Classical Hematology Referrals at an National Cancer Institute-Designated Cancer Center: Lessons Learned.

PURPOSE: To understand the spectrum and volume of classical hematology (CH) referrals to hematology clinics at a National Cancer Institute (NCI)-designated cancer center (CC) to plan for the delivery of effective and equitable care for this population. METHODS: One referral office at the Academic CC located in Bexar County, TX, handles all adult hematology referrals. From October 1, 2021, to September 30, 2022, all nonmalignant hematology (MH) referrals were triaged daily to define the category of CH problem. Declined referrals (confirmed at triage that no CH problem was evident) are included as part of this analysis. Electronic consultation (opinion rendered without patient seen) at our CC is available and is not part of this analysis. RESULTS: One thousand nine hundred forty-five CH referrals were received in the 12-month period. Seventy-six referrals (3.9%) were declined. During the study period, there were 2,289 medical oncology referrals and 779 referrals for MH. CH referrals therefore comprise 39% of all hematology-oncology referrals and 71% of all hematology referrals at the CC. Anemia and thrombotic disorders were the most common categories of the accepted CH referrals at 487 (26%) and 393 (21%), respectively. Video visits were used for 447 of all CH referrals (23%), and the rest were in person. CONCLUSION: Nearly 40% of all referrals to hematology and medical oncology at our NCI-designated CC are for CH. Effective management of the CH population of patients will allow ideal care for CH problems and also allow cancer-focused care to improve.

Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies.

Purpose: In this study, we aimed to validate our extensive preclinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics, and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential antitumor activity of the PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B-cell malignancies.Experimental Design: Single-center, exploratory phase Ib open-label, nonrandomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8 to 14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease.Results: Ten patients, median age 65 years with an average of three prior therapies, were enrolled. The median number of cycles administered was 4 (range, 1-13). Treatment was well tolerated; the most common ≥grade 2 treatment-related adverse events were fatigue, anorexia (≥25%), and transient ≥ grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49-315) versus 91 days (28-139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days (range, 28-315).Conclusions: Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active. Clin Cancer Res; 23(5); 1186-92. ©2016 AACR.

Association Between the Number of Suppliers for Critical Antineoplastics and Drug Shortages: Implications for Future Drug Shortages and Treatment.

PURPOSE: Congress has identified the critical need to evaluate contributors to ongoing cancer drug shortages. Because increased competition may reduce drug shortages, we investigated the association between the number of suppliers for first-line breast, colon, and lung antineoplastics and drug shortages. DATA AND METHODS: Using the 2003 to 2014 Red Book and national drug shortage data from the University of Utah's Drug Information Service, we used exploratory analysis to quantify time trends in first-line drug suppliers and shortages by cancer site. Generalized mixed models were used to examine the association between the number of suppliers for individual drugs and resulting drug shortages. RESULTS: Among 35 antineoplastic drugs approved for first-line treatment of breast, colon, and lung cancer, the number of unique suppliers varied greatly (range, 1 to 19). In 2003, 12.5%,33.3%, and 0%of breast, colon, and lung cancer drugs, respectively, experienced shortages, which increased overall by 2014, to 40.0%, 37.5%, and 54.5%, respectively. Having as mall number of drug suppliers more than doubled the odds of shortages compared with a large number of suppliers (≥5), although the results were only statistically significant with three to four suppliers (odds ratio = 2.6, P = .049) but not with one to two suppliers (odds ratio = 3.49, P = .105). One of the strongest risk factors for drug shortages was the age of the drug, with older drugs significantly more likely to experience shortages (P<.001). CONCLUSION: Cancer drugs with a small number of suppliers had a higher risk of drug shortages than did those with$5 suppliers, but the relationship was nonlinear. Because the age of the drug is the strongest risk factor, future studies should explore underlying causes of shortages in older drugs.

Use of Milestones and Development of Entrustable Professional Activities in 2 Hematology/Oncology Training Programs.

BACKGROUND: The Next Accreditation System (NAS) increases the focus on educational outcomes and meaningful evaluation of learners. This requires that key clinical faculty develop new assessment formats such as entrustable professional activities (EPAs). OBJECTIVES: To build and develop milestone-based assessment tools supporting 5 EPAs for a hematology/oncology fellow continuity clinic, and to educate key clinical faculty regarding the Clinical Competency Committee (CCC) and the NAS. METHODS: Program directors from 2 hematology/oncology fellowship programs developed 5 EPAs for continuity clinic evaluation supported by milestone-based assessment. The program directors met to create a unified CCC charter. Key clinical faculty helped to develop a milestone-based evaluation of fellow continuity clinic through creation of 5 hematology/oncology-specific EPAs. Formal entrustment regarding EPAs was deliberated by the CCC. RESULTS: A total of 18 fellows were evaluated. Clinical Competency Committee deliberation at each institution took approximately 10 minutes per fellow for discussion and decision regarding entrustment for all 5 EPAs supporting continuity clinic. One-third of postgraduate year (PGY)-4s, 50% of PGY-5s, and 100% of PGY-6s were deemed competent in all 5 EPAs by the CCC. CONCLUSIONS: All hematology/oncology trainees in San Antonio were evaluated using milestone-based assessment for continuity clinic, and entrustment decisions regarding 5 EPAs were made by the CCC. This project may provide other programs with a sound basis for adoption and further development of the next generation of evaluation tools at their institutions. Entrustable professional activities that are rotation specific should be used as a starting point for linking to the competencies, subcompetencies, and the reporting milestones.

Breast cancer treatment delays in a majority minority community: is there a difference?

PURPOSE: Recent studies from large nationwide cancer databases have consistently shown that Hispanic women with breast cancer have delays in treatment initiation compared with non-Hispanic white women. However, time to treatment initiation has not been studied in a community where Hispanics are the majority. PATIENTS AND METHODS: We conducted a retrospective, observational study of 362 female patients with breast cancer treated at a large National Cancer Institute (NCI) -designated cancer center with a largely Hispanic population. We examined the relationship between race/ethnicity and time from mammogram to biopsy as well as time from biopsy to treatment initiation using Kaplan-Meier analyses and multivariable Cox proportional hazards regression. RESULTS: Half of the female patients with breast cancer were of Hispanic descent (50.0%; n = 181). Hispanic patients were more likely to be obese, have an Eastern Cooperative Oncology Group functional status ≥ 1, and have higher histologic grade disease (all P ≤ .05); no differences in American Joint Committee on Cancer stage at diagnosis were observed. After comprehensive adjustment for demographic and clinical characteristics, we found no significant differences between Hispanic versus non-Hispanic white patients in time from mammogram to biopsy (hazard ratio [HR], 0.91; 95% CI, 0.68 to 1.21) or time from biopsy to treatment (HR, 1.13; 95% CI, 0.69 to 1.88). CONCLUSION: Hispanic women and Non-Hispanic white women with breast cancer treated at an NCI-designated cancer center had similar times to biopsy and treatment initiation. These findings suggest that in majority minority communities with large cancer centers, racial disparities can be reduced. With a growing Hispanic population throughout the United States, future studies should examine the long-term impact on improved breast cancer survival in this population.

Should we move beyond VEGF inhibition in metastatic colorectal cancer? Lessons from early phase clinical trials.

Data from recent clinical trials utilizing bevacizumab or other anti-VEGF agents in patients with metastatic colorectal cancer (mCRC) show improvements in progression-free survival (PFS) but modest, if any, improvements in overall survival (OS). Despite modest improvements, use of bevacizumab beyond first and second progression is routinely done in clinical practice. Recently, the CORRECT trial using regorafenib, a multi-kinase inhibitor with VEGF inhibitory properties, reported modest improvements in PFS and OS when compared to placebo, leading to FDA approval in the third-line setting. Prior to regorafenib, heavily pre-treated patients were often enrolled onto early phase clinical trials with many of these studies reporting efficacy amongst patients with mCRC; however, a collective efficacy analysis of mCRC patients enrolled into early phase clinical trials stratified by class of agents and their mechanism of action has not been done. To assess this, we performed an analysis of efficacy and stratified these findings based on VEGF inhibition versus non-VEGF inhibition in mCRC patients enrolled onto phase I trials at our institution from 3/2004-9/2012. Similar to many reported clinical studies, our data showed that VEGF inhibitors have a statistically significant improvement in PFS when compared to non-VEGF targeting agents; however, no differences in OS were observed between these two different classes of agents. We were not able to identify predictive biomarkers that correlate with efficacy of VEGF inhibitors. This should be further explored in prospective studies in order to identify active agents in this heavily pre-treated population that improve efficacy while minimizing cost and toxicity.

Tumor response evaluation in oncology: current update.

Quantification of tumor burden and assessment of changes in tumor size after chemotherapy are commonly performed to evaluate treatment response in oncology trials. Validation and adoption of different criteria have been attempted in the past to achieve uniformity in scanning techniques and measurement metrics so that comparison of different oncological trials is feasible. Response assessment of solid tumors is usually consisted of either bidimensional (World Health Organization criteria) or unidimensional (Response Evaluation Criteria in Solid Tumors [RECIST] guidelines) measurement of tumors before and after chemotherapy. RECIST 1.1 criteria have been recently published. In this article, we try to provide a comprehensive review of the tumor response evaluation guidelines that were recently updated in attempts to overcome limitations of the previous criteria as well as incorporate recent advances in imaging techniques.

Cancer rates, medical comorbidities, and treatment modalities in the oldest patients.

Cancer disproportionately afflicts older patients, with 56% of incident diagnoses and 71% of deaths occurring in this population. Yet little is known about the "oldest of the old", oncology patients underrepresented in clinical trials. We examined elderly veterans diagnosed with lung, colorectal, prostate or head-neck cancer in 2005 (n=194,797), analyses comparing treatment receipt by age group, 70-84 versus 85-115. Treatment was more common among younger elders, including surgery (1.3% versus 0.6%), chemotherapy (2.1% versus 0.8%) and radiation (1.7% versus 0.7%). Differences were sharper for certain cancers, e.g., chemotherapy for lung (9.0% versus 2.9%), or colorectal surgery (5.8% versus 3.4%). Cancer prevalence is high among elders yet treatment rates appear extremely low, despite evidence of well-tolerated treatment. Toxicity concerns and comorbidities may inhibit pursuit of definitive treatment. As we reconcile definitions of 'elderly' with appropriate treatment options, compassionate care requires identifying geriatric oncology guidelines that improve survival and quality of life.

Management of the unknown primary carcinoma: long-term follow-up on a negative PET scan and negative panendoscopy.

BACKGROUND: The unknown primary carcinoma in the head and neck has been estimated to represent up to 7% of all head and neck carcinomas. In an attempt to identify the occult primary tumor the evaluation of this patient population has included a complete head and neck examination, flexible fiberoptic endoscopy, and imaging with CT/MRI. More recently, positron emission tomography (PET) has been advocated as a tool to detect primary tumors. METHODS: A cohort of 31 patients with fine-needle aspiration biopsy-confirmed squamous cell carcinoma were prospectively entered into a diagnostic protocol to identify the occult primary tumor. The diagnostic protocol included a comprehensive head and neck examination (including flexible endoscopy) and CT and/or MRI. If the initial diagnostic evaluation failed to identify a primary tumor, the patients then underwent whole body PET imaging followed by staging endoscopy with biopsy of the at-risk occult tumor sites. The outcome measures included the accuracy of the PET to predict the presence of occult tumor at staging endoscopy and the accuracy of the negative PET and negative panendoscopy in predicting the subsequent development of a primary tumor in the upper aerodigestive tract during follow-up. RESULTS: The PET detected 9 occult primary tumors in the 31 patients (detection rate, 29%). Five occult primary tumors (2 base of tongue and 3 palatine tonsil) were detected during panendoscopy despite a negative PET. The combination of PET and panendoscopy detected 45.2% of the unknown primary tumors. Seventeen patients (N1, n = 7; N2a, n = 4; N2b, n = 2; N3, n = 4) had no primary tumor detected and were treated as an unknown primary carcinoma with primary neck dissection +/- radiation therapy +/- chemotherapy. In this series of 17 patients, there were 3 neck recurrences (17.6%). In addition, only 1 patient (5.8%) developed a primary tumor of the upper aerodigestive tract with a mean follow-up of 31.1 months (range, 21-60 months). CONCLUSION: A negative PET study in patients with an occult primary head and neck carcinoma does not preclude the need for panendoscopy with biopsy to detect the occult primary tumor. The risk of subsequent primary tumor appears to be low in the patients with a negative PET and a negative panendoscopy (<6%).

Phase II evaluation of an intensified induction therapy with standard daunomycin and cytarabine followed by high dose cytarabine for adults with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (SWOG-9500).

Induction therapy for acute myeloid leukemia (AML) usually consists of 7 days of cytarabine at 100-200 mg/m(2)/day and an anthracycline. Such combinations produce complete response (CR) rates of 60-80% in patients with de novo AML. On the basis of a previous report, suggesting a higher CR rate using a regimen of standard daunomycin and cytarabine followed by 3 days of high-dose cytarabine (HDAC), 101 eligible patients received this regimen in a phase II trial. Sixty patients [59%, 95% confidence interval (CI) 49-69%] achieved a CR, and 10 patients died of infection during induction. Although cytogenetic risk group affected overall survival (P = 0.0016) and relapse-free survival (P = 0.0043), it had no impact on CR rate (P = 0.63). Patients received postremission therapy with repetitive courses of alternate day high-dose cytarabine; this was associated with considerable toxicity and the majority of patients could not receive all of the scheduled postremission therapy. The estimated median survival was 23 months (95% CI 15-34 months), and the estimated probability of surviving 5 years was 34% (95% CI 24-43%). The results of this intensive induction regimen were similar to that seen in previous trials and were not as promising as reported in the previous pilot study.

Evaluation of Ki67, p53 and angiogenesis in patients enrolled in a randomized study of neoadjuvant chemotherapy with or without cystectomy: a Southwest Oncology Group Study.

In this prospective biomarker study, we evaluated the prognostic significance of Ki67, p53 and angiogenesis in patients with locally advanced bladder cancer. The patients were volunteers from a Southwest Oncology Group trial of locally advanced bladder cancer who were randomized to treatment with neoadjuvant chemotherapy plus cystectomy or cystectomy alone. Tissue specimens were obtained prior to neoadjuvant chemotherapy from 42 patients randomized to receive the combination-treatment arm and 52 randomized to cystectomy alone. The statistical power of the study was quite limited by the small sample size. The biomarkers were assayed by immunohistochemistry. Angiogenesis was determined using anti-CD34 immunostaining. Patients whose tumors had increased Ki67 expression had better progression-free survival that was marginally significant, p=0.063. The median survival in those with higher Ki67 expression was 73 months, and in those with lower expression was 38 months. However, this did not achieve statistical significance, p=0.25. There was a suggestion of worse survival among patients whose tumors exhibited altered p53 staining [hazard ratio (HR) = 1.48; p=0.15], but there was no difference in progression-free survival (HR=1.02; p=0.93). The enumeration of tumor microvessels did not provide prognostic information.

The role of positron emission tomography scans in the management of the N-positive neck in head and neck squamous cell carcinoma after chemoradiotherapy.

OBJECTIVE: The objective of this study was to determine the sensitivity, specificity, and predictive value of 18-fluorodeoxyglucose positron emission tomography (PET) in predicting residual cervical metastatic disease in patients with N-positive necks undergoing curative radiotherapy and chemoradiotherapy for squamous cell carcinoma (SCC) of the upper aerodigestive tract. METHODS: The authors studied a prospective case series of patients (2003-2005) of patients undergoing radiotherapy and chemoradiotherapy for advanced head and neck SSC. Study entry criteria included N-positive neck disease, a complete response to treatment at the primary tumor site, posttreatment PET scan (8-12 weeks after completion of treatment), followed by salvage neck dissection. The posttreatment PET scan neck findings were correlated to the salvage neck dissection pathology report. The sensitivity, specificity, and predictive values of the PET scan to predict residual cervical metastatic disease after curative chemoradiotherapy were calculated. RESULTS: Twenty-one neck dissections (pretreatment N1 = 5, N2a = 2, N2b = 8, N3 = 6) were entered into the protocol. Four (19.0%) of the 21 neck specimens were positive for residual cervical metastatic disease, whereas the remaining 17 (80.9%) specimens demonstrated no residual carcinoma. The overall sensitivity and specificity were 75.0% and 64.7%, respectively. The positive predictive value was 33% and the negative predictive value was 91.7%. CONCLUSIONS: Although the role of posttreatment neck dissection remains controversial, the surgeon must rely on clinical examination and imaging studies. Our practice has been to perform planned staged neck dissections on all N2 and N3 necks, as well as N1 necks with an incomplete response to treatment. Based on this small prospective study, it appears that PET imaging lacks adequate sensitivity and specificity to reliably predict the presence of residual cervical metastatic disease after completion of chemoradiotherapy. With a negative predictive value of 91.7%, however, a negative PET scan appears to be a reliable predictor of the absence of residual tumor.

Acquired methemoglobinemia: a rare but serious complication.

Topical and local anesthetics are employed during minor invasive procedures to increase patient tolerance and to reduce the need for intravenous sedation. A potentially fatal complication of these anesthetics is methemoglobinemia (Met-Hgb). Met-Hgb should be suspected in patients with cyanosis that does not respond to administration of oxygen and who have a discrepancy in oxygen saturation measured by pulse oximetry compared with the arterial partial pressure of oxygen (PaO2) determined by blood gas analysis. We present a patient who developed life-threatening Met-Hgb from the local anesthesia required during percutaneous endoscopic gastrostomy tube placement.

Boston City Hospital and the Thorndike Memorial Laboratory: the birth of modern haematology.

Established in 1923, the Thorndike Memorial Laboratory at Boston City Hospital was the first clinical research laboratory in a municipal hospital in the United States of America. Minot and Castle, who were the second and third directors of the Laboratory, were pioneer haematologists and clinical investigators of the highest calibre who created an atmosphere at the Laboratory that would foster patient-centred research and attract the best physician-scientists to work and train there. The haematology research division of the Laboratory made important original contributions to the understanding of the pathophysiology of anaemia, the mechanisms of red cell and platelet destruction and the phagocytic role of the spleen, the nature of haemoglobin (normal and sickle cell), the nature of haemophilia and its therapy and the early classification of lymphoma. It contributed to the Thorndike Memorial Laboratory's worldwide reputation as a model research laboratory and established its reputation as the birthplace of modern haematology.

Intervention in patients with pneumothorax immediately following CT-guided fine needle aspiration of pulmonary nodules.

BACKGROUND: The incidence of pneumothorax (PTX) as a complication of computerized tomography guided fine needle aspirates (CT-FNA) of solitary pulmonary nodules (SPN) varies from 8-61%. It has been suggested that the practice of obtaining a delayed chest radiograph in patients who have undergone CT-FNA of SPN is not cost effective and adds little information concerning lung expansion obtained by CT at the end of the procedure. It, however, is not known what percent of patients with a PTX present immediately after CT-FNA but do not require prompt chest tube placement will progress and require intervention later. MATERIAL/METHODS: One hundred-fifty-eight consecutive patients undergoing CT-FNA of SPN were included in the study. Immediately after CT-FNA each patient was reimaged with the CT scanner to check for PTX. Patients with a PTX immediately after CT-FNA were assessed as to whether intervention was undertaken or whether the PTX enlarged and/or required drainage at a later time. RESULTS: Thirty-eight patients developed a PTX while still on the CT scanner. Twenty-nine patients with an immediate PTX did not require drainage of their pleural space. Chest tube placement was required promptly after the CT-FNA in 4 patients. Five patients had their pleural space drained at a later time due to an increasing size of the PTX and/or the development of symptoms attributed to the PTX. CONCLUSIONS: These data suggest that patients who develop a PTX immediately after CT-FNA but who do not require prompt pleural space evacuation should be followed closely both clinically and radiographically.