, Egidio Del Fabbro, Shana L. Palla, Sriram Yennurajalingam, Eduardo Bruera
Journal: Journal of Clinical Oncology (2012)

9127 Background: TheFC provides the family information and emotional support in the transition to end-of-life care. There are a few, mainly qualitative, studies of FCs in a palliative care setting. A retrospective report suggested increased emotional expression by family members when patients were not present in the FC. The purpose of our study was to determine the characteristics of FCs and the effect of patient participation on emotional expression by family members. Methods: A prospective study was conducted during 18-month period with140 consecutive FCs conducted by an interdisciplinary team (palliative care physician, social worker, and others). Data collected included demographics, discharge disposition, number of participants, caregiver characteristics, expressions of emotional distress, conflict with healthcare providers, and topics discussed. Descriptive statistics and frequencies were calculated. Analysis was performed using a chi-square test. Results: 70 patients (50%) were female, 64 (46%) white, 127 (91%) with solid tumors and a median age of 59. In 68/140 family meetings (49%), patients actively participated. The primary caregivers were predominantly female (66%), white (49%), and either the spouse or partner (59%). A median number of 4 family members and 4 healthcare providers attended the FCs with median duration of 1 hour and median of 2 days prior to discharge. Questions concerning advanced directives, symptoms anticipated at death and caregiver well-being were infrequent. Patients verbalized distress frequently, (73.1%). Primary caregivers emotional expression of verbal distress were high but not significantly affected by patient presence (82% vs 82%, P:NS); however, verbal expressions of emotional distress by family were more common when patients were absent (87%) than when present (73%), p = 0.037. Conclusions: There was a high frequency of expression of emotional distress by patients and family members. Patient participation was associated with decreased verbal emotional expression by family members but not the primary caregiver. Further studies are needed on the benefits of allocating additional time to meet with family members without patient presence during a FC.
Contents, Vol. 10, 1962
Authors: A A N N E L L , Uppsala, Wien Aruso, K F I E R Z ,, S F O U Lk E S, London, V F R A N K L , Wien, T F R E N C H , Chicago, Wien Hoff, Jy M E N G , Basel, Heidelberg Oor, Zürich M O Ren O , Beacon, M Boss, Marseille S C H U L T Z , Berlin, C Se G U In, Sào Paulo, S La V So N, E S P E E R , Lindau, New York, N St R O T Z K A , Wien, I S Ü K R Ü A, Brin Tanner
Journal: Psychotherapy and Psychosomatics (1962)
Schizophrenia and substance use comorbidity: a genome-wide perspective
Authors: Renato Polimanti, Arpana Agrawal, Joel Gelernter
Journal: Genome Medicine (2017)

Dual diagnosis with substance use disorders (SUDs) consistently contributes to the premature mortality and increased disability observed in schizophrenia. Large genome-wide association studies are providing the information needed to investigate the genetic architecture of psychiatric disorders. Here, we discuss recent genetic investigations of dual diagnosis (i.e., schizophrenia plus a SUD) and how these findings can inform public health messages.
Clinical outcomes with yttrium-90 resin microsphere radioembolization for hepatocellular carcinoma in a multiethnic southeast Asian population.
Authors: Andrew Yu Keat Khor, Ying Toh, John Carson Allen, David Chee Eng Ng, Guili Zhu, SuPin Choo, Richard H. G. Lo, Kiang Hiong Tay, Anthony Goh, Pierce K. H. Chow
Journal: Journal of Clinical Oncology (2013)

e15137 Background: Treatment options for unresectable hepatocellular carcinoma (HCC) are limited. Intra-arterial yttrium-90 ( 90 Y) microsphere radioembolization is an emerging treatment option with good outcomes among Caucasian patients. We report clinical outcomes in a multi-ethnic south-east Asian population treated with 90 Y microspheres. Methods: A single-centre, retrospective, observational cohort study was conducted on patients who received 90 Y microsphere radioembolization at Singapore General Hospital between January 2008 and June 2012. Patients were followed from the date of treatment until January 30, 2013, or until the date of death. Disease was staged by Barcelona Clinic Liver Cancer (BCLC) and Child-Pugh class. Patient survival was estimated using the Kaplan-Meier method. Response rate was determined by RECIST criteria. Prognostic factors for survival were identified using Cox proportional hazards regression. Results: 103 patients comprising 40.8% Chinese, 30.1% Myanmar, 14.6% Indonesian, 6.8% Indochinese and 7.7% others were treated with 90 Y microspheres. Hepatitis B or C was recorded as the etiology in 47.6% and 23.3% of patients, respectively. The median overall survival (OS) was 14.4 months [95% CI 11.3-22.2 months] (BCLC B, 23.8 months ; BCLC C, 13.6 months; P = 0.048); (Child-Pugh A, 21.7 months; Child-Pugh B, 10.1 months; P &lt; 0.0001). Median OS in patients with portal vein thrombosis (PVT) was poorer than those without PVT (PVT, 11.0 months; No PVT, 18.1 months; P = 0.024). Overall disease control rate by RECIST was 64.7%, while target lesions response rate was 98.3%. Progression of disease was mainly due to new lesions (69.2%). Significant prognostic factors for survival were serum albumin levels, presence of ascites and PVT. Conclusions: Survival outcomes in south-east Asian patients treated with 90 Y microsphere radioembolization for HCC are comparable to Western populations in spite of the different etiologies. While target lesions response was good, new lesions are common and suggest that concomitant systemic therapy may have a role in disease control.
Longer Time to Best Response and Depth of Response Are Associated with Improved Duration of Best Achieved Response and Progression-Free Survival (PFS): Post-Hoc Analysis of Phase 3 Tourmaline-MM1 Trial in Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Laurent Garderet, Jacob P. Laubach, Anne-Marie Stoppa, Parameswaran Hari, Michele Cavo, Heinz Ludwig, Maria-Victoria Mateos, Katarina Luptakova, Jianchang Lin, Helgi van de Velde, Deborah Berg, Philippe Moreau, Paul G. Richardson
Journal: Blood (2016)
Recruitment in a randomized, double-blind, placebo-controlled study to assess siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in patients with multicentric Castleman’s disease.
Authors: Frits Van Rhee, Marcelo Capra, Raymond Wong, Jessica Vermeulen, Karim Safer, Marija Todorovic, Patricia Rhoten, Helgi Van De Velde
Journal: Journal of Clinical Oncology (2012)

TPS8117 Background: Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder in which dysregulated production of interleukin (IL)-6 results in lymph node enlargement and debilitating symptoms, including systemic inflammatory manifestations (eg, fever, fatigue, weight loss), autoimmune phenomena, and markedly abnormal laboratory findings (eg, anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis, increases in acute-phase proteins such as CRP, ESR, fibrinogen). There is currently no approved systemic treatment for MCD in the US or EU. Siltuximab (CNTO 328) is a chimeric mAb with high affinity for soluble IL-6. In a previous phase 1 study, high objective tumor response rate (64%) has been observed in patients with MCD (van Rhee F et al. Blood 2008;112:1008) , and the long-term safety profile looks favourable (Kurzrock R et al. Blood 2011;118:3959). These results have prompted a randomized, double-blind, placebo-controlled study to definitively assess the efficacy and safety of siltuximab in combination with best supportive care (BSC) compared with BSC in patients with MCD. Methods: Eligibility includes HIV- and HHV-8-negative, symptomatic, measurable MCD patients. Patients with prior lymphoma or prior exposure to treatment targeting IL-6 or its receptor are excluded. Patients can be enrolled when receiving stable doses of corticosteroids (&lt;1 mg/kg/d of prednisone or equivalent). Patients will be randomized in a 1:2 ratio to placebo + BSC or to 11 mg/kg siltuximab + BSC and will receive siltuximab/placebo in a 1-hour IV infusion every 3 weeks. The primary objective is to evaluate durable tumor and symptomatic response in the intent-to-treat population. Secondary objectives include additional efficacy measures, safety, patient reported outcomes, and pharmacologic assessment. Status: 67/78 patients have been randomly assigned. This is the first randomized, placebo-controlled study to be conducted in MCD. The rarity of the disease has posed unique challenges, and various enrollment strategies have been successfully implemented, with projected completion of enrollment in March 2012.