Special Considerations for Advanced Heart Failure Surgeries: Durable Left Ventricular Devices and Heart Transplantation.

Heart transplantation and durable left ventricular assist devices (LVADs) represent two definitive therapies for end-stage heart failure in the modern era. Despite technological advances, both treatment modalities continue to experience unique risks that impact surgical and perioperative decision-making. Here, we review special populations and factors that impact risk in LVAD and heart transplant surgery and examine critical decisions in the management of these patients. As both heart transplantation and the use of durable LVADs as destination therapy continue to increase, these considerations will be of increasing relevance in managing advanced heart failure and improving outcomes.

Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone.

BACKGROUND: Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies. METHODS: The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only). RESULTS: Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment. CONCLUSION: Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab. TRIAL REGISTRATION: ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

Uterine Papillary Serous Carcinoma: A Single-Institution Review of 62 Cases.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is a rare variant of endometrial carcinoma responsible for up to 40% of endometrial cancer deaths. Controversy remains regarding optimal adjuvant therapy for UPSC, with lack of randomized trials to date. The objective of this retrospective study was to evaluate clinicopathological factors and determine event-free survival and overall survival (OS) in patients with UPSC managed within a single institution. MATERIALS AND METHODS: Medical and pathological records between 1987 and 2004 were reviewed at the Royal Women's Hospital, Melbourne, Australia. Cox regression analysis was used to analyze effects of clinical and histopathological variables on patient survival and survival times following adjuvant therapy. Event-free survival and OS were analyzed using the Kaplan-Meier survival curve. RESULTS: Sixty-two patients were included; 96.8% were managed surgically and 56.5% were completely surgically staged. Myoinvasion was present in 72.6% (n = 45) of the patients.In patients with stage I disease, recurrence rate was 41.4% with a 5-year OS of 46%. In stage II, recurrence rate was 20% with a 5-year OS of 67%. In stage III, recurrence rate was 58.8% with a 5-year OS of 34%. In stage IV, recurrence rate was 71.4% with a 5-year OS of 29%.There was no significant difference in survival based on the presence of positive peritoneal cytology, positive lymphovascular space invasion or positive lymph nodes at diagnosis, and no significant difference in survival based on the type of adjuvant therapy administered. Depth of myometrial invasion was a significant determinant of poor prognosis (P = 0.027). CONCLUSIONS: Uterine papillary serous carcinoma is an aggressive variant of endometrial cancer associated with a high proportion of advanced-stage disease at diagnosis, high recurrence rates, and low OS. In our patients, prognosis was determined by myometrial invasion and International Federation of Gynecology and Obstetrics stage at diagnosis. Randomized trials in this area are required to clarify optimal adjuvant therapy for patients with UPSC.

Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone.

BACKGROUND: Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB. METHODS: Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection. RESULTS: Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery (n = 106; 48 %) or had a less morbid procedure (n = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4-28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % (n = 24/25) for patients with planned joint/prosthesis replacement and 86 % (n = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow-up 13.0 [8.5-17.9] months), local recurrence occurred in 17 (15 %) patients. CONCLUSION: For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure.

The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease.

BACKGROUND: We compared the activity of denosumab with zoledronic acid for delaying or preventing hypercalcaemia of malignancy (HCM) in patients with advanced cancer and bone metastases or with multiple myeloma. METHODS: Patient-level data were combined from two identically designed, randomised, double-blind, active-controlled, phase III trials of advanced cancer patients with breast cancer and other solid tumours (excluding breast or prostate cancer) or multiple myeloma. End-points included time to first on-study HCM, time to first and subsequent on-study HCM, proportion of patients experiencing HCM and proportion of patients experiencing recurrent HCM. RESULTS: Denosumab significantly delayed the time to first on-study HCM, representing a 37% reduction in the hazard ratio (HR) compared with zoledronic acid (HR, 0.63; 95% confidence interval (CI): 0.41-0.98; P = 0.042) and reduced the risk of developing recurrent HCM (time to first and subsequent on-study HCM) by 52% (rate ratio, 0.48; 95% CI: 0.29-0.81; P = 0.006). The median time on study was 12.9 months. Fewer patients receiving denosumab compared with zoledronic acid experienced an HCM event (1.7% versus 2.7%; P = 0.028). Of the 84 patients experiencing an HCM event, 40% of those receiving zoledronic acid experienced >1 event of HCM compared with 31% of those receiving denosumab. CONCLUSION: Denosumab treatment was more efficacious than treatment with zoledronic acid in delaying or preventing HCM in advanced cancer patients with breast cancer, other solid tumours or multiple myeloma.

Effects of denosumab on pain and analgesic use in giant cell tumor of bone: interim results from a phase II study.

BACKGROUND: Giant cell tumor of bone (GCTB) is an aggressive primary osteolytic tumor. GCTB often involves the epiphysis, usually causing substantial pain and functional disability. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κΒ ligand (RANKL), is an effective treatment option for patients with advanced GCTB. This analysis of data from an ongoing, open-label study describes denosumab's effects on pain and analgesic use in patients with GCTB. MATERIAL AND METHODS: Patients with unresectable disease (e.g. sacral or spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into Cohort 1 (N = 170), and patients with resectable disease whose planned surgery was associated with severe morbidity (e.g. joint resection, limb amputation, or hemipelvectomy) were enrolled into Cohort 2 (N = 101). Patients received denosumab (120 mg) subcutaneously every four weeks, with additional doses on study days 8 and 15. Patients assessed worst pain severity with the Brief Pain Inventory - Short Form (BPI-SF) at baseline, at each visit for the first six months, and every three months thereafter. RESULTS: Clinically relevant pain improvement was reported by 29% of patients in Cohort 1 and 35% in Cohort 2 during week 1 and by ≥ 50% of patients in each cohort at each study visit from months 2-30. Median time to clinically relevant improvement was 30 (95% CI 16, 57) days in Cohort 1 and 15 (95% CI 15, 29) days in Cohort 2. Results in patients with moderate/severe pain at baseline were similar. Fewer than 30% of patients in Cohort 1 and 10% in Cohort 2 experienced clinically relevant pain worsening at any visit through 27 months. Most patients had no/low analgesic use during the study. CONCLUSION: Most patients treated with denosumab experienced clinically relevant decreases in pain within two months.

Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.

PURPOSE: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. METHODS: Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. RESULTS: Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). CONCLUSIONS: Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.

Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial.

BACKGROUND AND OBJECTIVES: Quality of life (QOL) is markedly impaired in patients with anemia, diabetes mellitus, and chronic kidney disease. Limited data exist regarding the effect of anemia treatment on patient perceptions. The objectives were to determine the longitudinal impact of anemia treatment on quality of life in patients with diabetes and chronic kidney disease and to determine the predictors of baseline and change in QOL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a large, double blind study, patients with type 2 diabetes mellitus, nondialysis chronic kidney disease (estimated GFR, 20 to 60 ml/min per 1.73 m(2)), and anemia (hemoglobin 10.4 g/dl) were randomized to darbepoetin alfa or placebo. QOL was measured with Functional Assessment of Cancer Therapy-Fatigue, Short Form-36, and EuroQol scores over 97 weeks. RESULTS: Patients randomized to darbepoetin alfa reported significant improvements compared with placebo patients in Functional Assessment of Cancer Therapy-Fatigue, and EuroQol scores visual analog scores, persisting through 97 weeks. No consistent differences in Short Form-36 were noted. Consistent predictors of worse change scores include lower activity level, older age, pulmonary disease, and duration of diabetes. Interim stroke had a substantial negative impact on fatigue and physical function. CONCLUSION: Darbepoetin alfa confers a consistent, but small, improvement in fatigue and overall quality of life but not in other domains. These modest QOL benefits must be considered in the context of neutral overall effect and increased risk of stroke in a small proportion of patients. Patient's QOL and potential treatment risk should be considered in any treatment decision.

Use and prescribing patterns for erythropoiesis-stimulating agents in inpatient and outpatient hospital settings.

PURPOSE: Erythropoiesis-stimulating agent (ESA) use in the outpatient and inpatient settings through pharmacist-conducted, hospital-based chart audits is examined and discussed. METHODS: Data from four hospital chart audits conducted in 250 hospitals between October 2005 and July 2006 were pooled for analyses. Eligible hospitals were categorized by ESA sales volume, with approximately equal numbers randomly selected from each decile. The last five inpatients and outpatients within each specified month receiving either darbepoetin alfa or epoetin alfa were evaluated. Study variables by setting included ESA use, prescriber specialty, and dosage regimen. RESULTS: The most common hospital locations of ESA administration were a cancer center in the outpatient setting (49%) and general medicine (57%) in the inpatient setting. ESA prescribers were most commonly hematologists and oncologists in the outpatient setting, and nephrologists were the most common prescribers in the inpatient setting. In the outpatient analysis, 2155 patients were prescribed darbepoetin alfa and 3106 were prescribed epoetin alfa. The predominant administration frequencies were every two weeks and once weekly for darbepoetin alfa, and once weekly for epoetin alfa. In the inpatient analysis, 1633 patients were prescribed darbepoetin alfa and 3231 were prescribed epoetin alfa. The predominant administration frequencies were once weekly for darbepoetin alfa and once weekly and three times weekly for epoetin alfa. Common uses for both ESAs were chemotherapy-induced anemia (outpatient setting) and anemia of end-stage renal disease with chronic dialysis (inpatient setting). There was considerable variability in ESA dosages and administration frequencies in both settings within all patient groups when analyzed by specified use. CONCLUSION: ESA use differed between outpatient and inpatient settings in indication, frequency of administration, and specialty of the prescriber.