tbuckley/cabot-search huggingface dataset:
Improved palliation of cerebral metastases in epithelial ovarian cancer using a combined modality approach including radiation therapy, chemotherapy, and surgery.
Authors: G C Rodriguez, J T Soper, A Berchuck, J Oleson, R Dodge, G Montana, D L Clarke-Pearson
Journal: Journal of Clinical Oncology (1992)

PURPOSE Recent reports suggest an increasing incidence of CNS metastases in patients with ovarian cancer. We reviewed our experience in the management of brain metastases from ovarian carcinoma and merged our results with those of several other series reported in the literature to determine prognostic factors and the role of chemotherapy, radiation therapy, and surgery. PATIENTS AND METHODS From 1977 to 1990, 15 of 795 patients who were treated for epithelial ovarian cancer at Duke University developed brain metastases. Fourteen of the patients were treated for their brain metastases; this included radiation therapy (RT; four), surgery and RT (one), RT and systemic chemotherapy (six), and all three treatment modalities (three). A meta-analysis was performed that combined the data from the current series with those of several recent clinical series that reviewed patients with brain metastases from ovarian carcinoma (67 patients total) to elucidate the impact of treatment and extent of disease on survival. RESULTS In the current series, median survival (MS) after the diagnosis of brain metastases was 9 months. For the combined series, MS was 5 months. Thirteen patients who were treated with whole-brain RT and systemic chemotherapy (MS, 7 months), 10 patients who were treated with RT and surgery (MS, 10 months), and nine patients who were treated with all three modalities (MS, 16.5 months) had significantly longer survival than 19 patients who were treated with RT alone (MS, 3 months) (P = .05, P = .01, and P &lt; .001, respectively). In a multivariate analysis, the only variable that provided prognostic information was treatment, namely the addition of systemic chemotherapy or surgery to RT for the treatment of brain metastases. CONCLUSION Multimodal treatment of patients with brain metastases from ovarian cancer can result in significant palliation.
Age-dependent blood pressure elevation is due to increased vascular smooth muscle tone mediated by G-protein signalling
Authors: Angela Wirth, Shengpeng Wang, Mikito Takefuji, Cong Tang, Till F. Althoff, Frank Schweda, Nina Wettschureck, Stefan Offermanns
Journal: Cardiovascular Research (2015)

Arterial hypertension is a major risk factor for cardiovascular diseases. The kidney and its natriuretic function are in the centre of the prevailing models to explain the pathogenesis of hypertension; however, the mechanisms underlying blood pressure elevation remain unclear in most patients. Development of hypertension is strongly correlated with age, and this blood pressure increase typically accelerates in the fourth decade of life. The cause of age-dependent blood pressure elevation is poorly understood. This study aims to understand the role of procontractile G-protein-mediated signalling pathways in vascular smooth muscle in age-dependent hypertension. Similar to humans at mid-life, we observed in 1-year-old mice elevated blood pressure levels without any evidence for increased vessel stiffness, impaired renal function, or endocrine abnormalities. Hypertensive aged mice showed signs of endothelial dysfunction and had an increased vascular formation of reactive oxygen species (ROS) and elevated endothelial ET-1 expression. Age-dependent hypertension could be normalized by ETA receptor blockade, smooth muscle-specific inactivation of the gene encoding the ETA receptor, as well as by acute disruption of downstream signalling via induction of smooth muscle-specific Gα12/Gα13, Gαq/Gα11, or LARG deficiency using tamoxifen-inducible smooth muscle-specific conditional mouse knock-out models. Induction of smooth muscle-specific ETA receptor deficiency normalized the blood pressure in aged mice despite the continuous presence of signs of endothelial dysfunction. Age-dependent blood pressure elevation is due to a highly reversible activation of procontractile signalling in vascular smooth muscle cells indicating that increased vascular tone can be a primary factor in the development of hypertension.
Clinical Improvement of Alpha-mannosidosis Cat Following a Single Cisterna Magna Infusion of AAV1
Authors: Sea Young Yoon, Jessica H Bagel, Patricia A O'Donnell, Charles H Vite, John H Wolfe
Journal: Molecular Therapy (2015)

Lysosomal storage diseases (LSDs) are debilitating neurometabolic disorders for most of which long-term effective therapies have not been developed. Gene therapy is a potential treatment but a critical barrier to treating the brain is the need for global correction. We tested the efficacy of cisterna magna infusion of adeno-associated virus type 1 (AAV1) expressing feline alpha-mannosidase gene in the postsymptomatic alpha-mannosidosis (AMD) cat, a homologue of the human disease. Lysosomal alpha-mannosidase (MANB) activity in the cerebrospinal fluid (CSF) and serum were increased above the control values in untreated AMD cats. Clinical neurological signs were delayed in onset and reduced in severity. The lifespan of the treated cats was significantly extended. Postmortem histopathology showed resolution of lysosomal storage lesions throughout the brain. MANB activity in brain tissue was significantly above the levels of untreated tissues. The results demonstrate that a single cisterna magna injection of AAV1 into the CSF can mediate widespread neuronal transduction of the brain and meaningful clinical improvement. Thus, cisterna magna gene delivery by AAV1 appears to be a viable strategy for treatment of the whole brain in AMD and should be applicable to many of the neurotropic LSDs as well as other neurogenetic disorders.
Phase II multisite study to evaluate efficacy and safety of single weekly administration of bortezomib (BZ) and dexmethasone (dex) in newly diagnosed multiple myeloma (NDMM) patients (pts).
Authors: N. C. Munshi, S. Lee, G. D. Roodman, C. Behler, S. Kambhampati, M. G. Rose, M. T. Brophy, A. Houranieh, D. Esseltine, A. Lichtenstein
Journal: Journal of Clinical Oncology (2010)

TPS307 Background: BZ is proteasome inhibitor with demonstrated efficacy in NDMM when given on twice a week (wk) schedule. However, neuropathy is one of the side effects that limit its use in a proportion of pts. Therefore, there is a need to investigate efficacy and safety of a weekly regimen of BZ. Methods: We are conducting a one-stage phase II multicenter, open-label single-arm noninferiority study of once a wk BZ in combination with dex, for the treatment of NDMM in Veterans Hospitals nationwide. The purpose is to show that the study regimen is not inferior to the standard BZ therapy with respect to objective response (OR) rate in pts with NDMM not undergoing transplant. Previously untreated MM pts who are not considered for autologous stem cell transplant (ASCT) due to age > 65 and/or comorbidities, or who are age ≥60 and have declined ASCT are eligible.Pts receive 1.6 mg/m2 IV BZ weekly, for 4 weeks followed by 1 week off. They also receive 40 mg dex PO the day of and day after each dose of BZ. Patients may receive 6 such 5- week cycles. To assess noninferiority, 50 pts will be accrued. Currently, 22 pts have been enrolled. Response is assessed at the end of cycles 2, 4, and 6 at which time pts may be taken off the study if unresponsive to treatment. On day 1 of each cycle serum protein electrophoresis, quantitative immunoglobulins, and/or 24hr urine protein, and free light chain are measured. Pts achieving CR or PR (based on EBMT criteria) undergo bone marrow biopsy and bone survey at the end of the study. The primary efficacy endpoint is OR, which is defined as CR, NCR, or PR. We expect the OR to be close to 75%, a rate consistent with that seen for standard BZ regimen. An OR rate of 55% or lower would be inferior to the rate obtainable with standard BZ regimen. The secondary endpoints are tolerability and toxicity (assessed by CTCAE v3), time to progression, and duration of response. Achieving toxicity and efficacy endpoints in this study will provide an alternative convenient dose and schedule of weekly regimen of BZ+dex in NDMM and is likely to affect our future practice of using BZ in these pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Amgen, Celgene, Millennium, Novartis Millennium Amgen, Celgene, Millennium, Novartis Celgene, Millennium, Novartis
A Phase III randomized study comparing the effects of oxandrolone (Ox) and megestrol acetate (Meg) on weight (wt), lean body mass (LBM) and quality of life (QOL) in solid tumor patients (pts) receiving chemotherapy (chemo)
Authors: G. J. Lesser, D. Case, S. Sharp, J. Choksi, A. Miller, J. N. Atkins, E. Shaw
Journal: Journal of Clinical Oncology (2006)

18546 Background: Involuntary wt loss is a significant problem in pts with cancer and may lead to a decline in QOL, limit treatment options and reduce survival. Wt loss in these pts disproportionately represents a loss of muscle mass. Meg, a synthetic progesterone derivative, promotes wt gain mostly through an increase in adipose tissue rather than in LBM. Ox is a potent oral anabolic steroid with minimal androgenic activity which promotes wt gain primarily through increased LBM. Methods: Prospective, randomized phase III trial comparing the effects of Ox and Meg on wt, body composition and QOL in pts with solid tumors and wt loss receiving chemo. Body composition was serially assessed by Bioelectrical Impedance Analysis. QOL was evaluated with the FACT-G and the Anorexia/Cachexia subscale (FAACT). Eligibility: age ≥18; PS: 0–2; life expectancy ≥6 mos; near normal organ function; and progressive wt loss on chemo. Ineligibility: full dose anticoagulation; hormonally responsive or hematologic malignancies; and ongoing or planned treatment with corticosteroids (antiemetic use allowed), estrogens or progestins. The primary endpoint was LBM after 12 wks of drug therapy. Study design allowed 90% power for detecting a 1.5 kg difference between treatment groups using a 5% two-sided level of significance. A max of 155 pts were to be accrued. An interim analysis was planned after 62 pts had completed 12 wks on study. Results: As of 12/05, 74 pts have been accrued (72 eligible): median age 64 yrs, 42% females and 62% stage 4 disease. 25 pts (arm 1:8, arm 2:17) have completed 12 wks of therapy and 20 remain on study. 76 Grade 3/4 toxicities (arm 1:23, arm 2:53) and 1 grade 5 arrhythmia (arm 2) have been recorded. Accrual is ongoing and differing trends in wt gain and body composition between arms are emerging. Conclusions: This is the first and only trial comparing these two commonly utilized therapies for cancer-related anorexia/cachexia. Differences in efficacy, particularly effects on LBM, QOL and toxicity which emerge from this trial are likely to influence symptom management standards of care in the oncology community. Supported by Savient Pharmaceuticals and NCI grant 1 U10 CA81851. No significant financial relationships to disclose.
The MIROX Regimen: Intensive systemic chemotherapy combined with surgical treatment of colorectal cancer metastases. Results of a phase II study
Authors: J. Taïeb, P. Artru, F. Paye, M. Hebbar, F. Maindrault Goebel, T. André, C. Tournigand, C. Louvet, R. Parc, A. De Gramont
Journal: Journal of Clinical Oncology (2004)

3592 Background: This work was designed to evaluate the efficacy and tolerance of adjuvant FOLFOX-7 followed by FOLFIRI (the MIROX strategy) in patients with resectable metastatic colorectal cancer. Methods: Forty seven patients with resectable colorectal cancer metastases were prospectively enrolled in this study between September 1999 and October 2001. The treatment consisted in six cycles of FOLFOX-7 (leucovorin 400 mg/m2, Oxaliplatin 130 mg/m2 and 5-FU 2400 mg/m2 as a 46-hour infusion, every two weeks), followed by six cycles of FOLFIRI (leucovorin 400 mg/m2, CPT11 180 mg/m2 in 90 min infusion, 5-FU 400 mg/m2 and 5-FU 2400 mg/m2 as a 46-hour infusion, every two weeks). Surgery was performed before chemotherapy (26 patients) or after the 6 cycles of FOLFOX7 (21 patients), 6 cycles of FOLFIRI being administered thereafter. Results: All but one patient underwent curative surgery and two pts refused post-operative chemotherapy. Tolerance was generally good. The most relevant toxicities were grade 3–4 neutropenia and thrombocytopenia, observed in 12 patients (25%), without any febrile neutropenia or bleeding event. No toxic death occurred. Two pathologically confirmed complete responses and 15 partial responses (overall response rate of 80%, CI: 69–88) occurred with FOLFOX-7 for the 21 patients receiving this regimen before surgery. The 2-year overall survival rate was 88%. The two year recurrence free survival was 51%. Conclusion: The MIROX strategy is feasible and well tolerated in patients with resectable metastatic colorectal cancer. Progression free and overall survivals, with a 25 months median follow up, are similar to those observed with the best therapeutic strategies currently available, though a longer follow-up is needed to confirm these results. This regimen is currently compared to a LV5-FU2 regimen in a randomized phase III study. No significant financial relationships to disclose.
Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants
Authors: Ilyas Chachoua, Christian Pecquet, Mira El-Khoury, Harini Nivarthi, Roxana-Irina Albu, Caroline Marty, Vitalina Gryshkova, Jean-Philippe Defour, Gaëlle Vertenoeil, Anna Ngo, Ann Koay, Hana Raslova, Pierre J. Courtoy, Meng Ling Choong, Isabelle Plo, William Vainchenker, Robert Kralovics, Stefan N. Constantinescu
Journal: Blood (2015)
Hypersensitivity to cetuximab: Is there an association with race, region or both?
Authors: S. S. Azmi, J. Sachdev, L. Kronish, M. Jahanzeb, M. P. Smeltzer
Journal: Journal of Clinical Oncology (2008)

14002 Background: A higher incidence of hypersensitivity reactions (HSR) has been reported in the mid-southern US (22 %: O’Niel et al. JCO 2007; 24: 3644–48) as compared to the national average (≤ 4%). Our objective was to determine the rate of any HSR and grade 3 & 4 HSR in cetuximab treated patients at a university based oncology practice in the heart of the midsouth in Memphis, TN. We also attempted to identify patient, treatment, and tumor characteristics that are predictive of HSR to cetuximab. Methods: 79 cancer patients, who received cetuximab at any time during their treatment course were identified and their charts reviewed for documented HSR. Information on patient demographics, treatment history, type of pre-medication used and history of prior allergies was also collected. HSR were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0. Fisher’s exact test was used to test for association between HSR and other variables. Results: Patient cohort: Median age 58 (18–85), 62% black, 61% males. The observed rate of any HSR was 8.8% (7 of 79 patients) and grade 3 & 4 HSR was 7.5%. We found no significant association between HSR and any of the following variables: age, gender, history of allergies, tumor type, prior chemotherapy or radiation therapy, and premedications used {H1 vs. H1+H2 blockers, dexamethasone (D) vs. no D}. Race was significantly associated with any HSR and grade 3 & 4 HSR (p = 0.01 and 0.02 respectively) Caucasians were more likely than blacks to experience any HSR (20% vs. 2%) and grade 3 & 4 HSR (16% vs. 2%). Conclusions: Our rate of HSR to cetuximab is higher than the national average, but lower than that observed at two other institutions in the mid-south (Chapel Hill, NC and Nashville, TN). Demographic differences between the patient populations with 62% of our patients being black as opposed to only 19% in the report by O’Niel et al could explain this. Prospective confirmation of these findings and exploration of mechanisms to this racial disparity are warranted. No significant financial relationships to disclose.
Abstract 12583: C-Type Natriuretic Peptide Improves Left Ventricular Systolic and Diastolic Functional Performance at Rest and During Exercise After Heart Failure
Authors: Che Ping Cheng, Hiroshi Hasegawa, Atsushi Morimoto, Heng-Jie Cheng, William C Little
Journal: Circulation (2014)

Background: In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise (Ex). C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family produced by the vascular endothelium and heart is elevated in HF. However, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and lusitropic actions may prevent this abnormal Ex response after HF. Methods: We assessed the effects of CNP on LV functional performance at rest and during submaximum Ex (3.5-5.5 mph for 6-8 min) in 10 instrumented dogs with pacing-induced HF. Since CNP mediated its biological actions via cGMP, we also measured plasma cGMP levels in response to CNP infusion at rest before and after HF. Results: CNP (2 μg/kg plus 0.4 μg/kg/min, iv, 20 min) caused a similar increase in cGMP levels before (7.2±3.8 to 24.7±4.9 pmol/ml) and after HF (20.2±4.4 to 71.6±5.0 pmol/ml). After HF, at rest, CNP reduced LV end-systolic pressure (P ES , CNP: 93 vs Baseline: 104 mmHg), arterial elastance (E A , 8.3 vs 11.7 mmHg/ml) and end-diastolic pressure (P ED , 37.2 vs 42.4 mmHg) (p&lt;0.05). The peak mitral flow (dV/dt max , 201±51 vs 160±34ml/sec) was also increased due to decreased minimum LVP (LVP min , 17.1 vs 23.8 mmHg) and the time constant of LV relaxation (t, 40±4 vs 48±6 msec) (p&lt;0.05). In addition, the slope of LV end-systolic pressure-volume relations (E ES ) was increased (5.6±0.7 vs 4.2±0.9 mmHg/ml). The LV-arterial coupling, quantified as E ES /E A , was improved (0.69±0.22 vs 0.48±0.16) (p&lt;0.05). The beneficial effects persisted during Ex. At matched levels of Ex, treatment with CNP, Ex-induced significantly less increases in P ES (ΔP= 3.4±0.5 vs 7.4±0.8 mmHg), mean LAP (ΔP= -3.1±2.2 vs 3.6±2.9 mmHg), and LVP min (ΔP= -3.6±1.4 vs 1.4±1.2 mmHg) (p&lt;0.05). With CNP, t was much shortened (Δ= -0.8±4.0 vs 2.8±3.2 ms), and the peak mitral flow was further augmented (ΔdV/dt max , 75±20 vs 43±12 ml/sec) (p&lt;0.05). Conclusion: After HF, the generation of cGMP in response to CNP is not blunted. CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling and LV arterial coupling, thus improving LV performance, both at rest and during Ex after HF.
Adding the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin in first line for stage IC-IV epithelial ovarian cancer: A randomized phase II study
Authors: A. Reyners, W. M. Smit, M. S. Schaapveld, K. Hoekman, F. Erdkamp, R. Lalisang, H. Graaf, M. A. Wymenga, M. Polee, P. H. Willemse
Journal: Journal of Clinical Oncology (2009)

5545 Background: Inhibition of COX-2 reduces the growth rate of tumors in vitro and COX-2 is over-expressed in ovarian cancer, so a COX-2 inhibitor might be beneficial. Methods: After debulking surgery patients (pts) with advanced epithelial ovarian cancer (FIGO IC-IV) received docetaxel 75 mg/m2 and carboplatin AUC=5 (CT) for 6–9 cycles q 3-wks and were randomized to celecoxib 400 mg BID (COX) for max three years or to control (CTR), stratified for residual tumor present in 58% vs 54%. Response rates and progression-free survival were based on CA-125 levels according to Rustin. Primary endpoints were biochemical CR (bCR)and safety, secondary progression free- (PFS) and overall survival (OS). Results: 183 of 201 pts enrolled were analyzed and baseline characteristics were well balanced between COX (n = 91) and control (CTR) arms (n = 93). Safety: Docetaxel and carboplatin was given full dose in 89% vs 84% pts and creatinine clearance remained stable vs baseline in both arms (96% vs 97% at Cycle 6). Toxicity grade 3–4 (COX vs CTR) was neutropenia in 26 vs 32, febrile neutropenia 12 vs 12, N/V 6 vs 5, allergy 7 vs 0 pts. Neurosensory grade 2–3 was less in COX (4 vs 13 pts, p&lt; 0.05). Efficacy: Median duration of COX treatment was 6 months and 60% completed the combination with six or more cycles of CT. At a median follow-up of 20 months, CA-125 normalized (bCR) in COX 55/74 (74%) and CTR 49/74 (66%) pts with elevated baseline levels (n.s.). Median PFS was 17.4 vs 14.5 months (n.s.) and median survival 34.2 vs 34.7 months (n.s.). Conclusions: Celecoxib added to docetaxel/carboplatin in epithelial ovarian cancer had no effect on creatinine clearance, CA-125 response, PFS or OS. Celecoxib during CT was associated with allergic skin reactions but less neurotoxicity. No significant financial relationships to disclose.
Clinical benefit as a surrogate marker of survival in patients receiving primary endocrine therapy in locally advanced primary breast cancer
Authors: J. Mathew, A. Agrawal, L. R. Jackson, J. F. Robertson, K. L. Cheung
Journal: Journal of Clinical Oncology (2008)

22141 Background: Previous studies with neoadjuvant chemotherapy have shown superior survival in patients with objective response (OR), and in particular pathological complete response. Our recently published study on oestrogen receptor (ER) + locally advanced primary breast cancers (LAPC) receiving primary endocrine therapy (PET) has shown excellent outcome with 5-year overall survival (OS) and breast cancer specific survival (BCS) of 76% and 86% respectively. The aim of this study was to identify a surrogate clinical marker of survival in this group of patients. Methods: We looked into non-inflammatory ER + LAPC receiving PET between Jan 1988 - Jan 2007 in our institute. Patients were selected based on patient choice, being unfit for chemotherapy, or as part of a randomised trial. Tumours with histochemical (H) score of ≥ 20 were considered ER +. Clinical response was assessed at 6 months according to UICC criteria. Patients were followed for a median duration of 61 months. Results: 195 patients received PET. The median age was 69 years (36–92). The median clinical size of the tumour was 6 cm. At 6 months, OR was achieved in 47 (24%) patients (8 complete responses (CR) and 39 partial responses (PR). Majority of patients had stable disease (SD) (138) and 10 patients progressed. There was no statistical difference in 5-year OS (OR-85% Vs SD-73%; P=0.351) and BCS (OR-92% Vs SD-80%; P=0.237) between patients with OR and SD at 6 months. Patients with PD had significantly worse 5-year OS (41% Vs 79%; P=0.0002) and BCS (55% Vs 86%; P=0.00001) compared to rest of the group. Conclusion: A significant proportion of patients on PET have SD and their survival is statistically similar to those with OR. When assessing response to PET, it is more appropriate to consider the rates of non-progression or clinical benefit (CR+PR+SD) rather than OR. Achieving a clinical benefit at 6 months appears to be a strong surrogate marker of better survival. No significant financial relationships to disclose.