Research priorities to reduce risks from work hours and fatigue in the healthcare and social assistance sector.

BACKGROUND: The services of Healthcare and Social Assistance (HCSA) workers are needed by society around the clock. As a result, these workers are exposed to shift work and long work hours. The combination of demanding work schedules and other hazards in the HCSA work environment increases the health and safety risks to these workers, as well as to their patients/clients and the public. METHODS: This paper has three aims: (1) provide an overview of the burden of shift work, long hours, and related sleep and fatigue problems in this sector; (2) suggest research priorities that would improve these; and (3) discuss potential positive impacts of addressing these research priorities for the health and safety of workers and the public. The authors used a modified Delphi approach to anonymously rank-order priorities for improving HCSA worker health and safety and public safety. Input was also obtained from attendees at the 2019 National Institute for Occupational Safety and Health (NIOSH) Work Hours, Sleep, and Fatigue Forum. RESULTS: The highest rated research priorities were developing better designs for work schedules, and improving the HCSA culture and leadership approaches to shift work and long work hours. Additional priorities are identified. CONCLUSION: Research in these priority areas has the potential to benefit HCSA workers as well as their patients/clients, employers, and society.

Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas.

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.

Phase II Trial of Dolastatin-10, a Novel Anti-Tubulin Agent, in Metastatic Soft Tissue Sarcomas.

PATIENTS: Soft tissue sarcomas are uncommon malignancies with few therapeutic options for recurrent or metastatic disease. Dolastatin-10 (Dol-10) is a pentapeptide anti-microtubule agent that binds to tubulin sites distinct from vinca alkaloids. Based on the novel mechanism of action, limited activity of other anti-microtubular agents, and anti-neoplastic activity in pre-clinical screening of Dol-10, this multi-institutional phase II study was conducted to determine the objective response rate of Dol-10 in recurrent or metastatic soft tissue sarcomas that had not been treated with chemotherapy outside of the adjuvant setting. METHODS: Dol-10 was given intravenously at a dose of 400 mug/m(2) and repeated every 21 days. Toxicities were assessed using the Common Toxicity Criteria (version 2.0). Radiographic studies and tumor measurements were repeated every two cycles to assess response [Miller AB, et al. Cancer 1981; 47(1): 207]. RESULTS: Dol-10 was associated with hematological toxicity and with some vascular toxicities. There was no significant gastrointestinal, hepatic or renal toxicity. There was one death on study due to respiratory failure. There were no objective responses in 12 patients treated with Dol-10. DISCUSSION: Based on this phase II trial, further study of Dol-10 on this schedule is not recommended in advanced or metastatic soft tissue sarcomas.

Desmoid tumors in familial adenomatous polyposis: a pilot project evaluating efficacy of treatment with pirfenidone.

OBJECTIVES: Pirfenidone (Deskar, Marnac Inc., Dallas, TX), 5-methyl-1-phenyl-2-(1H)-pyridone, is a broad-spectrum, noncytotoxic, oral antifibrotic agent that is reported to inhibit or block the action of cytokine growth factors: transforming growth factor beta1, platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor, and to prevent formation of new fibrotic lesions. METHODS: We enrolled 10 women and four men with extensive familial adenomatous polyposis (FAP)-associated desmoid disease in a 2-yr open-label treatment trial with oral pirfenidone. Imaging of desmoids was conducted at baseline and 6, 12, and 24 months. RESULTS: No drug toxicity or drug intolerance was encountered. Seven patients dropped out (three because of progressive disease), and seven continued for at least 18 months. Of those that continued, two had partial but significant reduction in the size of all desmoids beginning in the first 6 months of treatment, and two others experienced relief of symptoms without change in desmoid size. Three patients experienced no change in tumor size or symptoms. CONCLUSIONS: Pirfenidone is well tolerated by patients with FAP-associated desmoid tumors. Some patients with FAP/desmoid tumors treated with pirfenidone had regression of tumors, some had progression, and some had no response. Patients with rapidly growing tumors did not respond to pirfenidone. A placebo-controlled trial is needed to determine whether there is a subset of patients for whom pirfenidone may result in partial shrinkage of desmoid tumors, because the natural history of desmoid tumors is not predictable or understood.

Comparison of conventional dose and double dose carboplatin in patients receiving cyclophosphamide plus carboplatin for advanced ovarian carcinoma: a North Central Cancer Treatment Group Study.

Between March 1992 and November 1994, 91 patients with stage III and IV ovarian carcinoma were enrolled in a randomized comparative study of cyclophosphamide 600 mg/m2 plus carboplatin 300 mg/m2 vs. cyclophosphamide 600 mg/m2 plus carboplatin 600 mg/m2, each regimen given monthly for six cycles. Patients on the intensive regimen also received 10 micrograms/kg of granulocyte macrophage colony stimulating factor (GM-CSF) (molgramostim) daily for 14 days following each chemotherapy treatment. The study was closed prematurely because of very poor case accrual following the preliminary announcement (in May 1993) that paclitaxel appeared superior to cyclophosphamide in the platinum-based treatment of ovarian cancer. More than 4 years after our last case entry, we analyzed the survival results for the 44 eligible patients who received the conventional dose of carboplatin and the 43 eligible patients receiving our intensified dose of carboplatin. More than 90% of the treated patients receiving the conventional dose regimen received at least 75% of the planned doses at each of the six treatment intervals, whereas the percentage of treated patients able to receive at least 75% of the assigned intensive dose regimen had declined from 95% in cycle 2 to 53% by cycle 6. Furthermore, although 32 patients received all six planned cycles of treatment in the conventional regimen group, only 15 received all six cycles of the intensified regimen. Patients receiving the intensive regimen had more fever, dermatitis, lethargy, musculoskeletal pain, and pulmonary complications than did the conventional dose patients. Median survival times for the two treatment groups were very similar (38.5 and 38.1 months, respectively, for the conventional and intensive regimens), and we saw no evidence that the distribution of survival times differed between the treatment regimens (p = 0.95).

Calcified left ventricular mass: unusual clinical, echocardiographic, and computed tomographic findings of primary cardiac osteosarcoma.

Primary cardiac osteosarcomas are rare and usually originate in the left atrium. In contrast, osteosarcomas metastatic to the heart most commonly involve the right cardiac chambers. This case report describes an unusual primary cardiac osteosarcoma, initially observed as a slowly growing, densely calcified mass of the left ventricle with subsequent secondary pulmonary metastasis. Although cardiac tumors may be asymptomatic, this patient had recurrent bouts of ventricular tachyarrhythmia. We describe the clinical, echocardiographic, and radiological observations spanning 6 years and the gross and microscopic features at autopsy.

Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience.

PURPOSE: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl-phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally. PATIENTS AND METHODS: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 microg, 30 microg, or 300 microg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 microg twice a week for 3 weeks, 750 microg weekly for 6 weeks, and 1,500 microg weekly for 6 weeks. RESULTS: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8(+) infiltration after treatment in the tumor samples of several patients (12 and 16, respectively). CONCLUSION: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.

Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome.

BACKGROUND: The objective of this descriptive analysis of a large cohort of patients with Langerhans cell histiocytosis (LCH) was to add to the understanding of the natural history, management, and outcome of this disease. METHODS: Three hundred fourteen Mayo Clinic patients with histologically proven LCH were categorized into those patients with multisystem disease and those patients with single system disease. Clinical features, treatment, and outcome were determined from the case history notes and tumor registry correspondence. Treatment included chemotherapy, radiotherapy, and surgical excision. The end points were disease free survival, active disease, or death. The median time of follow-up was 4 years (range, 1 month to 47.5 years). RESULTS: The age of the patients ranged from 2 months to 83 years. Of the 314 patients, there were 28 deaths. Multisystemic LCH was found in 96 patients, 25 of whom had continuing active disease after treatment. Isolated bone LCH lesions were observed in 114 of the 314 patients, 111 of whom (97%) achieved disease free survival after treatment. The most common sites of osseous LCH were the skull and proximal femur. Of the 87 patients with isolated pulmonary involvement, only 3 were nonsmokers. After treatment with corticosteroids (+/- cyclophosphamide or busulphan), 74 patients achieved disease free survival, but 10 patients died. Pituitary-thalamic axis LCH, characterized by diabetes insipidus, was found in 44 patients. After treatment, 30 of these patients had disease free survival, but all required long term hormone replacement with desmopressin acetate. Lymph node involvement was found in 21 patients, and mucocutaneous involvement was found in 77 patients. CONCLUSIONS: Patients with isolated bone LCH lesions have the best prognosis compared with patients with LCH involvement of other systems. By contrast, 20% of patients with multisystem involvement have a progressive disease course despite treatment. The identification of prognostic indicators to facilitate appropriate treatment and long term follow-up surveillance is recommended.

Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group.

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

Can molgramostim enhance the antitumor effects of cytotoxic drugs in patients with advanced sarcomas?

BACKGROUND: A phase I study was designed for the amalgamation of two previously studied antisarcoma regimens (ifosfamide+doxorubicin and mitomycin+doxorubicin+cisplatin) supported by molgramostim. Thus, we hoped to develop a better regimen for the treatment of advanced sarcomas. PATIENTS AND METHODS: Fifteen adult advanced sarcoma patients and six other patients were registered and sequentially assigned to receive three progressively more myelosuppressive levels of chemotherapy: level I-ifosfamide 2500 mg/m2 + doxorubicin 40 mg/m2 + cisplatin 60 mg/m2 all given on day 0, followed by molgramostim 5 micrograms/kg every 12 hours for 14 days; level II-exactly the same chemotherapy from level I given on day 1 preceded on day 0 by ifosfamide 2500 mg/m2 and an additional four days of molgramostim given on days-6 through-3; level III-same as level II except for the addition of mitomycin 4 mg/m2 immediately prior to cisplatin on day 1. MENSA 500 mg/m2 was given five times on each day that involved ifosfamide treatment. For all levels, treatment was repeated at four-week intervals. RESULTS: Preliminary results and toxicity were reported three years ago (J Natl Cancer Inst 86: 312-4, 1994). Mature results confirm these unexpectedly favorable results with five advanced sarcoma patients still surviving after more than three years (four more than four years). HYPOTHESIS: Molgramostim given subcutaneously in a relatively intensive schedule might enhance the antitumor effects initiated by cytotoxic drugs in patients with advanced sarcomas. This idea should be tested formally in phase III studies.