Interactive Pathology Tutorial in Neoplastic Hematology Disorders for Medical Hematology-Oncology Fellows.

Hematology-oncology (HO) fellows receive limited instruction in the process of establishing a diagnosis for hematologic neoplasms, and learning neoplastic hematology often occurs in limited encounters. In the current study, we developed a web-based interactive pathology tutorial in neoplastic hematologic disorders for HO fellows to work up simulated cases and establish the diagnosis. An online system ("Pathology Playground") was utilized to load case materials including microscopic images and ancillary studies. Twelve high-yield simulated cases of common leukemias and lymphoma were included. At the beginning of each case, trainees review the clinical history and slide images, and then, they are given the option to request additional pathology work-up. Based on the results, they can enter their diagnostic impression. If the diagnosis is correct, the user is shown a short educational presentation. If the diagnosis is not correct, the user gets notified by the message "Incorrect." The tutorial was integrated in the educational curriculum of our HO fellowship program, and bimonthly teaching sessions were held to review two cases each time. During the sessions, trainees request ancillary studies to complete the diagnostic work-up using the software and interpret the findings. As the case is being worked up by the trainee, the hematopathologists and HO fellowship program director discuss the findings, the appropriate work-up tools, and the implications on management. All of our six HO fellows attended the sessions, and a survey from the trainees showed high ease of use of the system and they viewed it as a very useful educational tool. A pre-test and post-test were administered for one of the sessions, and the result showed improvement in the average from 62 to 73%. Expanding the use of this online interactive tutorial and incorporating additional cases would enhance its value as a learning resource.

Acute Promyelocytic Leukemia Treatment Masking Hepatic Tuberculosis: A Management Dilemma.

Acute promyelocytic leukemia is a form of acute myeloid leukemia (AML) that is characterized by presence of a promyelocytic leukemia-retinoic acid receptor alpha fusion. In most patients, this fusion is detected on conventional karyotype as the t(15;17)(q24.1;q21.2) translocation, but some patients have cryptic translocations with a normal karyotype. Historically, AML is associated with a poor prognosis. Treatment with all-trans retinoic acid and arsenic trioxide assures long-term survival in the majority of patients. This treatment is generally well-tolerated but may cause hepatotoxicity. This is usually identified by transaminitis but resolves after temporary cessation of treatment. Our patient's hepatotoxicity did not resolve following all-trans retinoic acid and arsenic trioxide cessation which posed a diagnostic dilemma. This prompted exploration of other possible causes of hepatotoxicity. An eventual liver biopsy identified acid-fast bacilli, confirming a diagnosis of hepatic tuberculosis. A broad differential diagnosis is imperative when investigating abnormalities in liver function, especially in chemotherapy patients when treatment cessation may cause cancer progression.

Amiodarone-Induced Immune Thrombocytopenia: A Rare Hematologic Side Effect of a Common Cardiac Drug.

Thrombocytopenia is a rare immune-mediated hematologic complication of amiodarone. We describe a case of delayed-onset amiodarone-induced thrombocytopenia in a 72-year-old male and highlight the process of working it up. A timely diagnosis of drug-induced immune thrombocytopenia is crucial in order to minimize unnecessary testing, avoid treatments with potential harm, and prevent life-threatening hemorrhagic complications.

Low-dose cyclophosphamide and continuous-infusion interleukin-2 with famotidine in previously treated metastatic melanoma or kidney cancer.

UNLABELLED: The cytotoxic ability of T-cells against tumor cells may be increased by interleukin (IL)-2. The infiltration of tumors by these cytotoxic T-cells may be enhanced by low-dose cyclophosphamide, which may also serve to deplete regulatory T-cells. Famotidine may increase IL-2 internalization by the IL-2 receptor on T-lymphocytes. We have treated 14 patients with either metastatic melanoma or kidney cancer, using CY 350 mg/M(2) intravenously (i.v.) over 1 hour followed by a continuous infusion IL-2 9 MIU/M(2)/24 hours for 72 hours and famotidine 20 mg i.v. twice per day. All patients had received prior systemic therapy. Cycles were repeated every 4 weeks until disease progression. PATIENT CHARACTERISTICS: 8 with melanoma, 8 males, median age, 64, median Eastern Cooperative Oncology Group performance status, 1; most common metastatic sites: lungs, lymph nodes, bone, and liver. Median number of cycles received=2 (range, 2-4). Most common toxicities were fever, nausea/emesis, hypomagnesemia, hypophosphatemia, hyponatremia, and rigors. All patients were treated on an oncology inpatient unit. One (1) patient with kidney cancer has had a partial response in lung and lymph nodes for 5 months, while 1 patient with melanoma had a partial response in pulmonary metastases. Cyclophosphamide and IL-2 with famotidine has evidence of antitumor activity in previously treated kidney cancer and melanoma.

Nursing care of patients receiving high-dose, continuous-infusion interleukin-2 with pulse dose and famotidine.

High-dose, continuous-infusion interleukin-2 (IL-2) followed by pulse dose and concurrent administration of famotidine has demonstrated response rates of 64% and 33% in patients with metastatic melanoma and metastatic renal cell carcinoma, respectively. Currently, no information is available concerning the nursing care of patients receiving that IL-2 regimen. Given the high response rates of patients on the treatment, attention by the nursing profession is warranted. Effective nursing care of patients receiving IL-2 is essential to the regimen's success. Recognition and prompt treatment of common side effects lead to better patient outcomes. This article provides nurses with an overview of the treatment regimen, expected side effects, psycho-social considerations, and discharge instructions for patients receiving continuous-infusion plus pulse IL-2 and famotidine.

Complete response in a cutaneous facial metastatic nodule from renal cell carcinoma after hypofractionated radiotherapy.

Cutaneous metastases from renal cell carcinoma (RCC) are uncommon, but may be painful and deforming. A review of the English language literature yields no references regarding the use of radiotherapy in the palliation of cutaneous RCC metastases. We report the first documented case of a patient with a single RCC facial metastatic nodule treated with hypofractionated electron beam radiotherapy followed by administration of sorafenib. The patient achieved a complete resolution of the cutaneous metastasis.

Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy.

Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum-derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers.Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed.Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs.Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074-81. ©2017 AACR.

Continuous infusion interleukin-2 and famotidine in metastatic kidney cancer.

Infusional interleukin-2 (IL-2) is able to elicit lymphokine-activated killer cell (LAK) cytotoxicity against kidney cancer in vitro and in vivo. Famotidine may be able to augment LAK cytotoxicity against neoplastic cells. Fifteen (15) patients were treated with continuous-infusion IL-2 (9-18 MIU/m2/24 hours) for 72 hours and famotidine 20 mg intravenously twice per day. Cycles were repeated every 3 weeks. These patients had a median age of 60 years (range, 29-72), had a median performance status of 1 (range, 0-1), and had metastatic sites, including lung, bone, lymph node, and liver. The most common toxicities of this regimen were hypophosphatemia, fever, nausea/emesis, rigors, elevated creatinine, and hypomagnesemia. One (1) complete and 6 partial responses have been seen (47% response rate). The median duration of response is 9 months. The median survival for all patients is 20 months. Five (5) patients are alive at a median of 36+ months. This combination of infusional IL-2 with famotidine is active in metastatic kidney cancer.

Activity of continuous infusion plus pulse interleukin-2 with famotidine in patients with metastatic kidney cancer or melanoma previously treated with interleukin-2.

Lymphokine-activated killer (LAK) cells generated by high-dose continuous infusion interleukin-2 (IL-2) are able to nonspecifically lyse melanoma and kidney cancer cells. In vitro famotidine enhances cytotoxicity of LAK against tumor cells, possibly by increasing IL-2 uptake at the IL-2 receptor on lymphocytes. Outpatient IL-2 regimens typically have response rates of 15% or less, with most patients eventually experiencing progressive disease. Second-line therapy is, therefore, needed. We treated 11 patients (6 with metastatic melanoma; 5 having metastatic kidney cancer) who had previously experienced progressive disease on prior IL-2 regimens, with a combination of famotidine 20 mg intravenously (i.v.) twice per day and continuous-infusion IL-2 18 MIU/M2/24 hours x 72 hours, followed 24 hours later by a pulse IL-2 dose (18 MIU/M2 over 15 minutes). Cycles were repeated every 3 weeks. Patient characteristics were: 9 males, median age 63 years (range, 57-75), median Eastern Cooperative Oncology Group (ECOG) performance status: 1; most common metastatic sites: lungs, lymph nodes, and soft tissue/subcutaneous (s.c.); median number of cycles received: 4; most common toxicities were fever, nausea/emesis, hypophosphatemia, and hypomagnesemia. Five (5) patients (3 with melanoma, 2 with kidney cancer) have had partial responses. Two (2) patients with kidney cancer have been converted to complete responders with resection of residual disease, remaining without relapse at 5+ and 20+ months. Responding sites are lungs, lymph nodes, abdominal mass, and s.c. Median duration of response was 9.5 months. Median survival was 12 months. This combination has activity in patients with metastatic kidney cancer or melanoma who have received prior IL-2.

Continuous infusion interleukin-2 and intravenous famotidine in metastatic melanoma.

Lymphokine-activated killer cell (LAK) cytotoxicity against tumor cells is induced by the use of high-dose infusional interleukin-2 (IL-2). LAK cytotoxicity against neoplastic cells may be augmented by famotidine. Twelve (12) patients have been treated with continuous infusion IL-2 (18 MIU/m2/24 hours) for 72 hours and famotidine 20 mg IVPB twice per day. Cycles were repeated every 3 weeks. These patients were of median age--67 years (range, 25-79), had a median performance status of 1 (range, 0-1), and had metastatic sites, including lung, lymph node, subcutaneous/soft tissue, and liver. The most common toxicities of this regimen were fever, rigors, nausea/emesis, hypophosphatemia, and hypomagnesemia. Three (3) partial responses have been seen (25% response rate). One (1) of these responders has undergone complete surgical resection and is disease-free at 15+ months. Four (4) patients are alive at a median of > 25 months. The median survival for all patients is 13 months. This combination of infusional IL-2 with famotidine is active in metastatic melanoma.

Continuous infusion interleukin-2 and antihistamines in metastatic kidney cancer.

A prior randomized trial suggested a possible survival advantage favoring the combination of histamine and subcutaneous interleukin-2 (IL-2), compared to IL-2 alone in patients with metastatic melanoma. It has been postulated previously that antihistamines may, therefore, actually be antagonistic to IL-2 and thus interfere with its antitumor activity. We have previously shown no such antagonistic effect in patients with melanoma receiving IL-2 and antihistamines when reviewing the known literature. We sought to determine whether there was any negative effect of the combination in patients with metastatic kidney cancer. A PubMed literature search between 1985 and 2005 was done. High-dose continuous (or constant) infusion (CIV) interleukin-2 was used as the reference therapy because of the relatively constant IL-2 levels generated by this approach. Studies in which cimetidine, ranitidine, or famotidine were regularly scheduled and administered concurrently with IL-2 were included. Thirteen studies were identified. A total of 47 patients responded to therapy. Total response rate = 22%; 95%; Confidence Interval: 17%-28%. Eleven complete responses were noted. Complete response rate = 5%; 95% Confidence Interval: 3%-9%. These response rates are consistent with previously noted IL-2 response rates. In this study of CIV IL-2 and antihistamines, this combination appears to be active in metastatic kidney cancer. There appears to be no negative effect of antihistamine on the CIV IL-2 response rate in this disease.

Administration of high-dose continuous infusion interleukin-2 to patients age 70 or over.

High-dose bolus or continuous infusion interleukin-2-based therapy can cause capillary leak syndrome. Significant cardiovascular/hemodynamic events, including myocardial infarction, hypotension, pulmonary edema, and cardiac arrhythmia, have been described with such therapy. Concern over the toxicity of highdose interleukin-2 (IL-2) therapy has led to some clinicians excluding patients 70 years of age or over. We have treated 15 patients 70 years of age or over having an Eastern Conference Oncology Group (ECOG) performance status of 0 or 1, with therapy based on continuous infusion IL-2 18 MIU/sq m/24 hours for 72 hours. All patients underwent a pretreatment evaluation of cardiac status with a low-level stress or adenosine stress test. Cycles were typically repeated every 3 weeks for 4 cycles, then every 3-4 weeks thereafter. Patients were treated by oncology nurses in either the stem cell transplant (intermediate unit) or the oncology inpatient unit. Patient characteristics were: median age, 72 years (range, 70-83 years); tumor types: melanoma (10), kidney cancer (5); most common sites of disease: lung (11), lymph nodes (6), subcutaneous (3), liver (2); prior therapy included: none (8), outpatient IL-2 (5), other immunotherapy (4). Median number of cycles received: 3 (1-10). Most common toxicities were: fever, rigors, nausea, emesis, hypophosphatemia, and hypomagnesemia. Three patients required the use of dopamine for blood pressure support. Two patients declined further therapy. There were no treatment-related deaths. No patients required endotracheal intubation or transfer to an intensive care unit. One complete and 8 partial responses (60% response rate) have been seen. Responding sites include the lung, lymph node, intact kidney primary, and liver. Median survival has not been reached at over 14 months (range 3+-26+ months). Patients who are 70 years of age and older with an ECOG performance status of 0 or 1 are able to tolerate high-dose continuous infusion IL-2-based therapy and may respond to such treatment.

High-dose continuous infusion plus pulse interleukin-2 and famotidine in metastatic kidney cancer.

High-dose continuous infusion interleukin-2 (IL-2) regimens generate a higher degree of lymphokine activated killer cell (LAK) cytotoxicity when tested against tumor cells in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 have increased cytotoxicity against cancer cells when they are subsequently pulsed with additional IL-2. Famotidine may enhance LAK cytolytic ability. Six patients with kidney cancer have been treated with a combination of famotidine 20 mg intravenous bid and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes. The most common metastatic sites were the lung, lymph node, and bone. Median number of cycles received = 5 (range, 3-8). The most common toxicities were fever, rigors, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and metabolic acidosis. There were no treatment-related deaths, and no patients required intensive care admission. Two partial responses (33% response rate) have been seen. Median survival has not been reached at greater than 8 months. The combination of high-dose continuous infusion plus pulse IL-2 and famotidine is active in metastatic kidney cancer. An accrual of additional patients is needed to better assess the response rate.

Correlation between development of pulmonary edema and response of pulmonary metastases of metastatic melanoma and kidney cancer to high-dose continuous-infusion interleukin-2.

The administration of high-dose continuous intravenous infusion interleukin-2 (IL-2) is able to induce the presence of lymphokine-activated killer (LAK) cells. LAK are able to nonspecifically lyse tumor cells. They are also able to lyse endothelial cells, which accounts for, at least in part, the capillary leak syndrome seen as one of the toxicities with this therapy. A pulmonary manifestation of capillary leak syndrome is the presence of pulmonary edema. We postulated that capillary leak may also be a mechanism by which LAK could conceivably reach pulmonary metastases or could be a reflection of damage of endothelial cells in vasculature supplying metastases and that capillary leak syndrome may actually correlate with the response of pulmonary metastases. We examined our database of patients with lung metastases treated with high-dose continuous infusion IL-2 (18 MIU/m(2)/day for 3 days) regimens. Eighteen patients had the following characteristics: melanoma (11), renal cancer (7), median age of 67 years (range, 28-79 years), and males (15). All patients were treated by oncology nurses on either the stem cell transplant unit or oncology ward. Pulmonary edema was defined as the presence of pleural fluid on a chest X-ray, computed tomography (CT) scan, and/or as noted on a physical examination by at least 2 observers. No patients required endotracheal intubation, mechanical ventilation, or an intensive care unit transfer. The median number of cycles received was 6 (range, 1-13). All 8 responding patients (6 patients with melanoma, 2 patients with kidney cancer) manifested pulmonary edema during interleukin-2 therapy. Four patients with pulmonary edema were nonresponders. The presence of pulmonary edema correlated with the response to therapy (p = 0.01). The median duration of response of pulmonary nodules was 5 months (range, 1-16 months). There is a correlation between the development of pulmonary edema and the response of pulmonary metastases in patients with melanoma and kidney cancer treated with high-dose continuous infusion interleukin-2.

Continuous infusion interleukin-2 and antihistamines in melanoma: a retrospective review showing activity of this combination.

A recent randomized trial suggests that there may be an advantage in terms of survival with the combination of histamine and subcutaneous interleukin-2 (IL-2), compared to IL-2 alone. It has been postulated, then, that antihistamines may actually be antagonistic to IL-2 and, therefore, interfere with its antitumor activity. Because antihistamines such as cimetidine and ranitidine are commonly used as prophylaxis against gastrointestinal toxicity commonly seen with IL-2, and, because antihistamines may increase natural killer cell activity, it is reasonable to examine the response rate for this combination. An OVID Medline literature search between 1985 and 2003 was done. Continuous infusion (CIV) interleukin- 2 was used as the reference therapy because of the relatively constant IL-2 levels generated by this approach. Included studies were those in which either cimetidine, ranitidine, or famotidine were regularly scheduled and administered concurrently with IL-2, typically for gastrointestinal ulcer prophylaxis. Six (6) studies were identified. A total of 21 patients responded to therapy. Total response rate was 11%, with a 95% Confidence Interval: 7-17%. Four (4) complete responses were noted. Complete response rate was 2%, with a 95% Confidence Interval: 1-6%. These response rates are consistent with previously noted IL-2 response rates. In this retrospective review of CIV IL-2 and antihistamines, this combination appears to be active in melanoma. There appears to be no deleterious effect of routine antihistamine on the CIV IL-2 response rate.

Bolus followed by continuous infusion interleukin-2 in patients with metastatic malignant melanoma and kidney cancer previously treated with interleukin-2.

Six patients with either melanoma (3) or kidney cancer (3) who had experienced disease progression on outpatient interleukin-2 regimens were subsequently treated with inpatient bolus Interleukin-2 (IL-2) 36 MIU/m(2) followed by continuous infusion IL-2 18 MIU/m(2)/day for 3 days. Cycles were repeated every 2 weeks up to four times, then every 3-4 weeks if tolerated and in the absence of disease progression. Two patients (one each with kidney cancer and melanoma) have achieved partial responses. One patient with kidney cancer and hepatic metastases has had a minor response. Interleukin-2 given at this dose and schedule shows some evidence of activity in patients who have received prior outpatient IL-2.

High-dose continuous infusion plus pulse interleukin-2 and famotidine in melanoma.

High-dose, continuous infusion interleukin-2 (IL-2) regimens generate greater Lymphokine Activated Killer cell (LAK) cytotoxicity in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 then subsequently pulsed with IL-2 have increased cytotoxicity against cancer cells. Famotidine may enhance the lysis of tumors by cytotoxic lymphocytes. Fourteen patients with melanoma were treated with famotidine 20 mg intravenously twice per day and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes for 1 dose (12 patients) or daily for 3 doses (2 patients). Most common toxicities were fever, nausea/emesis, hypophosphatemia, hypomagnesemia, and rigors. Nine partial responses (64% response rate; 95% Confidence Interval: 39%-84%) have been seen. Median survival has not been reached at greater than 10 months. Two patients responding to therapy showed an increase in detectable CD 56(+) cells in serial subcutaneous or lymph node biopsies, while 1 patient undergoing progression of disease had no such infiltrate. High-dose, 72-hour continuous infusion plus pulse interleukin-2 with famotidine has activity in melanoma. CD 56(+) cells may play a role in responding patients.

Repeated cycles with 72-hour continuous infusion interleukin-2 in kidney cancer and melanoma.

While high-dose bolus inpatient interleukin-2 is generally given on 8-week cycles, continuous infusion interleukin-2 could potentially allow for more rapidly repeated cycles. Fourteen (14) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, having either kidney cancer (6) or melanoma (8), have been treated with continuous infusion (CIV) interleukin-2 (IL-2) 18 MIU/m(2)/24 hours for 72 hours. Cycles were repeated every 3 weeks up to 4 cycles, then every 3-4 weeks for 2 cycles, then every 6-8 weeks, until progression or intolerable toxicity. All patients received famotidine 20 mg intravenously (i.v.) twice per day during the 72-hour infusions. Patient characteristics included a median ECOG performance status of 1; median age = 63 (range: 25-79); most common metastatic sites: lung (9), bone (5), lymph nodes (5), and the liver (3). No patients with metastatic kidney cancer underwent a nephrectomy prior to interleukin-2. Median number of cycles received = 5 (1-9). No patients required Intensive Care Unit (ICU) admission. There have been no treatment-related deaths. Most common toxicities have been rigors, fever, nausea/emesis, and the reversible elevation of creatinine. One complete response and three partial responses (67% response rate; 95% confidence interval: 30%-90%) have been seen in kidney cancer, and two partial responses (25% response rate; 95% confidence interval: 7%-60%) have occurred in melanoma. Median survival has not been reached at >9+ months. Responding sites include the liver, bone, lung, lymph node and subcutaneous sites. Inpatient 72-hour continuous infusion interleukin-2 at this dose and schedule is well tolerated by patients with an ECOG performance status of 0 or 1 and has activity in kidney cancer and melanoma.

Activity of outpatient intravenous interleukin-2 and famotidine in metastatic clear cell kidney cancer.

Outpatient daily intravenous infusions of interleukin-2 (IL-2) have been developed to maintain anticancer activity and decrease toxicity of this agent against kidney cancer. Lymphokine activated killer cell (LAK) numbers are increased with these IL-2 schedules. Famotidine may enhance the LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. Fifteen patients with metastatic clear cell kidney cancer received IL-2 18 million IU/M² intravenously over 15-30 minutes preceded by famotidine 20 mg IV daily for 3 days for 6 consecutive weeks as outpatients. Cycles were repeated every 8 weeks. Patient characteristics were seven males/eight females, median age 59 (range: 28-70), median Eastern Cooperative Oncology Group (ECOG) performance status-1; common metastatic sites were lungs (14), lymph nodes (9), liver (4), bone (4), and pancreas (4). Prior systemic therapies were oral tyrosine kinase inhibitor (8), IL-2 (6), and mTor inhibitor (2). Most common toxicities were rigors, arthralgia/myalgia, nausea/emesis, fever, and hypotension. All episodes of hypotension were reversible with intravenous fluid. No patients required hospitalization due to toxicity. One complete response (7%) and four partial responses (26%) were seen (total response rate=33%; 95% confidence interval: 15%-59%). Responses occurred in the lungs, liver, lymph nodes, and bone. Outpatient intravenous IL-2 with famotidine has activity in metastatic clear cell kidney cancer.