Results from the National Taskforce for Humanity in Healthcare's Integrated, Organizational Pilot Program to Improve Well-Being.

BACKGROUND: In health care, burnout remains a persistent and significant problem. Evidence now exists that organizational initiatives are vital to address health care worker (HCW) well-being in a sustainable way, though system-level interventions are pursued infrequently. METHODS: Between November 2018 and May 2020, researchers engaged five health system and physician practice sites to participate in an organizational pilot intervention that integrated evidence-based approaches to well-being, including a comprehensive culture assessment, leadership and team development, and redesign of daily workflow with an emphasis on cultivating positive emotions. RESULTS: All primary and secondary outcome measures demonstrated directionally concordant improvement, with the primary outcome of emotional exhaustion (0-100 scale, lower better; 43.12 to 36.42, p = 0.037) and secondary outcome of likelihood to recommend the participating department's workplace as a good place to work (1-10 scale, higher better; 7.66 to 8.20, p = 0.037) being statistically significant. Secondary outcomes of emotional recovery (0-100 scale, higher better; 76.60 to 79.53, p = 0.20) and emotional thriving (0-100 scale, higher better; 76.70 to 79.23, p = 0.27) improved but were not statistically significant. CONCLUSION: An integrated, skills-based approach, focusing on team culture and interactions, leadership, and workflow redesign that cultivates positive emotions was associated with improvements in HCW well-being. This study suggests that simultaneously addressing multiple drivers of well-being can have significant impacts on burnout and workplace environment.

An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.

Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance).

LESSONS LEARNED: Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma.Patients treated with 10 mg per day dose were most likely to require dose reductions.Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. BACKGROUND: Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). METHODS: This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements. RESULTS: A total of 53 patients were enrolled in cohort 1 (n = 24) and cohort 2 (n = 29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%-49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes. CONCLUSION: Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.

Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors.

AIM: To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations. METHODS: Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings. RESULTS: Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled secretory symptoms, octreotide LAR doses can be titrated up to 60 mg every 4 wk or up to 40 mg every 3 or 4 wk. CONCLUSION: Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.

Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study.

PURPOSE: Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. METHODS: In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS. RESULTS: Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively. CONCLUSIONS: Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.

A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H.

CONTEXT: Pazopanib is a small molecule inhibitor of kinases principally including vascular endothelial growth factor receptors-1, -2, and -3; platelet-derived growth factor receptors-α and -ß; and c-Kit. We previously reported a tumor response rate of 49% in patients with advanced differentiated thyroid cancer and 0% in patients with advanced anaplastic thyroid cancer. The present report details results of pazopanib therapy in advanced medullary thyroid cancer (MTC). OBJECTIVE, DESIGN, SETTING, PATIENTS, INTERVENTION, AND OUTCOME MEASURES: Having noted preclinical activity of pazopanib in MTC, patients with advanced MTC who had disease progression within the preceding 6 months were accrued to this multiinstitutional phase II clinical trial to assess tumor response rate (by Response Evaluation Criteria In Solid Tumors criteria) and safety of pazopanib given orally once daily at 800 mg until disease progression or intolerability. RESULTS: From September 22, 2008, to December 11, 2011, 35 individuals (80% males, median age 60 y) were enrolled. All patients have been followed up until treatment discontinuation or for a minimum of four cycles. Eight patients (23%) are still on the study treatment. The median number of therapy cycles was eight. Five patients attained partial Response Evaluation Criteria In Solid Tumors responses (14.3%; 90% confidence interval 5.8%-27.7%), with a median progression-free survival and overall survival of 9.4 and 19.9 months, respectively. Side effects included treatment-requiring (new) hypertension (33%), fatigue (14%), diarrhea (9%), and abnormal liver tests (6%); 3 of 35 patients (8.6%) discontinued therapy due to adverse events. There was one death of a study patient after withdrawal from the trial deemed potentially treatment related. CONCLUSIONS: Pazopanib has promising clinical activity in metastatic MTC with overall manageable toxicities.

Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675.

OBJECTIVE: Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents (temozolomide [TMZ]) and inhibition of tumor angiogenesis. METHODS: We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/wk) and 200 mg/m/d of TMZ for 5 days each cycle. RESULTS: Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%-59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). CONCLUSIONS: The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma.

Development of a multidisciplinary, multicampus subspecialty practice in endocrine cancers.

PURPOSE: Relative to more abundant neoplasms, endocrine cancers have been historically neglected, yet their incidence is increasing. We therefore sought to build interest in endocrine cancers, improve physician experience, and develop innovative approaches to treating patients with these neoplasms. METHODS: Between 2005 and 2010, we developed a multidisciplinary Endocrine Malignancies Disease Oriented Group involving all three Mayo Clinic campuses (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ). In response to higher demand at the Rochester campus, we sought to develop a Subspecialty Tumor Group and an Endocrine Malignancies Tumor Clinic within the Division of Medical Oncology. RESULTS: The intended groups were successfully formed. We experienced difficulty in integration of the Mayo Scottsdale campus resulting from local uncertainty as to whether patient volumes would be sufficient to sustain the effort at that campus and difficulty in developing enthusiasm among clinicians otherwise engaged in a busy clinical practice. But these obstacles were ultimately overcome. In addition, with respect to the newly formed medical oncology subspecialty endocrine malignancies group, appointment volumes quadrupled within the first year and increased seven times within two years. The number of active therapeutic endocrine malignancies clinical trials also increased from one in 2005 to five in 2009, with all three Mayo campuses participating. CONCLUSION: The development of subspecialty tumor groups for uncommon malignancies represents an effective approach to building experience, increasing patient volumes and referrals, and fostering development of increased therapeutic options and clinical trials for patients afflicted with otherwise historically neglected cancers.

Phase II trial of intravenous administration of Reolysin(®) (Reovirus Serotype-3-dearing Strain) in patients with metastatic melanoma.

Reovirus, a replication competent RNA virus, has preclinical activity against melanoma lines and xenografts. We conducted a phase II trial of reovirus in metastatic melanoma patients. Patients received 3 × 10(10) TCID50 on days 1-5 of each 28 day cycle, administered intravenously. Twenty-one eligible patients were enrolled. Treatment was well tolerated without any dose reductions having to be implemented. Post-treatment biopsy samples were obtained in 15 patients, 13/15 contained adequate tumor for correlative analysis. In two patients, productive reoviral replication (viral antigen coexpression with tubulin) was demonstrated, despite increase in neutralizing antibody titers. There were no objective responses although 75-90% tumor necrosis, consistent with treatment effect, was observed in one patient who had metastatic lesions surgically removed. Median time to progression and survival were 45 days (range 13-96 days) and 165 days (range 15 days-15.8 months) respectively. In conclusion, reovirus treatment was well tolerated in metastatic melanoma patients; viral replication was demonstrated in biopsy samples. Based on preclinical data showing synergy with taxane and platinum compounds, a phase II combination trial in metastatic melanoma patients is ongoing.

A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.

CONTEXT/OBJECTIVES: Pazopanib, an inhibitor of kinases including vascular endothelial growth factor receptor, demonstrated impressive activity in progressive metastatic differentiated thyroid cancer, prompting its evaluation in anaplastic thyroid cancer (ATC). DESIGN/SETTING/PATIENTS/INTERVENTIONS/OUTCOME MEASURES: Preclinical studies, followed by a multicenter single arm phase 2 trial of continuously administered 800 mg pazopanib daily by mouth (designed to provide 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true response rate is >5%), were undertaken. The primary trial end point was Response Evaluation Criteria in Solid Tumors (RECIST) response. RESULTS: Pazopanib displayed activity in the KTC2 ATC xenograft model, prompting clinical evaluation. Sixteen trial patients were enrolled; 15 were treated: 66.7% were female, median age was 66 yr (range 45-77 yr), and 11 of 15 had progressed through prior systemic therapy. Enrollment was halted, triggered by a stopping rule requiring more than one confirmed RECIST response among the first 14 of 33 potential patients. Four patients required one to two dose reductions; severe toxicities (National Cancer Institute Common Toxicity Criteria-Adverse Events version 3.0 grades >3) were hypertension (13%) and pharyngolaryngeal pain (13%). Treatment was discontinued because of the following: disease progression (12 patients), death due to a possibly treatment-related tumor hemorrhage (one patient), and intolerability (radiation recall tracheitis and uncontrolled hypertension, one patient each). Although transient disease regression was observed in several patients, there were no confirmed RECIST responses. Median time to progression was 62 d; median survival time was 111 d. Two patients are alive with disease 9.9 and 35 months after the registration; 13 died of disease. CONCLUSIONS: Despite preclinical in vivo activity in ATC, pazopanib has minimal single-agent clinical activity in advanced ATC.

Hepatic arterial infusion and systemic chemotherapy after multiple metastasectomy in patients with colorectal carcinoma metastatic to the liver: a North Central Cancer Treatment Group (NCCTG) phase II study, 92-46-52.

BACKGROUND: Patients with multiple liver metastases from colorectal cancer are at high risk of recurrence after resection. Hepatic artery infusion (HAI) alternating with systemic therapy after surgical resection may improve survival after surgery. METHODS: Patients with liver-only metastases from colorectal cancer amenable to resection/cryoablation were eligible. Previous adjuvant chemotherapy for a completely resected primary tumor was allowed. Alternating courses of HAI and systemic therapy included floxuridine (FUDR) by HAI. Systemic chemotherapy consisted of bolus leucovorin (LV) plus 5-fluorouracil (5-FU). RESULTS: Forty-nine patients had complete resection of their liver metastases, with 44% having more than 4 hepatic metastases and 78% having bilobar disease. Thirty-six patients had HAI FUDR alternating with systemic therapy. Patients received a median of 3.5 cycles (range, 1-4) and 3 cycles (range, 0-6) of therapy with HAI FUDR and systemic therapy, respectively. At the time of final analysis the estimated median disease-free survival and hepatic disease-free survival was 1.2 years (95% confidence interval [CI], 0.9-2.1) and 1.8 years (95% CI, 1.8-not available), respectively. Eleven patients (31%) were alive at this writing. All surviving patients had a minimum of 5.5 years of follow-up. CONCLUSION: This trial of adjuvant chemotherapy in patients who underwent complete resection with unfavorable characteristics demonstrates apparent improvement in outcome compared with historical series treated with surgery alone. However the results of this trial and other randomized trials of HAI do not appear to support its use at this time because of the development of more effective systemic options.

Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study.

BACKGROUND: Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. METHODS: This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. FINDINGS: 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. INTERPRETATION: Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. FUNDING: National Cancer Institute, supported in part by NCI CA15083 and CM62205.

The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): well-differentiated nets of the distal colon and rectum.

Neuroendocrine tumors (NETs) of the distal colon and rectum are also known as hindgut carcinoids based on their common embryologic derivation. Their annual incidence in the United States is rising, primarily as a result of increased incidental detection. Symptoms of rectal NETs include hematochezia, pain, and change in bowel habits. Most rectal NETs are small, submucosal in location, and associated with a very low malignant potential. Tumors larger than 2 cm or those invading the muscularis propria are associated with a significantly higher risk of metastatic spread. Colonic NETs proximal to the rectum are rarer and tend to behave more aggressively. The incidence of rectal NETs in African Americans and Asians is substantially higher than in Caucasians. Colorectal NETs are generally not associated with a hormonal syndrome such as flushing or diarrhea. A multidisciplinary approach is recommended in diagnosing and managing hindgut NETs.

NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus).

Neuroendocrine tumors (NETs) of the thorax, including bronchial and thymic neuroendocrine NETs, are often referred to as NETs of the foregut. The incidence and prevalence of NETs are increasing in the United States as demonstrated in the Surveillance, Epidemiology, and End Results from 1973 to 2004 (J Clin Oncol. 2008;26[18]:3063-3072). Although the majority of bronchial and thymic NETs are sporadic, approximately 5% to 10% can be associated with hereditary syndrome, multiple endocrine neoplasms type 1 (Nat Rev Cancer. 2005;5[5]:367-375). Diagnosis is made by tissue pathology, allowing for characterization and classification of the NET. Radiologic evaluation is performed to determine the extent of disease involvement. Clinical symptoms from hormonal overproduction or from paraneoplastic processes are medically managed to improve patients' quality of life. Locoregional disease can be curative with surgery; however, distant or metastatic disease is rarely curable. Therapeutic options for metastatic/advanced NETs of the thorax are mainly to palliate symptoms. Final treatment recommendations for patients with either bronchial or thymic NETs should be individualized, weighing the risks and benefits of therapy.

A study of paclitaxel, carboplatin, and bortezomib in the treatment of metastatic malignant melanoma: a phase 2 consortium study.

BACKGROUND: Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3-drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma). METHODS: A 2-stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3-agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m2 intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m2; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21-day cycle. The primary endpoint of this trial was tumor response rate (TRR). RESULTS: Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1-7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade>or=3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression-free survival was 3.2 months, and the median overall survival was 7.0 months. CONCLUSIONS: Due to insufficient clinical efficacy, this trial did not proceed to second-stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity.

Quality: the Mayo Clinic approach.

Developing highly reliable care for patients requires changes in some traditional beliefs of medical practice, an evolution toward a "system" of health care, the disciplined application of scientific principles, modifications in the way all future providers are trained, and a fundamental understanding by leadership that quality must become a business strategy and core work, not an expense or regulatory requirement. Quality at Mayo is defined as a composite of outcomes, safety, and service. A 4-part strategic construct focusing on Culture, Infrastructure, Engineering, and Execution has been developed to guide improvement activities and to ensure a comprehensive approach to better patient care. The Mayo Clinic experience has led to a greater understanding of the leadership commitment, organizational challenges, and the breadth of initiatives necessary to achieve highly reliable care.

Pancreatic and multiorgan resection with inferior vena cava reconstruction for retroperitoneal leiomyosarcoma.

BACKGROUND: Inferior vena cava (IVC) leiomyosarcoma is a rare tumor of smooth muscle origin. It is often large by the time of diagnosis and may involve adjacent organs. A margin-free resection may be curative, but the resection must involve the tumor en bloc with the affected segment of vena cava and locally involved organs. IVC resection often requires vascular reconstruction, which can be done with prosthetic graft. CASE PRESENTATION: We describe a 39-year-old man with an IVC leiomyosarcoma that involved the adrenal gland, distal pancreas, and blood supply to the spleen and left kidney. Tumor excision involved en bloc resection of all involved organs with reimplantation of the right renal vein and reconstruction of the IVC with a polytetrafluoroethylene graft. The patient recovered without renal insufficiency, graft infection, or other complications. Follow-up abdominal imaging at 1 year showed a patent IVC graft and no locally recurrent tumor. Prosthetic graft provides a sufficient diameter and length for replacement conduit in extensive resection of IVC leiomyosarcoma. CONCLUSION: To our knowledge, this is the first case of resection of an IVC sarcoma with prosthetic graft reconstruction in combination with pancreatic resection. Aggressive surgical resection including vascular reconstruction is warranted for select IVC tumors to achieve a potentially curative outcome.

Malignant melanoma in the 21st century, part 2: staging, prognosis, and treatment.

Critical to the clinical management of a patient with malignant melanoma is an understanding of its natural history. As with most malignant disorders, prognosis is highly dependent on the clinical stage (extent of tumor burden) at the time of diagnosis. The patient's clinical stage at diagnosis dictates selection of therapy. We review the state of the art in melanoma staging, prognosis, and therapy. Substantial progress has been made in this regard during the past 2 decades. This progress is primarily reflected in the development of sentinel lymph node biopsies as a means of reducing the morbidity associated with regional lymph node dissection, increased understanding of the role of neoangiogenesis in the natural history of melanoma and its potential as a treatment target, and emergence of innovative multimodal therapeutic strategies, resulting in significant objective response rates in a disease commonly believed to be drug resistant. Although much work remains to be done to improve the survival of patients with melanoma, clinically meaningful results seem within reach.

Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis.

Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.

Phase II study of daily oral perifosine in patients with advanced soft tissue sarcoma.

BACKGROUND: A multicenter Phase II study was performed to evaluate the clinical activity of an initial loading (150 mg every 6 hours x 4 doses) dose followed by continuous daily oral dosing (100 mg/day) of perifosine in patients with advanced soft tissue sarcomas (STSs). METHODS: Patients with measurable metastatic STS received perifosine as first-, second-, or third-line treatment and underwent disease assessment every 8 weeks until disease progression, excessive toxicity, or patient refusal. RESULTS: Twenty-three patients received 66 cycles (1 cycle = 4 weeks) of perifosine. One partial response of 9 months duration was observed. The overall 3 and 6 month progression-free survival was 22% and 9%. NCI CTC (v2.0) Grade 1 to 2 gastrointestinal toxicity or fatigue were the most common (>50% of subjects) toxicities observed. The steady-state plasma perifosine levels (Css) were similar to prior experience (mean 6 microg/mL). Patients with Css levels >6 microg/mL appeared more likely to remain on study past 2 months than those with levels <6 microg/mL. CONCLUSIONS: Despite not achieving the primary objective of > or =40% 6-month progression-free survival rate, optimism remains for this agent in STS patients. Prolonged responses in heavily pretreated STS patients continue to be observed with perifosine treatment. Continued assessment of perifosine in STS appears warranted, with special attention to specific histologies or tumor characteristics that might identify a more sensitive population and achieving perifosine Css levels >6 microg/mL.