tbuckley/cabot-search huggingface dataset:
Clarithromycin, pomalidomide, and dexamethasone (ClaPD) in relapsed or refractory multiple myeloma.
Authors: Adriana C. Rossi, Tomer Martin Mark, Melissa Rodriguez, Manan Shah, Ryann Quinn, Roger N Pearse, Faiza Zafar, Karen Pekle, Stephanie Speaker, David Jayabalan, Scott Ely, Morton Coleman, Selina Chen-Kiang, Ruben Niesvizky
Journal: Journal of Clinical Oncology (2012)

8036 Background: Clarithromycin has been shown to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is an immunomodulatory agent effective in relapsed/refractory MM (RRMM). We hypothesized that clarithromycin may similarly enhance pomalidomide + dexamethasone in RRMM. We now report updated results from a phase 2 trial of ClaPD in RRMM. Methods: 73 patients with RRMM were enrolled in a single-institution phase 2 study of ClaPD. All subjects had ≥ 3 prior lines of therapy, one of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; dexamethasone 40mg weekly; and pomalidomide 4mg for days 1-21 of a 28-day cycle. All patients had VTE prophylaxis with aspirin. Monthly disease response evaluation included immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM responses. Treatment continued as tolerated until disease progression. Results: The 66 patients who completed ≥ 1 cycle of ClaPD are reported. Median number of cycles was 6 (range 1-17). Responses were progressive disease: 10%, stable disease: 21%, minimal response: 12%, partial response: 33%, very good partial response: 18%, stringent complete remission: 5%, for an overall response rate (ORR) of 56% and ≥VGPR rate of 23%. Median time to PR was 1.25 cycles (range 1-8). Median PFS was 5 months. Response and PFS were not different in patients refractory to lenalidomide (85%), bortezomib (82%), or double-refractory patients (76%). After a median follow up of 12 months,28 pts (42%) remain on study without progression and 56pts (85%) are alive. Two pts withdrew due to toxicity (1 Grade 3 fatigue, 1 Grade 4 muscular weakness). One patient withdrew consent. Conclusions: ClaPD is highly effective for heavily pre-treated RRMM, particularly in lenalidomide-refractory disesase and compares favorably to previously published Phase 2 data of Pom/Dex (ORR 56% vs 40% - Lacy et. al JCO 2009) without excess toxicity. Response to ClaPD is rapid, well tolerated, and sustained over 7 months in most subjects. These data support the clinical efficacy of pomalidomide based regimens in RRMM.
Targeting STAT3 in castration-resistant prostate cancer: Galiellalactone as a direct inhibitor of STAT3 in prostate cancer cells.
Authors: Rebecka Hellsten, Nicholas Don-Doncow, Zilma Escobar, Martin Hans Johansson, Sven Kjellstrom, Victor Garcia, Eduardo Munoz, Olov Sterner, Anders Bjartell
Journal: Journal of Clinical Oncology (2014)

e16065 Background: The transcription factor STAT3 is constitutively active in castration-resistant prostate cancer (CRPC) and constitutes a promising therapeutic target. The reactive fungal metabolite galiellalactone (GL), a STAT3-signaling inhibitor, inhibits the growth, both in vitro and in vivo, of prostate cancer cells expressing activated STAT3 and inhibits growth and induces apoptosis of prostate cancer stem cell-like cells expressing pSTAT3. We aim in this study to identify the STAT3 signaling inhibiting mechanism of GL. Methods: A biotinylated analogue of galiellalactone (GL-biot) was synthesized to be used for identification of GL target proteins. The STAT3 inhibitory activity of GL-biot was confirmed with STAT3 luciferase reporter gene assay. The pSTAT3 expressing human prostate cancer cell line DU145 was incubated with GL-biot, followed by streptavidin beads to isolate proteins bound to GL-biot. Localization of GL-biot in DU145 cells was assessed using confocal microscopy. EMSA was performed on GL treated DU145 cell lysates for analysis of STAT3 binding to DNA. Mass spectrometry analysis (MS) was performed on recombinant STAT3 pretreated with GL in order to identify modified cysteines. Results: By adding streptavidin beads to GL-biot treated DU145 cell lysates, STAT3 was isolated and identified as a target protein. Using confocal microscopy of DU145 cells treated with GL-biot, STAT3 appeared to co-localize with GL-biot in the nucleus. GL inhibited STAT3 binding to DNA in DU145 cell lysates without affecting phosphorylation status of STAT3. MS analysis of recombinant STAT3 pretreated with GL revealed three modified cysteines (C367, C468 and C542). Conclusions: We here demonstrate with chemical and molecular pharmacological methods that galiellalactone is a cysteine reactive inhibitor that covalently binds to one or more cysteines on STAT3 and that this leads to inhibition of STAT3 binding to DNA and thus blocks STAT3 signaling. This further validates GL as a promising STAT3-inhibitor for the treatment of CRPC.
Late effects among testicular cancer survivors (1994-2011).
Authors: Mohammed Hassan Hussain Al-Temimi, Alison M Fraser, Yuan-Chin Amy Lee, Kerry G. Rowe, Braden D. Rowley, Micky Daurelle, Ken R Smith, James VanDerslice, Lorenzo Richiardi, Mia Hashibe
Journal: Journal of Clinical Oncology (2013)

1582 Background: More than 95% of testicular cancer (TC) patients survive at 10 years; however, they develop many complications following diagnosis. Our study is toassess the risk of developing morbidities among TC survivors. Methods: We used the Utah Population Database to identify TC patients (age&gt;13) who 1) were diagnosed between 1994 and 2008, 2) had medical records at the University of Utah and Intermountain Health Care hospitals and 3) survived at least 3 years. Cases were matched to five TC-free patients (controls) from the same hospitals on birth year, birth region and date of residence in Utah. Individuals (cases and controls) with morbidities of interest before the date of TC diagnosis were excluded. Adjusted Cox regression analysis was used to identify the risk of developing ischemic heart disease, renal failure, infertility, hearing loss, peripheral neuropathy, osteoporosis and restrictive lung disease among TC patients relative to controls. The models were adjusted for age, race and other confounders. We also compared the risk of these morbidities among patients with regional/advanced tumor relative to patients with in situ/localized tumor. The latter was adjusted for age and tumor histology. Results: We identified 955 TC patients and 4775 controls. TC stage was: 73.7 % in situ/localized and 26.3% regional/advanced. The hazard rate (HR) of developing any of the target morbidities was 2.57, 95% confidence interval (CI), 2.2-2.9 for patients with localized cancer, 3.85 (95% CI: 2.9-5.1) for patients with regional cancer and 3.3 (95% CI: 2.3-4.8) for patients with advanced cancer relative to controls. Risk of developing renal failure, infertility, peripheral neuropathy, hearing loss and restrictive lung disease was significantly higher among TC survivors (P&lt;0.05). We also identified a significant association (HR 5.2; 95% CI 1.8-15.5) of cancer stage and the risk of developing hearing loss and non-significant positive association of TC stage with the other morbidities. Conclusions: TC survivors were more than twice as likely to develop morbidities following diagnosis when compared to controls. The risk increases when the comparison is stratified by stage, which might be related to the differences in the treatment used for different stages of TC.
Risk of hospital-related morbidity among survivors of breast cancer in British Columbia, Canada.
Authors: Christine E. Simmons, Elaine Wai, Scott Tyldesley, Maria Lorenzi, Dongdong Li, Mary L McBride
Journal: Journal of Clinical Oncology (2013)

1551 Background: Long-term consequences of cancer diagnosis and treatment are of increasing concern, as therapeutic interventions improve survival. Various survivorship programs exist; few address the importance of bridging oncology and primary care. This study assesses risk of late hospital-related morbidity among a population-based cohort of 39,436 3-year survivors of female breast cancer in British Columbia, Canada and compares the risk of morbidity to a similarly-aged comparison group. Methods: Demographic and clinical records of breast cancer survivors diagnosed between 1986 and 2005 were linked to inpatient records from provincial administrative databases. A comparison group from the provincial health insurance plan registry, frequency-matched by birth cohort was identified. Morbidity was ascertained from diagnosis codes listed on hospital records, and categorized by organ system. Poisson regression was used to assess the relative risk of morbidity, adjusting for sociodemographic factors. Results: Compared to controls, non-relapsed survivors diagnosed age 18-39 (N=1158) had more than twice the risk of morbidity (RR 2.57, 95%CI 2.21-2.98); those with a relapse (N=580) had eight times the risk (95% CI 6.78-9.44). Among those diagnosed age ≥40, non-relapsed survivors (N=20473) had a 62% increase in risk RR 1.62, 95% CI 1.57-1.68; relapsed survivors (N=5223) had triple the risk of morbidity (RR 2.89, 95% CI 2.78-3.01). In both cohorts, excess risks were statistically significant for most types of non-neoplastic morbidity, with highest rates seen for disorders of the blood, endocrine, skin and circulatory systems. Among survivors, those diagnosed with a higher stage cancer had increased risk of morbidity. Type of treatment received did not correlate with increased risk of morbidity (RR 1.05, 95% CI 1.00–1.11 for combination of surgery, radiation and systemic therapy vs surgery alone); majority of the risk increase is likely related to the impacts of cancer itself rather than treatment. Conclusions: Survivors of breast cancer are at an increased risk of a wide range of morbidities years after diagnosis. This underscores calls for improved models of survivorship care and continued survivorship research.
The health of prisoners: summary of NICE guidance
Authors: Richard Bradshaw, Ben A J Pordes, Hannah Trippier, Nick Kosky, Steve Pilling, Fionnuala O’Brien
Journal: BMJ (2017)

#### What you need to know

Compared with the general population, adults in contact with the criminal justice system have higher rates of mental and physical health problems. Such people include those under arrest, in prison, on license, or serving a community sentence. Most live in the community or serve short custodial sentences,1 and will feature on the patient list of most general practices. Care for these people should be equivalent to that of people without a history of contact with the criminal justice system. There is little to suggest that, for most people, treatments that are effective in a non-criminal justice setting are not effective in the criminal justice setting.

Some of the most prevalent problems include substance misuse, personality disorder, depression, anxiety, respiratory disease, diabetes, and other chronic health conditions. Being held in prison is associated with increased suicide rates and high levels of mental health problems. People in contact with the criminal justice system should have the same access to NHS treatment as the general population at all stages. Lack of access to healthcare can exacerbate existing problems and affect reintegration to society …
The Combination of MRD and Copy Number Alterations (CNAs) Defines an Ultra-High Risk Group of Children with Primary T-Lymphoblastic Leukemia (T-ALL)
Authors: Joachim B. Kunz, Julia Seemann, Martin Zimmermann, Paulina Richter-Pechanska, Obul Reddy Bandapalli, Elena Orlova, Gunnar Cario, Martin Stanulla, Martin Schrappe, Marketa Zaliova, Jan Trka, Renate Panzer-Grümayer, Georg Mann, Martina U. Muckenthaler, Jan O. Korbel, Andreas E Kulozik
Journal: Blood (2016)
Exploratory analysis of angiotensin converting enzyme (ACE) and aldosterone (Ald) serum levels as prognostic and predictive biomarkers on the NCIC CTG BR24 trial.
Authors: Jair Bar, Keyue Ding, Huijun Zhao, Scott Andrew Laurie, Lei Han, Frances A. Shepherd, Christina L. Addison, Glenwood D. Goss, Jim Dimitroulakos, Penelope Ann Bradbury
Journal: Journal of Clinical Oncology (2013)

8048 Background: Benefit from angiogenesis inhibitors (AI) has been linked to high blood pressure. One of the main determinants of blood pressure is the renin-angiotensin axis. We undertook an exploratory, retrospective analysis of ACE and Ald serum levels on specimens banked during the conduct of the BR24 study. The aim was to evaluate these markers for their prognostic significance and their predictive value regarding Cediranib (Ced) treatment. Methods: The NCIC CTG BR24 study randomized advanced non-small cell lung cancer patients (pts) to carboplatin and paclitaxel (CP) +/- Ced. ACE and Ald serum levels were retrospectively tested on baseline samples using commercial ELISA kits. A graphic method, differentiating treatment effect by the range of marker, was used to determine cutoff points (JCO 2010, 28: 5247). Exploratory analyses were performed to correlate biomarkers levels with pts characteristics and overall survival (OS). Association between categorical variables was assessed by Chi-square test or Fisher’s exact test; time to event correlation with biomarkers was tested using a Cox regression model. Potential confounding factors including medications were integrated into the statistical model. Results: Biomarker data was available in 226 of 296 randomized pts. The tested pts vs. all the randomized pts were more likely to have a lower performance status (PS, p=0.03), a normal LDH (p=0.05) and to be ever-smokers (p=0.015). The determined cutoffs were ACE: 115ng/ml and Ald: 250 pg/ml. High ACE was associated with a better PS (p=0.03). High ACE levels were prognostic for longer OS (adjusted HR 0.52 [95%C.I. 0.29-0.92], p=0.025). High ACE pts had no OS benefit (HR 1.27 [95% C.I. 0.78–2.08], p=0.34), while low ACE predicted OS benefit from the addition of Ced to CP (HR 0.64 [95%CI 0.42-0.97], p=0.03). Interaction p value=0.03; this remained significant after adjustment in multivariate analyses. Ald levels were neither prognostic nor predictive. Conclusions: This exploratory analysis suggests high ACE serum levels maybe prognostic for better OS, while low ACE may predict benefit from Ced when added to CP.
A phase III, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of pregabalin in the prevention and reduction of oxaliplatin-induced painful neuropathy (PreOx).
Authors: Daniel Ciampi de Andrade, Manoel Jacobsen Teixeira, Ricardo Galhardoni, Karine A.S.L. Ferreira, Paula Braz Malieno, Nathalia Scisci, Rachel Pimenta Riechelmann, William G.J. Teixeira, Daniel Fernandes Saragiotto, Valquiria Aparecida Silva, Irina Raicher, Isac de Castro, Daniella Parravano, Julia Tizue Fukushima, Jean-Pascal Lefaucheur, Didier Bouhassira, Ricardo Silvestre e Silva Macarenco, Evandro Sobroza de Mello, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2015)

3575 Background: Patients with colorrectal cancer receiving Oxaliplatin usually develop acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN). Despite having different mechanisms, both conditions lead to central sensitization (CS). Recent data suggest that the degree of CS after acute use of Oxaliplatin increases the risk of painful CIPN. We hypothesized that preemptive use of anti-hyperalgesic drug (pregabaline) during Oxaliplatin infusions would decrease the incidence of chronic painful CIPN. Methods: Pain-free, chemotherapy-naïve patients (stage III/IV) receiving at least one complete cycle of modified FLOX (5-FU+leucovorin for 6 consecutive weeks+oxaliplatin 85 mg/m2 at weeks 1, 3 and 5, every 8 weeks) were randomised (1:1). Eligible patients received either pregabaline or placebo (150-600mg/d) for three days before and three days after each oxaliplatin infusion. Patients were followed for 3-6 months after the end of chemotherapy. Clinical assessments were performed at baseline, at the end of chemotherapy treatment and after the followup period. The main outcome was average pain at the last visit assessed by the visual numerical scale (0-10) item of the Brief Pain Inventory in pts with neuropathic pain according to the Douleur Neuropathique-4 score (DN4). Secondary endpoints were pain interference (BPI), pain dimensions (McGill Pain Questionnaire), score of the Neuropathic Pain Symptom Inventory (NPSI). Results: 206 patients (56.6±11yo, 111 female) were enrolled. Both groups presented similar baseline demographic characteristics (p > 0.20). The cumulative dose of oxaliplatin was similar between groups throughout the study. Data from 82 patients in the pregabaline and 84 in the placebo group were retained for analises. At the last visit, pain intensity in the pregabaline group was 0.85±2.35 and 0.88±2.40 in the placebo group (p = 0.673). Scores from other pain scales did not differ between groups. Conclusions: The preemptive use of the antihyperalgesic drug pregabaline during oxaliplatin infusions was safe, but did not decrease the incidence of chronic pain related to CIPN. Clinical trial information: NCT0145016.
Initial dosing of epoetin alfa 60,000 U QW followed by Q2W maintenance for anemic patients with cancer receiving chemotherapy
Authors: B. Baltz, S. A. Gregory, W. C. Ehmann, D. Williams
Journal: Journal of Clinical Oncology (2004)

8212 Background: The efficacy of epoetin alfa (EPO) at a starting dose of 40,000 U SC once weekly (QW) has been established in previous clinical studies. Higher starting doses followed by less frequent maintenance dosing may shorten time to Hb response, and increase response rates. Methods: In this ongoing open-label, multicenter, pilot study in 130 anemic (Hb ≤11 g/dL) pts with cancer receiving CT, EPO 60,000 U SC QW was administered for up to 12 weeks (wks) until a target Hb ≥12 g/dL was reached (initiation phase [IP]). Pts who achieved Hb ≥12 g/dL then received maintenance dosing of 60,000 U SC every 2 wks (Q2W; maintenance phase [MP]). Primary end point was proportion of pts with Hb ≥12 g/dL or Hb increase ≥2 g/dL from baseline (BL) in IP. Eligible pts were ≥18 y with nonmyeloid malignancy scheduled to receive CT QW or every 4 wks for ≥16 wks. Pts were followed for up to 24 wks and received 1 dose of EPO after last CT cycle. Pts are withdrawn for missed doses and for Hb <11 g/dL in MP. Results: Fifty-five patients are evaluable for analysis (mean BL Hb, 10.0 ± 0.8 g/dL). Thirty-three pts entered MP after a median of 4 wks. Mean Hb was 12.4 ± 0.3 g/dL (n = 33) at first MP dose and has been maintained for a median 7 wks of follow-up (mean Hb after 4 wks in MP, 12.4 ± 0.1 g/dL [n = 20]). Proportion of pts with Hb ≥12 g/dL or Hb increase ≥2 g/dL from BL in IP was 64%. Twenty-seven (57%) of 47 pts had Hb increase ≥1 g/dL after 4 wks and 8 (25%) of 32 pts had Hb increase ≥2 g/dL after 8 wks. EPO dose was reduced to 40,000 U QW in 6 (11%) pts during IP and 40,000 U Q2W in 14/33 (42%) pts during MP. Twenty-eight pts have been withdrawn (16 in IP; 12 in MP) due to Hb <11 g/dL in MP (n = 7), disease progression (n = 4), death (n = 3), loss to follow-up (n = 1), failure to reach Hb ≥12 g/dL in IP (n = 1), and other/missing (n = 12). Conclusions: Preliminary data suggest that EPO 60,000 U QW increases Hb and that 40,000–60,000 U Q2W can maintain Hb in the majority of pts entering maintenance. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho Biotech Products, L.P. Johnson & Johnson; Ortho Biotech Products, L.P. Johnson & Johnson Ortho Biotech Corixa; IDEC; Genentech; Genta; Millennium; Ortho Biotech Products, LP; Ligand; Berlex
Phase II trial evaluating axitinib for patients with unresectable, recurrent, or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Assuntina Gesualda Sacco, Lili Zhao, Thomas E. Carey, Irina Y. Dobrosotskaya, Jonathan B. McHugh, Douglas Brian Chepeha, Carol Rossier Bradford, Gregory T. Wolf, Mark E Prince, Jeffrey Moyer, Erin Lynn McKean, Scott A McLean, Kelly M Malloy, Matthew E Spector, Norman D Hogikyan, Susan Urba, Brent Ward, Francis P. Worden
Journal: Journal of Clinical Oncology (2014)

e17027 Background: Patients with R/M HNSCC experience poor survival outcomes with standard cytotoxic agents. Targeted therapies present an attractive alternative, particularly as various growth factors and cytokines have been implicated in HNSCC. Axitinib is a potent angiogenesis inhibitor with demonstrated clinical activity and acceptable toxicity in various advanced malignancies. Evaluation of axitinib for HNSCC is thus warranted. Methods: Prospective, single-institution, single-arm, open-label phase II trial. Inclusion: R/M HNSCC not amenable to curative treatment, measurable disease, ECOG PS 0-2. Exclusion: uncontrolled hypertension (HTN), tumor involvement/ encasement of major blood vessels, hemoptysis, malabsorption, prior anti-angiogenesis agents, untreated/progressive brain metastases. Primary endpoint: 6-month progression-free survival (PFS) rate. Posterior distribution of this rate was estimated assuming time-to-progression has a Weibull distribution. Secondary endpoints: objective response and disease control rates, overall survival, 2 and 4-month PFS, toxicity and correlatives. Correlatives include dynamics of VEGF, EGF, PDGF, HGF, FGF, and their receptors, IL-6, IL-8, JAK2, STAT3, HPV status and microvessel density. Patients receive axitinib 5mg twice daily (bid) with dose escalation at 2 weeks (7mg bid) and 3 weeks (10mg bid) in the absence of ≥ grade 2 toxicity or uncontrolled HTN. Tissue and blood samples permit correlative analyses of biomarker data with clinical outcome. Results: 28 of 40 evaluable patients have been accrued. Interim analysis of 20 patients demonstrated a 99% probability of 6-month PFS rate >25%, and 80% probability of 6-month PFS rate >40%. 1 (5%) patient had partial response (PR), 13 (65%) had stable disease (SD), 3 (15%) had progressive disease, and 3 (15%) died of disease. Conclusions: 70% of patients derived clinical benefit (PR + SD) at 6 months, suggesting axitinib may be efficacious for treatment of R/M HNSCC. Interim analysis meets protocol specifications for trial continuation. Final results will also include HPV status, toxicity and correlative analyses. Clinical trials.gov identifier: NCT01469546. Clinical trial information: NCT01469546.