Management and use of healthcare resources in patients with chronic lymphocytic leukemia initiating venetoclax in routine clinical practice.

Venetoclax is a first-in-class B-cell lymphoma-2 (BCL-2) inhibitor approved as continuous monotherapy and in combination with rituximab as fixed-treatment duration for relapsed and refractory chronic lymphocytic leukemia (R/R CLL). DEVOTE was a 24-week, multicenter observational study (NCT03310190) evaluating the safety, healthcare resource utilization (HCRU) and health-related quality of life (HRQoL) of patients initiating venetoclax for R/R CLL in Canada. Overall, 89 patients received 1 dose of venetoclax; 80% had prior exposure (42% resistant) to ibrutinib. Biochemical tumor lysis syndrome (TLS) occurred in five patients. We observed differences in hospitalization across Canadian provinces including in patients at low risk for TLS with no clear impact on TLS incidence. Additionally, a rapid and sustained improvement in several domains of HRQoL was observed during venetoclax initiation. Early adoption of venetoclax was mainly for R/R CLL patients with few treatment options; nonetheless, acceptable toxicity and a positive impact on HRQoL were observed.

Remote, proactive, telephone based management of toxicity in outpatients during adjuvant or neoadjuvant chemotherapy for early stage breast cancer: pragmatic, cluster randomised trial.

OBJECTIVE: To evaluate the effectiveness of remote proactive management of toxicities during chemotherapy for early stage breast cancer. DESIGN: Pragmatic, cluster randomised trial. SETTING: 20 cancer centres in Ontario, Canada, allocated by covariate constrained randomisation to remote management of toxicities or routine care. PARTICIPANTS: All patients starting adjuvant or neoadjuvant chemotherapy for early stage breast cancer at each centre. 25 patients from each centre completed patient reported outcome questionnaires. INTERVENTIONS: Proactive, standardised, nurse led telephone management of common toxicities at two time points after each chemotherapy cycle. MAIN OUTCOME MEASURES: The primary outcome, cluster level mean number of visits to the emergency department or admissions to hospital per patient during the whole course of chemotherapy treatment, was evaluated with routinely available administrative healthcare data. Secondary patient reported outcomes included toxicity, self-efficacy, and quality of life. RESULTS: Baseline characteristics of participants were similar in the intervention (n=944) and control arms (n=1214); 22% were older than 65 years. Penetration (that is, the percentage of patients who received the intervention at each centre) was 50-86%. Mean number of visits to the emergency department or admissions to hospital per patient was 0.91 (standard deviation 0.28) in the intervention arm and 0.94 (0.40) in the control arm (P=0.94); 47% (1014 of 2158 patients) had at least one visit to the emergency department or a hospital admission during chemotherapy. Among 580 participants who completed the patient reported outcome questionnaires, at least one grade 3 toxicity was reported by 48% (134 of 278 patients) in the intervention arm and by 58% (163 of 283) in the control arm. No differences in self-efficacy, anxiety, or depression were found. Compared with baseline, the functional assessment of cancer therapy trial outcome index decreased by 6.1 and 9.0 points in the intervention and control participants, respectively. CONCLUSIONS: Proactive, telephone based management of toxicities during chemotherapy did not result in fewer visits to the emergency department or hospital admissions. With the rapid rise in remote care because of the covid-19 pandemic, identifying scalable strategies for remote management of patients during cancer treatment is particularly relevant. TRIAL REGISTRATION: ClinicalTrials.gov NCT02485678.

Magnetic resonance imaging in boys with severe hemophilia A: Serial and end-of-study findings from the Canadian Hemophilia Primary Prophylaxis Study.

BACKGROUND: This study examined the structural outcomes for joints of boys with severe hemophilia A receiving frequency/dose-escalated primary prophylaxis using magnetic resonance imaging (MRI), and the importance of interval MRI changes. METHODS: Forty-six subjects (27 with interval studies) were evaluated by radiographs (X-rays) and mid- and end-of-study MRIs (using the International Prophylaxis Study Group scale), as part of the Canadian Hemophilia Prophylaxis Study. The primary outcome was the presence of MRI osteochondral findings. RESULTS: The median (range) time on study at the end-of-study MRI examination was 9.6 (4.8-16.0) years, during which 18 of 46 subjects (39%) had osteochondral changes in at least one joint. An interval change in MRI score of at least 1 point was observed in 44% of joints (43 ankles, 21 elbows, 4 knees); at least one joint showed this change in all 27 subjects. Self-reported interval hemarthrosis was associated with a higher likelihood of interval osteochondral change (odds ratio [OR], 1.49; 95% confidence interval [CI] = 1.08-2.06). Presence of synovial hypertrophy or hemosiderin on interval MRIs was associated with an OR of 4.71 (95% CI, 1.92-11.57) and 5.25 (95% CI, 2.05-13.40) of later osteochondral changes on MRI. DISCUSSION: MRI changes were seen in 39% of subjects. Interval index joint bleeding was associated with an increased risk of later MRI changes, and earlier soft-tissue changes were associated with subsequent osteochondral changes.

Telehealth in Oncology: ASCO Standards and Practice Recommendations.

PURPOSE: To provide standards and practice recommendations specific to telehealth in oncology. METHODS: A systematic review of the literature on telehealth in oncology was performed, including the use of technologies and telecommunications systems, and other electronic methods of care delivery and sharing of information with patients. The evidence base was combined with the opinion of the ASCO Telehealth Expert Panel to develop telehealth standards and guidance. Public comments were solicited and considered in preparation of the final manuscript. RESULTS: The Expert Panel determined that general guidance on implementing telehealth across general and specialty settings has been published previously and these resources are endorsed. A systematic search for studies on topics specific to oncology resulted in the inclusion of two clinical practice guidelines, 12 systematic reviews, and six primary studies. STANDARDS AND GUIDANCE: Standards and guidance are provided for which patients in oncology can be seen via telehealth, establishment of the doctor-physician relationship, role of allied health professionals, role of advanced practice providers, multidisciplinary cancer conferences, and teletrials in oncology. Additional information is available at www.asco.org/standards.

Unexpected diagnosis of acute lymphoblastic leukemia in a 2-year-old with acute appendicitis - Case report.

INTRODUCTION AND IMPORTANCE: Appendicitis is an extremely common surgical problem, especially in the pediatric population. However, leukemic infiltration of the appendix is rare and even more so is having acute appendicitis as the initial manifestation. CASE PRESENTATION: The patient is a 2-year-old female with multiple febrile illnesses since birth, who presented to the emergency department with a 3-day history of abdominal pain, fever, and decreased appetite. Ultrasound of her right lower quadrant was consistent with acute appendicitis. A laparoscopic appendectomy was performed successfully without complication. However, pathological examination of the specimen revealed an appendix with partial involvement of B-lymphoblastic lymphoma/leukemia in a background of lymphoid hyperplasia. This prompted referral to a pediatric hematologist/oncologist. Further workup revealed abnormal immature cells on peripheral blood flow cytometry. Bone marrow biopsy confirmed a diagnosis of B-cell acute lymphoblastic leukemia. CLINICAL DISCUSSION: Though acute appendicitis is very common and management is well documented, it is rare for pathological examination to uncover leukemia as an underlying etiology and to have acute appendicitis as the initial manifestation of hematologic malignancy. To our knowledge, very few similar events have occurred and been documented in the medical literature. CONCLUSION: Physicians and surgeons should be aware that, though quite rare, leukemic infiltration of the appendix can occur and should be considered in the differential diagnosis of acute appendicitis. Notably, pathologic examination of the appendix may be particularly informative. Diligent follow-up of abnormal pathology is crucial in cases suggestive of underlying hematologic malignancy.

Patterns of joint damage in severe haemophilia A treated with prophylaxis.

OBJECTIVE: The primary objective of this study was to assess whether there are different patterns (classes) of joint health in young boys with severe haemophilia A (SHA) prescribed primary tailored prophylaxis. We also assessed whether age at first index joint bleed, blood group, FVIII gene abnormality variant, factor VIII trough level, first-year bleeding rate and adherence to the prescribed prophylaxis regimen significantly predicted joint damage trajectory, and thus class membership. METHODS: Using data collected prospectively as part of the Canadian Hemophilia Primary Prophylaxis Study (CHPS), we implemented a latent class growth mixture model technique to determine how many joint damage classes existed within the cohort. We used a multinomial logistic regression to predict the odds of class membership based on the above predictors. We fitted a survival model to assess whether there were differences in the rate of dose escalation across the groups. RESULTS: We identified three distinct classes of trajectory: persistently low, moderately increasing and rapidly increasing joint scores. By multinomial regression, we found that only age at first index joint bleed predicted rapidly increasing joint scores. The rapidly increasing joint score class group moved through dose escalation significantly faster than the other two groups. CONCLUSIONS: Using tailored prophylaxis, boys with SHA follow one of three joint health trajectories. By using knowledge of disease trajectories, clinicians may be able to adjust treatment according to a subject's predicted long-term joint health and institute cost-effective programmes of prophylaxis targeted at the individual subject level.

Telehealth Delivery of Outpatient Pediatric Surgical Care in Hawai'i: An Opportunity Analysis.

In the state of Hawai'i, nearly all pediatric surgical care is delivered on the main island of O'ahu at the state's primary tertiary children's hospital. Outpatient clinic visits require patients and families to travel to O'ahu. The direct and opportunity costs of this can be significant. The objective of this study was to characterize potential telehealth candidates to estimate the opportunity for telehealth delivery of outpatient pediatric surgical care. A retrospective chart review including all patients transported from neighbor islands for outpatient consultation with a pediatric surgeon on O'ahu over a 4-year period was performed. Each patient visit was examined to determine if the visit was eligible for telehealth services using stringent criteria. Direct, insurance-based costs of the travel necessary were then determined. Demographic data was used to characterize the patients potentially affected. A total of 1081 neighbor island patients were seen in the pediatric surgery clinic over 4 years. Thirty-one percent of these patients met criteria as candidates for telehealth visits. The majority of patients came from Hawai'i and Maui. Most patients were identified as Native Hawaiian or Asian. The average cost per trip was $112.53 per person, leading to a potential direct cost savings of $37,697 over 4 years. Over 30% of outpatient pediatric surgical encounters met stringent criteria as candidates for telehealth delivery of care. Given the significant number of patients that met our criteria, we believe there is an opportunity for direct, travel-based cost savings with the implementation of telehealth delivery of outpatient pediatric surgical care in Hawai'i.

Hemophilia prophylaxis adherence and bleeding using a tailored, frequency-escalated approach: The Canadian Hemophilia Primary Prophylaxis Study.

BACKGROUND: Standard of care for persons with severe hemophilia A includes regular replacement of factor VIII (FVIII). Prophylaxis regimens using standard half-life (SHL) FVIII concentrates, while effective, are costly and require frequent intravenous infusions. AIM: This study evaluated the adherence of 56 boys with severe hemophilia A to tailored, frequency-escalated prophylaxis with an SHL recombinant FVIII concentrate. METHODS: We reviewed the factor infusion and bleeding logs of study subjects. Adherence to the prescribed regimen was calculated on a weekly basis, and bleeding rates were determined from self/proxy-reported bleeding logs. The primary outcome was adherence to the prescribed prophylaxis regimen. RESULTS: The median (range of values [ROV]) weekly adherence to prophylaxis was 85.7% (37.4%-99.8%). The median (ROV) adherent weeks on steps 1 (weekly), 2 (twice weekly), and 3 (alternate-day) were 92.9% (50%-100%), 80.3 (32%-96%), and 72.6% (14%-98%); relative to step 1, subjects were less likely to be adherent on steps 2 and 3 (P < 0.00). On step 1, our cohort had higher adherence than previously reported rates. The median (ROV) adherence to the breakthrough bleeding protocol was 47.1% (0%-100%). At any given time, bleeding risk was reduced by 15% for each 10% increase in adherence during the preceding 12 weeks (hazard ratio, 0.85; 95% confidence interval, 0.81-0.90). CONCLUSION: This cohort had high rates of adherence to the prescribed prophylaxis regimen. Initiating prophylaxis with once-weekly infusions facilitated adherence to the prophylaxis regimen in this cohort of boys with severe hemophilia A started on primary prophylaxis at a very young age.

Expanding Urgent Oncofertility Services for Reproductive Age Women Remote from a Tertiary Level Fertility Centre by Use of Telemedicine and an On-site Nurse Navigator.

The objective of this study was to examine a 1-year pilot program aimed at increasing access to fertility preservation (FP) information and services for reproductive-age women newly diagnosed with cancer at a centre geographically remote from a tertiary fertility clinic. An oncofertility nurse navigator (ONN) position was created within the regional cancer centre with the goals of (1) improving local physician knowledge of FP and FP services and (2) improving patient access to FP counselling and services. The ONN identified all women diagnosed with cancer requiring treatment that could impact their fertility and discussed FP options with them and their physicians. As part of a comprehensive program aimed at facilitating access to FP services, the ONN arranged consultations with fertility specialists via telemedicine and coordinated satellite cycle monitoring with a local gynaecologist in order to minimize travel. Patients were surveyed about their reproductive plans, decision-making around FP and experiences with the program. Physicians were surveyed about their engagement with FP services, barriers to FP access and satisfaction with the program. Twenty-two women were eligible for FP during the year-long pilot program. All participated in the study. The most common diagnoses were breast and cervical cancer. At the time of diagnosis, 36.4% of women had no biological children and 68.2% did not desire (more) children. Four women had an FP consultation, and two proceeded with oocyte or embryo cryopreservation. At the end of the pilot program, more physician respondents often or always discussed FP with their patients, stated they frequently refer for FP consultations and stated their patients could obtain FP services in a timely fashion. An ONN within a cancer centre remote from tertiary fertility care can enable access to FP services with minimal need for travel by using local gynaecologic expertise and telemedicine.

Ambulatory Toxicity Management (AToM) Pilot: results of a pilot study of a pro-active, telephone-based intervention to improve toxicity management during chemotherapy for breast cancer.

BACKGROUND: Chemotherapy is associated with a significant risk of toxicity, which often peaks between ambulatory visits to the cancer centre. Remote symptom management support is a tool to optimize self-management and healthcare utilization, including emergency department visits and hospitalizations (ED+H) during chemotherapy. We performed a single-arm pilot study to evaluate the feasibility, acceptability, and potential impact of a telephone symptom management intervention on healthcare utilization during chemotherapy for early stage breast cancer (EBC). METHODS: Women starting adjuvant or neoadjuvant chemotherapy for EBC at two cancer centres in Ontario, Canada, received standardized, nurse-led calls to assess common toxicities at two time points following each chemotherapy administration. Feasibility outcomes included patient enrollment, retention, RN adherence to delivering calls per the study schedule, and resource use associated with calls; acceptability was evaluated based on patient and provider feedback. Impact on acute care utilization was evaluated post hoc by linking individual patient records to provincial data holdings to examine ED+H patterns among participating patients compared to contemporaneous controls. RESULTS: Between September 2013 and December 2014, 77 women were enrolled (mean age 55 years). Most commonly used regimens were AC-paclitaxel (58%) and FEC-docetaxel (16%); 78% of patients received primary granulocyte colony-stimulating factor prophylaxis. 83.8% of calls were delivered per schedule; mean call duration was 9 min. The intervention was well received by both patients and clinicians. Comparison of ED+H rates among study participants versus controls showed that there were fewer ED visits in intervention patients [incidence rate ratio (IRR) (95% CI) = 0.54 (0.36, 0.81)] but no difference in the rate of hospitalizations [IRR (95% CI) = 1.02 (0.59, 1.77)]. Main implementation challenges included identifying eligible patients, fitting the calls into existing clinical responsibilities, and effective communication to the patient's clinical team. CONCLUSIONS: Telephone-based pro-active toxicity management during chemotherapy is feasible, perceived as valuable by clinicians and patients, and may be associated with lower rates of acute care use. However, attention must be paid to workflow issues for scalability. Larger scale evaluation of this approach is in progress.

Inhibition of microRNA-124-3p as a novel therapeutic strategy for the treatment of Gulf War Illness: Evaluation in a rat model.

Gulf War Illness (GWI) is a chronic, multisymptom illness that continues to affect up to 30% of veterans deployed to the Persian Gulf during the 1990-1991 Gulf War. After nearly 30 years, useful treatments for GWI are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood, although exposures to pyridostigmine bromide (PB) and pesticides are consistently identified to be among the strongest risk factors. Alleviation of the broad range of symptoms manifested in GWI, which involve the central nervous system, the neuroendocrine system, and the immune system likely requires therapies that are able to activate and inactivate a large set of orchestrated genes. Previous work in our laboratory using an established rat model of GWI identified persistent elevation of microRNA-124-3p (miR-124) levels in the hippocampus whose numerous gene targets are involved in cognition-associated pathways and neuroendocrine function. This study aimed to investigate the broad effects of miR-124 inhibition in the brain 9 months after completion of a 28-day exposure regimen of PB, DEET (N,N-diethyl-3-methylbenzamide), permethrin, and mild stress by profiling the hippocampal expression of genes known to play a critical role in synaptic plasticity, glucocorticoid signaling, and neurogenesis. We determined that intracerebroventricular infusion of a miR-124 antisense oligonucleotide (miR-124 inhibitor; 0.05-0.5 nmol/day/28 days), but not a negative control oligonucleotide, into the lateral ventricle of the brain caused increased protein expression of multiple validated miR-124 targets and increased expression of downstream target genes important for cognition and neuroendocrine signaling in the hippocampus. Off-target cardiotoxic effects were revealed in GWI rats receiving 0.1 nmol/day as indicated by the detection in plasma of 5 highly elevated protein cardiac injury markers and 6 upregulated cardiac-enriched miRNAs in plasma exosomes determined by next-generation sequencing. Results from this study suggest that in vivo inhibition of miR-124 function in the hippocampus is a promising, novel therapeutic approach to improve cognition and neuroendocrine dysfunction in GWI. Additional preclinical studies in animal models to assess feasibility and safety by developing a practical, noninvasive drug delivery system to the brain and exploring potential adverse toxicologic effects of miR-124 inhibition are warranted.

Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort.

BACKGROUND: Severe haemophilia A has high morbidity, and treatment, while effective, is very expensive. We report the 16-year follow-up of the Canadian Hemophilia Prophylaxis Study, which examined the effectiveness of tailored frequency-escalated primary prophylaxis with a focus on health outcomes within the domains of body structures and functions, and activities and participation (according to the WHO International Classification of Functioning, Disability and Health [WHO-ICF] framework) and a view to reducing consumption of costly clotting factor, which accounts for more than 90% of the cost of care of severe haemophilia. METHODS: In this longitudinal study, boys with severe haemophilia A from 12 Canadian centres were enrolled at age 1·0-2·5 years. They were treated with standard half-life recombinant factor VIII (SHL-rFVIII), beginning as once-weekly prophylaxis with 50 IU/kg and escalating in frequency (with accompanying dose adjustments) in response to breakthrough bleeding as determined by the protocol. The primary endpoint for this analysis was joint health, as measured by the modified Colorado Child Physical Examination Scores (CCPES) at study end. All analyses were done by intention to treat. The trial is complete, and is registered with ClinicalTrials.gov, number NCT01085344. FINDINGS: Between June 26, 1997, and Jan 30, 2007, 56 boys were enrolled. They were followed for a median of 10·2 years (to a maximum of 16·1 years). Median rFVIII usage was about 3600 IU/kg per year. The median end-of-study CCPES physical examination score was 1 (IQR 1-3; range 0-12) for the left ankle and 1 (1-2; 0-12) for the right ankle, with all other joints having a median score of 0. No treatment-related safety events occurred over the duration of the study, including central venous catheter infections. The median annualised index joint bleeding rate was 0·95 per year (IQR 0·44-1·35; range 0·00-13·43), but 17 (30%) patients had protocol-defined unacceptable breakthrough bleeding at some point during the study. INTERPRETATION: Tailored frequency-escalated prophylaxis leads to very little arthropathy and very good health outcomes within the WHO-ICF domains, and only uses a moderate amount of expensive clotting factor as compared with standard prophylaxis protocols. Some sequelae of bleeding were observed in our cohort, and future studies should consider a more stringent protocol of escalation. FUNDING: This study was initially funded by grants from the Medical Research Council of Canada/Pharmaceutical Manufacturers Association of Canada Partnership Fund and the Bayer/Canadian Blood Services/Hema-Quebec Partnership Fund. Subsequent renewals were funded by Bayer.

Cryoanalgesia in Patients Undergoing Nuss Repair of Pectus Excavatum: Technique Modification and Early Results.

PURPOSE: The Nuss procedure for surgical correction of pectus excavatum often causes severe postoperative pain. Cryoanalgesia of intercostal nerves is an alternative modality for pain control. We describe our modification of the cryoICE™ probe that allows for nerve ablation through the ipsilateral chest along with early results utilizing this technique. METHODS: To allow for ipsilateral nerve ablation, a 20-French chest tube was cut and secured to the cryoICE probe, thus providing insulation for the malleable end of the probe. A 3-year retrospective review of patients undergoing Nuss repair at our institution was performed. Patients who received cryoanalgesia (cryo, n = 6) were compared with a historical control cohort who did not receive cryoanalgesia (nocryo, n = 13) during Nuss repair. Hospital length of stay, postoperative narcotic requirement (PNR), and highest postoperative pain score were collected. RESULTS: Both cohorts were similar regarding age, BMI, and pectus index. The cryo group had a significantly less PNR (6.4 versus 17.9 doses, P = .05) and was discharged on average >1 day earlier than nocryo patients (3.7 versus 2.2 days, P = .01). No complications occurred in either group. CONCLUSIONS: Our technique modification simplifies previously described approaches to intercostal nerve cryoablation. Patients undergoing this adjunct benefit with less PNR and a faster discharge time.

Spontaneous Endometriosis Within a Primary Umbilical Hernia.

Umbilical hernias are rather common in the General Surgery clinic; however, endometriosis of an umbilical hernia is rare. It is especially unusual to have endometriosis of an umbilical hernia spontaneously occur compared to occurring at a site of a prior surgery. We present a case of spontaneous endometriosis of an umbilical hernia without prior surgery to her umbilicus. She had not presented with the usual symptoms of endometriosis and it was not considered as a diagnosis prior to surgery. Umbilical endometriosis is rare but usually occurs after prior laparoscopic surgery. We believe this is the second reported case in the English literature and the first such case reported from North America of spontaneous endometriosis of an umbilical hernia. This case highlights the importance of a full review of systems and qualifying the type and occurrence of pain. Additionally, it is always important to analyze surgical specimens in pathology to avoid errors in diagnosis.

Salvage chemotherapy and autologous stem cell transplantation for peripheral T-cell lymphoma: a subset analysis of the Canadian Cancer Trials Group LY.12 randomized phase 3 study.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogeneous malignancy. Of the 619 patients with relapsed and refractory (R/R) aggressive lymphoma enrolled in the Canadian Cancer Trials Group LY.12 phase 3 trial, 59 (9.5%) had PTCL. Among these, 81% had advanced stage disease, 41% had an International Prognostic Score ≥3, and 41% were refractory to primary therapy. Within the PTCL cohort, the overall response rate after two cycles of salvage chemotherapy was 36%; no difference was observed between dexamethasone, cytarabine, cisplatin (10/30, 33%), and gemcitabine, cisplatin, dexamethasone (11/29, 38%) therapy. At one year, event-free survival (EFS) was 16% and overall survival (OS) was 28%. For PTCL patients, who received autologous stem cell transplant, two-year EFS and OS were 21% and 42%, respectively. Patients with PTCL had inferior OS (HR 0.49, p < .0001) and EFS (HR 0.53, p < .0001) compared to B-cell lymphoma. Outcomes for patients with R/R PTCL are poor with currently available therapies.

Evolving Therapeutic Options for Polycythemia Vera: Perspectives of the Canadian Myeloproliferative Neoplasms Group.

Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, reduced quality of life, risk of thrombohemorrhagic complications, and risk of transformation to myelofibrosis and acute myeloid leukemia. The discovery of the JAK2 V617 mutation marked a significant milestone in understanding the pathophysiology of the disease and subsequently the diagnostic and therapeutic approaches. The current diagnostic criteria for PV are based on hemoglobin level and presence of the JAK2 V617 mutation. The treatment is geared toward prevention of thrombotic events, normalization of blood counts, control of disease-related symptoms, and potential prolongation of survival. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapy and is superior to phlebotomy in reducing risk of arterial and venous thrombosis. Interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. The results of pegylated IFN in phase 2 studies appear encouraging, with molecular responses occurring in some patients. Ongoing phase 3 studies of HU versus pegylated IFN will define the optimal first-line cytoreductive therapy for PV. A recent phase 3 trial has shown the superiority of the JAK1/2 inhibitor ruxolitinib in comparison to best available treatment in HU-intolerant or -resistant patients. The therapeutic landscape of PV is likely to change in the near future. In this report, we assess the potential impact of the changing landscape of PV management on daily practice.

Female military medical school graduates entering surgical internships: are we keeping up with national trends?

BACKGROUND: Ratios of women graduating from the only US military medical school and entering surgical internships were reviewed and compared with national trends. METHODS: Data were obtained from the Uniformed Services University of the Health Sciences graduation announcements from 2002 to 2012. RESULTS: There were 1,771 graduates from 2002 to 2012, with 508 female (29%) and 1,263 male (71%) graduates. Female graduates increased over time (21% to 39%; P = .014). Female general surgery interns increased from 3.9% to 39% (P = .025). Female overall surgical subspecialty interns increased from 20% in 2002 to 36% in 2012 (P = .046). Women were represented well in obstetrics (57%), urology (44%), and otolaryngology (31%), but not in neurosurgery, orthopedics, and ophthalmology (0% to 20%). CONCLUSIONS: The sex disparity between military and civilian medical students occurs before entry. Once in medical school, women are just as likely to enter general surgery or surgical subspecialty as their male counterparts. Increased ratio of women in the class is unlikely to lead to a shortfall except in specific subspecialties.

Phase I evaluation of telatinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan and capecitabine in patients with advanced solid tumors.

PURPOSE: We studied the safety and tolerability of telatinib, an orally available, small-molecule tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR-2/VEGFR-3), platelet-derived growth factor receptor beta, and c-Kit in combination with capecitabine and irinotecan. EXPERIMENTAL DESIGN: Telatinib twice daily continuously, irinotecan once every 3 weeks, and capecitabine oral twice daily on day 1 to 14 were administered in cycles of 21 days in escalating doses in successive cohorts. Toxicity was evaluated to conform to the Common Terminology Criteria for Adverse Events version 3.0. Pharmacokinetic and (circulating) endothelial (progenitor) cell measurements were done. Tumor efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty-three patients were included in this phase I trial. Most frequently (>25%) reported adverse events of any grade were vomiting, nausea, fatigue, diarrhea, alopecia, and hand-foot syndrome. A silent myocardial infarction and two cases of decreased left ventricular ejection fraction were reported; both were reversible. Cardiac monitoring of the subsequent patients did not reveal other abnormalities. The study was terminated when the recommended single agent phase II doses of telatinib (900 mg twice daily) and capecitabine/irinotecan was reached. Pharmacokinetic profiles showed no clinically relevant changes upon coadministration of the three drugs. (Circulating) endothelial (progenitor) cell levels stabilized during treatment. Five of 23 patients had partial remission and 9 of 23 patients showed stable disease. CONCLUSIONS: Continuous administration of 900 mg telatinib twice daily can be safely combined with irinotecan (180 mg/m(2)) and capecitabine (1,000 mg/m(2) twice daily, day 1-14) and is the recommended schedule for further phase II studies. Tumor shrinkage and disease stabilization was observed. Cardiac toxicity needs further investigation in following studies.

Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer.

This trial was conducted to assess the efficacy and safety of sorafenib in patients with metastatic breast cancer. In this multinational, open-label phase II study, patients with metastatic breast cancer that had progressed after at least one prior chemotherapy regimen were continuously treated with oral sorafenib, 400 mg twice daily. The primary endpoint was overall best response; a secondary endpoint was percentage of patients with stable disease for greater than or equal to 16 weeks. Biomarker analysis were also performed. Of the 56 patients enrolled into the study, 54 were treated with at least one dose of sorafenib. Partial response was observed in one patient (2%) and stable disease in 20 patients (37%); no complete responses were observed. Disease stabilization for greater than or equal to 16 weeks was seen in 12 patients (22%); stabilization for greater than or equal to 6 months in seven patients (13%). The most common drug-related grade 3 adverse events were rash/desquamation (6%), hand-foot skin reaction (4%), and fatigue (4%). Baseline vascular endothelial growth factor levels, levels of soluble epidermal growth factor receptor during treatment and both baseline and changes in soluble human epidermal growth factor receptor 2 levels correlated significantly with clinical outcomes. Although the primary endpoint of overall response rate showed minimal improvement on sorafenib 400 mg twice-daily treatment, the rate of disease stabilization was encouraging in patients treated with one or more lines of chemotherapy. The treatment had a clinically manageable toxicity profile. Further investigation of single-agent sorafenib in this patient population is not recommended; however, studies investigating combinations of sorafenib with chemotherapeutic agents are warranted and ongoing.

Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma.

PURPOSE: An open-label, phase II study to evaluate progression-free survival (PFS), overall best response, adverse events (AEs), and patient-reported outcomes with sorafenib versus interferon alfa-2a (IFN-alpha-2a) in patients with untreated, advanced renal cancer. PATIENTS AND METHODS: A total of 189 patients were randomly assigned to oral sorafenib 400 mg twice daily or to subcutaneous IFN-alpha-2a 9 million U three times weekly (period 1). Sorafenib patients who progressed were dose-escalated to 600 mg twice daily; IFN-alpha-2a patients who progressed were switched to sorafenib 400 mg twice daily (period 2). RESULTS: In period 1 PFS was similar for sorafenib-treated (n = 97; 5.7 months) and IFN-alpha-2a-treated patients (n = 92; 5.6 months); more sorafenib-treated patients had tumor shrinkage (68.2% v 39.0%). Common drug-related AEs (Grades > or = 3) for sorafenib were hand-foot skin reaction (11.3%), diarrhea (6.2%), and rash/desquamation (6.2%); for IFN-alpha-2a, these were fatigue (10.0%), nausea (3.3%), flu-like syndrome (2.2%), and anorexia (2.2%). Sorafenib-treated patients reported fewer symptoms, better quality of life (QOL), and greater treatment satisfaction. In period 2, 41.9% of patients who received sorafenib 600 mg twice daily (n = 43) experienced tumor reduction (median PFS, 3.6 months). After the switch to sorafenib 400 mg twice daily, tumors were reduced in 76.2% of 50 patients (median PFS, 5.3 months). AEs were mostly grade 1 to 2; no increase in AEs of grades > or = 3 occurred after sorafenib dose escalation. CONCLUSION: In this study, sorafenib resulted in similar PFS as IFN-alpha-2a in patients with untreated RCC. However, sorafenib-treated patients experienced greater rates of tumor size reduction, better QOL, and improved tolerability. Both dose escalation of sorafenib after progression and a switch to sorafenib after progression on IFN-alpha-2a resulted in clinical benefit.