A Case Series of Rare Immune-Mediated Adverse Reactions at the New Mexico Veterans Affairs Medical Center.

Background: Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several solid tumors. The use of ICIs is expected to rise as a growing number of indications are approved for their use by the US Food and Drug Administration and with the increasing number of patients with cancer. Unfortunately, ICIs are associated with the development of immune-mediated adverse reactions (IMARs). About 5% to 10% of patients developing severe toxicities requiring treatment postponement or discontinuation. IMARs can affect any organ, but most frequently the skin and endocrine glands are involved. Case Presentation: We present a case series of IMARs observed at the New Mexico Veterans Affairs Medical Center. First, we present a case of grade 4 myocarditis in an 84-year-old man receiving chemoimmunotherapy for lung adenocarcinoma to demonstrate the rapid progression of this rare condition. Second, we present a case of uveitis in a 70-year-old man with superficial bladder cancer undergoing treatment with pembrolizumab. Finally, we present a case of a 63-year-old man with pleuritis and organizing pneumonia secondary to dual ICI treatment (nivolumab and ipilimumab) for mesothelioma. A discussion regarding the epidemiology of these IMARs, expected course, and optimal management follows each rare toxicity described. Conclusions: Though these toxicities are uncommon, they serve as a reminder to clinicians across specialties that IMARs can drive the acute deterioration of any organ, and consideration of toxicities secondary to ICIs should be considered for any atypical presentation of unclear etiology.

Acute lymphoblastic leukemia secondary to myeloproliferative neoplasms or after lenalidomide exposure.

Philadelphia-negative (Ph-) myeloproliferative neoplasms (MPN) do rarely transform to acute lymphoblastic leukemia (ALL). While causality is difficult to establish, a few cases of ALL arising after exposure to lenalidomide for registered indications (multiple myeloma, myelodysplastic syndrome with 5q deletion) have been described in the literature.

Elastin turnover in malignant solid tumors.

Desmosine, a crosslinking amino acid unique to elastin, was investigated as a possible biomarker for cancer. Twenty-eight normal controls, median age 67 years, had a median value for urine desmosine of 43.5 picomoles desmosine/mg creatinine. The median for 19 untreated cancer subjects of similar age was significantly higher (175 picomoles desmosine/mg creatinine, p < 0.001). Urine desmosine levels in 55 subjects currently receiving chemotherapy, as well as 67 individuals who had survived cancer and were currently clinically disease free, were not significantly different from controls. Our findings indicate that elastin is being turned over in malignant solid tumors, releasing significantly elevated levels of desmosine in the urine.

Determination of qualitative telomerase activity as an adjunct to the diagnosis of pancreatic adenocarcinoma by EUS-guided fine-needle aspiration.

BACKGROUND: Telomerase activity is up-regulated in pancreatic cancer. Hence, measurement of telomerase activity in pancreatic needle-biopsy specimens could assist in establishing a positive diagnosis in specimens that are inadequate for cytology. OBJECTIVE: To determine the sensitivity and specificity of telomerase activity for neoplasia in a series of EUS-guided fine-needle aspirate (EUS-FNA) biopsies of pancreatic mass lesions. DESIGN: Prospective, consecutive, non-randomized cohort. SETTING: Academic hospital, tertiary referral center. PATIENTS: Seventy-one patients with a pancreatic mass diagnosed by cross-sectional imaging. INTERVENTIONS: EUS-FNA of 52 solid and 18 cystic pancreatic lesions. MAIN OUTCOME MEASUREMENTS: (1) Cytologic diagnosis; (2) tissue telomerase activity by semi-quantitative polymerase chain reaction; (3) patient demographics; (4) clinical outcomes. RESULTS: Cytology results were positive for adenocarcinoma in 40 patients with a solid pancreatic mass; of these, telomerase activity was detected in 31. There were no telomerase false-positive results. Telomerase results were positive in 6 of the 7 patients (86%) who had negative cytology results and who eventually were found to have biopsy-proven adenocarcinoma. The sensitivity and specificity of telomerase activity for detecting pancreatic adenocarcinoma in solid masses was 79% (95% CI, 64%-89%) and 100% (95% CI, 55%-100%). LIMITATIONS: Extremely high sensitivity and specificity of EUS-FNA cytology in solid lesions minimized the incremental benefit of telomerase. CONCLUSIONS: Telomerase activity can be measured readily in specimens obtained at EUS-FNA and accurately predicts malignancy. Used in combination with cytology, telomerase increased the sensitivity from 85% to 98% while maintaining the specificity at 100%. Lesions with negative cytology result and positive telomerase activity should be evaluated aggressively to exclude malignancy.

Predictive value of 18-fluoro-deoxy-glucose-positron emission tomography (18F-FDG-PET) in the identification of responders to chemoradiation therapy for the treatment of locally advanced esophageal cancer.

OBJECTIVE: To evaluate the utility of F-FDG-PET in predicting response to concomitant chemoradiation in locally-advanced esophageal cancer. SUMMARY BACKGROUND DATA: Approximately 25% of esophageal cancer patients experience a pathologic complete response (pCR) to preoperative chemoradiation therapy. Computed tomography, endoscopy, and endoscopic ultrasound are unable to identify patients experiencing a pCR. Growing evidence supports the use of F-FDG-PET in the staging of esophageal cancer in its ability to detect occult metastatic and lymph nodal disease. The identification of patients with a pCR to chemoradiation could potentially spare those patients the morbidity associated with a resection. METHODS: Eligibility criteria included T3-T4N0M0 or T1-T4N1M0 esophageal cancer. Patients underwent an initial F-FDG-PET before treatment and then repeated 4 to 6 weeks after chemoradiation, prior to the esophagectomy. Chemoradiation consisted of: cisplatinum, 5-fluorouracil, and radiation to a median dose of 50.4 Gy. Pathologic response was determined from a systematic review of the esophagectomy specimens. RESULTS: Sixty-four patients have completed therapy to date. Response was as follows: pCR 27%, pathologic residual microscopic (pCRmicro) 14.5%, partial response 19%, and stable or progressive disease 39.5%. A pretreatment standardized uptake value (SUVmax1hour) > or = 15 was associated with an observed 77.8% significant response (pCR + pCRmicro) compared with 24.2% for patients with a pretreatment SUVmax1hour < 15 (P = 0.005). Significant response was observed in 71.4% of patients with a decrease in SUVmax1hour > or = 10 compared with 33.3% when the SUVmax1hour decreased <10 (P = 0.004). CONCLUSIONS: Pretreatment and posttreatment F-FDG-PET can be useful for predicting significant response to chemoradiation in esophageal cancer. These data should be considered in evaluation of patients for esophagectomy after chemoradiation.

Phase Ia/Ib chemo-radiation trial of gemcitabine and dose-escalated thoracic radiation in patients with stage III A/B non-small cell lung cancer.

INTRODUCTION: The safety of dose-escalated thoracic radiation concurrent with gemcitabine in patients with inoperable stage III non-small cell lung cancer has not been studied. PATIENTS AND MATERIALS: The maximal tolerated dose of 35 mg/m twice-weekly gemcitabine and concurrent standard thoracic radiation was established in a previous phase Ia trial. In this study, a second patient cohort (phase Ib) received twice-weekly gemcitabine concurrent with three-dimensional dose-escalated thoracic radiation (60-74 Gy) after two cycles of induction chemotherapy: gemcitabine (1000 mg/m) day 1 and 8 and carboplatin (area under the curve 5.0-5.5) day 1 every 21 days. RESULTS: Twenty-three patients were entered in the phase Ib portion of this trial. Grade III/IV hematologic toxicity was primarily thrombocytopenia (22%) and neutropenia (26%). Grade III/IV esophageal toxicities occurred in 17% of patients, and grade III radiation pneumonitis/dyspnea was observed in 7 of 23 patients. The median and 2-year survival for phase Ib patients were 17.4 months and 32%, respectively. The overall 1- and 2-year survival for all 39 patients (16 phase Ia, 23 phase Ib) was 69% and 32%, respectively. CONCLUSIONS: Combining 74-Gy thoracic radiation and concurrent gemcitabine is feasible, but the use of this regimen should be limited to the confines of a clinical trial. A randomized phase II trial through the Cancer and Leukemia Group B is underway to further evaluate the efficacy of this regimen.

Staging and current treatment of hepatocellular carcinoma.

Early-stage hepatocellular carcinoma (HCC) is typically clinically silent, and HCC is often advanced at first manifestation. Without treatment, the 5-year survival rate is less than 5%. The selected treatment depends on the presence of comorbidity; tumor size, location, and morphology; and the presence of metastatic disease. Complete surgical resection followed by hepatic transplantation offers the best long-term survival, but few patients are eligible for this therapy. All other therapies are palliative. Radiofrequency ablation is the preferred method for managing unresectable small HCCs that are few in number. More widespread disease is treated with percutaneous therapies such as chemoembolization and selective internal radiation therapy. Systemic administration of biologic and chemotherapeutic agents is minimally successful in slowing the growth of HCC and typically is used to control symptoms in patients with overwhelming disease. A multidisciplinary approach that includes surgery, systemic therapy, and radiation therapy and that is based on the cooperation of radiation oncologists, interventional and diagnostic radiologists, hepatologists, and pathologists may offer the best chance of a cure or at least a longer and more normal life. To participate effectively in this effort, radiologists must be familiar with staging and treatment options for HCC and with the factors that affect the choice of management method.

Phase II trial of induction gemcitabine/CPT-11 followed by a twice-weekly infusion of gemcitabine and concurrent external beam radiation for the treatment of locally advanced pancreatic cancer.

PURPOSE: This phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation was initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer. METHODS: Patients with locally advanced, nonmetastatic adenocarcinoma of the pancreas received 2 cycles of induction irinotecan (100 mg/m2 IV) and gemcitabine (1000 mg/2 IV) on days 1 and 8 of each 3-week cycle. Following the induction, patients without disease progression received gemcitabine administered twice weekly (40 mg/m2/day) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy over 5.5 weeks). RESULTS: From April 2000 to August 2003, 20 patients were entered into this study, 17 of whom were evaluable for treatment response. Characteristics included a median age of 67 years (range, 44-87 years) and 14 men (70%). Grades III and IV hematologic toxicity occurred in 25% and 5% of patients respectively and was primarily thrombocytopenia. No grade IV gastrointestinal toxicities or deaths due to therapy were observed. All therapy was completed in 8 patients, 7 patients were removed due to progression, 2 due to toxicity, 2 refused further treatment, and 1 was removed per the treating physician. The median time to progression and median survival was 5.1 months (95% CI, 3.2-6.7) and 8.8 months (95% CI, 6.4-10.1) respectively. Four patients (20%) were alive at 12 and 18 months. CONCLUSION: Induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation is feasible in patients with locally advanced pancreatic cancer. This regimen, however, has only modest activity and should not be explored further.

Split-course versus continuous thoracic radiation therapy for limited-stage small-cell lung cancer: final report of a randomized phase III trial.

The optimal integration of radiation and chemotherapy for limited-stage small-cell lung cancer (SCLC) remains unclear. This phase III trial was conducted to determine whether chemotherapy plus interdigitating split-course thoracic radiation therapy (RT) improved survival compared with standard-dose continuous thoracic RT. One hundred fourteen patients were randomized to receive 50 Gy thoracic RT delivered in 2.0-Gy fractions given continuously (5 weeks) concurrent with the first 2 cycles of chemotherapy (arm A) or 50 Gy delivered via an interdigitating split course in 2.5-Gy fractions (8 weeks) concurrent with the first 3 cycles of chemotherapy (arm B). During the split-course RT, once-daily radiation was delivered on days 8-17 of each of the first two 21-day cycles and days 8-11 of the third 21-day cycle. All patients received the following chemotherapy: cisplatin/etoposide on cycles 1, 2, and 5 and cyclophosphamide/vincristine/doxorubicin on cycles 3, 4, and 6. Prophylactic cranial irradiation was recommended after a complete response to all therapy. One hundred ten eligible patients were randomized. Grade 3/4 esophagitis was reported in 9% of patients receiving continuous thoracic RT versus 4% of patients receiving split-course RT. Grade 3/4 hematologic toxicity was common in both treatment arms. Complete/partial response was observed in 80% of patients on arm A versus 84% on arm B. Overall survival rates at 5 years were 18% and 17% for arms A and B, respectively. Interdigitating split-course thoracic RT delivered in 2.5-Gy fractions was tolerable in patients with limited-stage SCLC but did not provide a survival advantage.