Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2.

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2-positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a > 10% decline in left ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.

Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were down-regulated, consistent with S- phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, a well-tolerated off-patent approved drug, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.

Using value-based analysis to influence outcomes in complex surgical systems.

BACKGROUND: Value-based analysis (VBA) is a management strategy used to determine changes in value (quality/cost) when a usual practice (UP) is replaced by a best practice (BP). Previously validated in clinical initiatives, its usefulness in complex systems is unknown. To answer this question, we used VBA to correct deficiencies in cardiac surgery at Memorial Healthcare System. STUDY DESIGN: Cardiac surgery is a complex surgical system that lends itself to VBA because outcomes metrics provided by the Society of Thoracic Surgeons provide an estimate of quality; cost is available from Centers for Medicare and Medicaid Services and other contemporary sources; the UP can be determined; and the best practice can be established. RESULTS: Analysis of the UP at Memorial Healthcare System revealed considerable deficiencies in selection of patients for surgery; the surgery itself, including choice of procedure and outcomes; after care; follow-up; and control of expenditures. To correct these deficiencies, each UP was replaced with a BP. Changes included replacement of most of the cardiac surgeons; conversion to an employed physician model; restructuring of a heart surgery unit; recruitment of cardiac anesthesiologists; introduction of an interactive educational program; eliminating unsafe practices; and reducing cost. CONCLUSIONS: There was a significant (p < 0.01) reduction in readmissions, complications, and mortality between 2009 and 2013. Memorial Healthcare System was only 1 of 17 (1.7%) database participants (n = 1,009) to achieve a Society of Thoracic Surgeons 3-star rating in all 3 measured categories. Despite substantial improvements in quality, the cost per case and the length of stay declined. These changes created a savings opportunity of $14 million, with actual savings of $10.4 million. These findings suggest that VBA can be a powerful tool to enhance value (quality/cost) in a complex surgical system.

Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial.

PURPOSE: Anthracycline- and taxane-based three-drug chemotherapy regimens have proven benefit as adjuvant therapy for early-stage breast cancer. This trial (NSABP B-38; Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer) asked whether the incorporation of a fourth drug could improve outcomes relative to two standard regimens and provided a direct comparison of those two regimens. PATIENTS AND METHODS: We randomly assigned 4,894 women with node-positive early-stage breast cancer to six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), four cycles of dose-dense (DD) doxorubicin and cyclophosphamide followed by four cycles of DD paclitaxel (P; DD AC→P), or DD AC→P with four cycles of gemcitabine (G) added to the DD paclitaxel (DD AC→PG). Primary granulocyte colony-stimulating factor support was required; erythropoiesis-stimulating agents (ESAs) were used at the investigator's discretion. RESULTS: There were no significant differences in 5-year disease-free survival (DFS) between DD AC→PG and DD AC→P (80.6% v 82.2%; HR, 1.07; P = .41), between DD AC→PG and TAC (80.6% v 80.1%; HR, 0.93; P = .39), in 5-year overall survival (OS) between DD AC→PG and DD AC→P (90.8% v 89.1%; HR, 0.85; P = .13), between DD AC→PG and TAC (90.8% v 89.6%; HR, 0.86; P = .17), or between DD AC→P versus TAC for DFS (HR, 0.87; P = .07) and OS (HR, 1.01; P = .96). Grade 3 to 4 toxicities for TAC, DD AC→P, and DD AC→PG, respectively, were febrile neutropenia (9%, 3%, 3%; P < .001), sensory neuropathy (< 1%, 7%, 6%; P < .001), and diarrhea (7%, 2%, 2%; P < .001). Exploratory analyses for ESAs showed no association with DFS events (HR, 1.02; P = .95). CONCLUSION: Adding G to DD AC→P did not improve outcomes. No significant differences in efficacy were identified between DD AC→P and TAC, although toxicity profiles differed.

Clinical impact of a value-based decision: a surgical case study.

BACKGROUND: Value is an economic utility defined by quality and cost, with the maximum benefit achieved by improving quality and reducing cost simultaneously. Health care systems are using value-based analysis to identify the best practices (BPs) that accomplish this goal. STUDY DESIGN: We chose a clinical condition, deep venous thrombophlebitis (DVT) to test this hypothesis by identifying the BPs available in the literature; determining the usual practice for DVT prophylaxis at each of 8 hospitals (ie, community, tertiary, and a university hospital) in an integrated system; measuring clinical outcomes (mortality and morbidity) for each hospital; determining cost for each treatment algorithm in each hospital; and measuring the savings opportunity if a single BP was used by all of the hospitals. RESULTS: The literature suggests that the BPs for DVT prophylaxis consist of sequential compression devices for short-stay procedures; unfractionated heparin for inpatient procedures, and low molecular weight heparin for thrombotic events. Four of the hospitals were using these BPs; the others relied on sequential compression devices and low molecular weight heparin for prophylaxis. Outcomes were identical and value-based analysis suggested a savings opportunity of nearly $4 million if a single BP was adopted. CONCLUSIONS: There were substantial variations in the type of DVT prophylaxis used by the hospitals with no difference in outcomes. A single BP increased value and resulted in savings of $1.5 million, with a savings opportunity of nearly $4 million.

Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer.

PURPOSE: Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. PATIENTS AND METHODS: In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. RESULTS: At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. CONCLUSION: The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab.

Clonal dominance of CD133+ subset population as risk factor in tumor progression and disease recurrence of human cutaneous melanoma.

Chemotherapeutic refractoriness of advanced cutaneous melanoma may be linked with melanoma-initiating cells, also known as melanoma stem cells. This study aimed to determine relative risk of clonal dominance of the CD133+ phenotype in tissues from melanoma patients with different clinical outcomes that could be applied to early diagnosis, prognosis or disease monitoring. Significant overexpression of CD133 (p<0.02) was observed by immunohistochemical staining in tissues from patients with recurrent disease versus those without disease recurrence. Relative risk analysis between these two groups suggested that the patients with recurrence or metastatic lesion had a greater than 2-fold overexpression of CD133. In addition, immunodetectable CD133 corroborated with upregulation of CD133 RNA levels (14- to 30-fold) as assessed by quantitative real-time reverse transcription-PCR (qRT-PCR) comparison of melanoma cell lines derived from patients with poor clinical outcomes and short overall survival (<10 months), vs. those derived from patients with good clinical outcomes and longer overall survival (>24 months). Further, cells derived from patients, and MACS-sorted according to their CD133 status retained their CD133-positivity (>95%) or CD133-negativity (>95%) for more than 8 passages in culture. CD133+ cells could repopulate and form tumors (p<0.03) in athymic NCr-nu/nu mice within 8 weeks while no tumors were observed with CD133- phenotype (up to 200,000 cells). Taken together, the study demonstrates, for the first time, that there exists a clonal dominance of a CD133+ population within the hierarchy of cells in cutaneous tissues from patients that have undergone successive progressive stages of melanoma, from primary to metastatic lesions. CD133, thus, provides a predictive marker of disease as well as a potential therapeutic target of high-risk melanoma.

Sequential administration of GM-CSF (Sargramostim) and IL-2 +/- autologous vaccine as adjuvant therapy in cutaneous melanoma: an interim report of a phase II clinical trial.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) are 2 cytokines with distinct mechanisms of action that complement one another in the adjuvant management of melanoma. Forty-five patients with high-risk melanoma were enrolled in an open-label, single-arm, phase II clinical trial to examine the safety, tolerability, and effectiveness of this combination. After potentially curative surgery, each patient received 12 months of GM-CSF 125 microg/m2/d subcutaneously (SC) for 14 days followed by IL-2, 9 million IU/m2/d SC for 4 days (given every other cycle from months 7-12), followed by 10 days of no treatment. In addition, patients who had tumors yielding an adequate number of live cells received autologous melanoma vaccines. For months 13-24, patients received only GM-CSF 250 microg/m2 twice weekly. This is an interim analysis based on the 45 enrolled patients with a median of 15.9 months follow-up (range, 1-50 months). Thirty-two patients are alive: 9 of 13 with stage IV resected melanoma, 16 of 25 with stage III disease, and 7 of 7 with stage II disease. Twelve died of the disease, and one due to stroke. Adjuvant use of sequential GM-CSF and IL-2 +/- autologous vaccine was well tolerated with good patient compliance and seemed to benefit high-risk patients with surgically resected melanoma.

Perioperative adjuvant biotherapy in high-risk resected cutaneous melanoma: the results of 5 years of follow-up.

A feasibility study was conducted to establish the safety and, to some extent, the effectiveness of a new approach of perioperative adjuvant biotherapy in patients with resected cutaneous melanoma. The candidates for this study included patients with primary cutaneous melanoma greater than 1 mm deep, those with resectable regional lymph node (LN) metastases and patients with resectable distant metastases. Interleukin-2 was administered 1 week before definitive surgery as 22 million IU, and again 1 week after the surgery. This was followed by interferon alpha-2b, 10 million IU three times a week for 4 weeks. Fifty-six patients were studied. The program was well tolerated with low, mainly symptomatic, grade I-II toxicity, occasionally with grade III toxicity. Patients' compliance was good. The 5-year survival data were expressed by Kaplan-Meier analysis, and compared with matched historical controls by the log-rank method. The results suggested an improvement in disease-free survival (P=0.021) and a disease-specific overall survival (P=0.05), but not in overall survival, owing to all causes of death (P=0.089). The consequent administration of low-dose interleukin-2 and interferon, initiated preoperatively on outpatient bases, resulted in several constitutional symptoms that were self-limiting and did not delay surgery. No surgical complications related to this approach were observed. This program was well tolerated in all age groups, and the results suggested some survival benefits when compared with matched historical controls.

Diminished dose minimally invasive radioguided parathyroidectomy: a case for radioguidance.

Minimally invasive radioguided parathyroidectomy (MIRP) has been established as an alternative to bilateral neck exploration (BNE) for primary hyperparathyroidism. We investigate whether a diminished dose of technetium-99m sestamibi gives similar results to the standard dose. One hundred one patients were offered MIRP or diminished-dose MIRP (ddMIRP). Patients received intravenous Tc-99m sestamibi at a dose of either 25 mCi 1.5 hours or 5 mCi 1 hour preoperatively. The procedure was terminated when the 20 per cent rule was satisfied. All tissue was confirmed to be parathyroid tissue by frozen section analysis. In addition, intraoperative parathyroid hormone levels were measured in a majority of patients. Patients who failed IOM underwent BNE. Frozen section analysis and intraoperative parathyroid hormone monitoring were also performed in the BNEs. Postoperatively, serum calcium levels were measured at 1 week and 6 months. Fifteen per cent of patients were male and 85 per cent were female. The median age was 63 years (range, 25-89 years). The first 58 patients had the standard dose of 25 mCi, whereas 43 patients had ddMIRP. Six patients (10%) failed intraoperative mapping in the MIRP group and were found to have single-gland disease. Five patients (12%) failed intraoperative mapping in the ddMIRP group. However, two patients were identified to have multigland disease making the true failure rate of intraoperative mapping 7 per cent (three patients). Median operative times for MIRP, ddMIRP, and BNE were 40 minutes, 46 minutes, and 105 minutes, respectively. The 20 per cent rule was satisfied in 96 per cent of patients undergoing MIRP and 98 per cent of patients undergoing ddMIRP. Frozen section analysis and intraoperative parathyroid hormone monitoring did not result in a change in management. Median follow up was 193 days and serum calcium levels at 6 months were normal. Diminished-dose MIRP is a feasible alternative to standard-dose MIRP without compromising surgical outcomes.

Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07.

PURPOSE: This phase III clinical trial evaluated the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin as surgical adjuvant therapy for stage II and III colon cancer. PATIENTS AND METHODS: Patients who had undergone a potentially curative resection were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). RESULTS: A total of 2,407 patients (96.6%) of the 2,492 patients randomly assigned were eligible. Median follow-up for patients still alive is 42.5 months. The hazard ratio (FLOX v FULV) is 0.80 (95% CI, 0.69 to 0.93), a 20% risk reduction in favor of FLOX (P < .004). The 3- and 4-year disease-free survival (DFS) rates were 71.8% and 67.0% for FULV and 76.1% and 73.2% for FLOX, respectively. Grade 3 neurosensory toxicity was noted in 8.2% of patients receiving FLOX and in 0.7% of those receiving FULV (P < .001). Hospitalization for diarrhea associated with bowel wall thickening occurred in 5.5% of the patients receiving FLOX and in 3.0% of the patients receiving FULV (P < .01). A total of 1.2% of patients died as a result of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens. CONCLUSION: The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.

In vivo effects of sequential granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-2 (IL-2) on circulating dendritic cells (DC) in patients with surgically resected high risk cutaneous melanoma.

Dendritic cells were assayed repeatedly in the peripheral blood of consenting melanoma patients receiving adjuvant biotherapy for high risk (stages IIb-IV) melanoma. Postoperatively, adjuvant biotherapy consisted of granulocyte-macrophage colony-stimulating factor [125 microg/m2/day] for 14 consecutive days, followed by interleukin-2 [9 million IU/m2/day] for the next 4 days, and then no treatment for 10-12 days. This was repeated monthly for six cycles. Although white blood cell counts increased, there was no significant elevation in dendritic cell counts during therapy of eleven patients. Within the first cycle during granulocyte-macrophage colony-stimulating factor treatment of seven patients, the absolute DC count decreased (p < 0.04), the percentage of myeloid BDCA-1+ BDCA-2- dendritic cells was significantly lower than baseline (p < 0.003) and the percentage of plasmacytoid BDCA-1- BDCA-2+ dendritic cells was significantly higher than baseline (p < 0.009). Our data suggest mechanisms of potential anti-tumor responses in patients receiving systemic sequential granulocyte-macrophage colony-stimulating factor and interleukin-2 do not include a cumulative gain in peripheral dendritic cell counts or an increase in myeloid BDCA-1+ BDCA-2- dendritic cell subset in the peripheral blood.

GM-CSF and IL-2 combination as adjuvant therapy in cutaneous melanoma: early results of a phase II clinical trial.

Cytokines have been used in the treatment of patients with cutaneous melanoma. Granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) leads to dendritic cell/macrophage priming and activation, and also increases interleukin-2 (IL-2) receptor expression on T. lymphocytes. IL-2 creates lymphokine-activated killer cells and tumor-infiltrating lymphocyte cells. In this open-label, single-arm study of 16 high-risk patients, we combined these two agents to take advantage of their different but complementary functions. All patients underwent potentially curative surgery. Postoperatively, each patient received GM-CSF at 125 microg/m2/d subcutaneously (SC) for 14 days; this was followed by IL-2 at 9 million IU/m2/d SC for 4 days, and then 10 to 12 days of no treatment. In addition, patients who had large tumors that could yield over 100 million live tumor cells received autologous melanoma vaccines. The duration of follow-up ranged from 21 to 42 months (median: 27 months). During follow-up, five patients developed metastases. This program was carried out on an outpatient basis, and no hospitalization was required. It was well tolerated with minimal side effects. The combination treatment regimen of GM-CSF and IL-2 with or without autologous vaccine used adjuvantly appears to benefit high-risk melanoma patients; further clinical testing of this regimen is warranted.

Dendritic cell counts in the peripheral blood of healthy adults.

The normal range for adult blood dendritic cells (DC) has not been established. Blood DC counts were assayed directly from blood for 16 female and 11 male healthy adults with an age range of 22-60 years old (median, 46 years). DC were defined as lineage 1-negative/dim, CD34-negative/dim, and HLA-DR-positive within the total peripheral blood leukocyte (PBL) population. Impedance counter complete blood counts were used with flow cytometry percentages to calculate the absolute DC count and DC percentage of mononuclear cells (MNC). The normal adult ranges for DC calculated as the mean +/- 2SD were 0.16-0.68% PBL, 0.55-1.63% MNC, and 13-37 DC/microL of blood.

The risk of regional lymph node metastases in patients with melanoma less than 1.0 mm thick: recommendations for sentinel lymph node biopsy.

BACKGROUND: Lymphatic mapping and sentinel lymph node biopsy can upstage patients with intermediate thickness (1.0 to 4.0 mm) melanoma. Currently, there are no strict guidelines for sentinel lymph node biopsy in patients with melanoma <1.0 mm thick. STUDY DESIGN: A retrospective review of our patient database (598 patients treated at two institutions in Baltimore, MD, between January 1970 and June 2002) was performed to identify patients with primary cutaneous melanoma <1.0 mm thick who developed recurrent disease. This cohort of patients with > or =5 years of followup from the date of diagnosis was compared with patients with primary melanoma of similar thickness and similar followup intervals without recurrent disease. RESULTS: A total of 114 patients with primary cutaneous melanoma <1.0 mm thick were identified, 17 of whom developed disease recurrence. In 13 patients, the site of first recurrence was the regional lymph nodes and in 4 patients disease recurred with distant metastases. The median time to lymph node recurrence was 55 months (range 2 to 112) months. Patients with regional lymph node recurrences had a significant (p = 0.02) difference in median primary tumor thickness of 0.80 mm versus 0.45 mm in patients without recurrent disease; there was no association of Clark level of invasion to recurrence (p = 0.42). In all, 35% of patients (7 of 20) presenting with melanoma 0.80 to 0.99 mm thick developed lymph node recurrence a median of 41 months (range 8 to 112 months) after surgical treatment. CONCLUSIONS: Sentinel lymph node biopsy can be justified for patients with melanoma > or =0.8 mm thick provided that the technique would detect metastatic disease years before it becomes clinically evident.