Characterization of on-target adverse events caused by TRK inhibitor therapy.

BACKGROUND: The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. PATIENTS AND METHODS: Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. RESULTS: Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%-62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. CONCLUSIONS: TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

5-day/5-drug myeloablative outpatient regimen for resistant neuroblastoma.

5-day/5-drug (5D/5D) is a novel high-dose regimen administered with autologous hematopoietic SCT (HSCT). It was designed to maximize cytoreduction via high dosing of synergistically interacting agents, while minimizing morbidity in patients with resistant neuroblastoma (NB) and ineligible for clinical trials due to myelosuppression from previous therapy. 5D/5D comprises carboplatin 500 mg/m(2)/day on days 1-2, irinotecan 50 mg/m(2)/day on days 1-3, temozolomide 250 mg/m(2)/day on days 1-3, etoposide 200 mg/m(2)/day on days 3-5 and cyclophosphamide 70 mg/kg/day on days 4-5. HSCT is on day 8. Sixteen patients received 21 courses. Treatment was in the outpatient clinic. Responses were noted against progressive disease (PD) that had developed while patients were off, or receiving only low-dose, chemotherapy but not against PD that emerged despite high-dose chemotherapy. Responses were also seen in patients with PD or stable disease after (131)I-metaiodobenzylguanidine therapy. Grade 3 toxicities were limited to transient elevations in liver enzymes (three courses) and hyponatremia (one course). Bacteremia occurred in 2/21 (10%) courses. Hematological recovery allowed patients to be enrolled on clinical trials. In conclusion, 5D/5D (including HSCT) spares vital organs, entails modest morbidity, shows activity against resistant NB and helps patients meet eligibility requirements for formal clinical trials.

Is endosonography guided fine needle aspiration (EUS-FNA) for sarcoidosis as good as we think?

BACKGROUND: Preliminary data show that endosonography guided fine needle aspiration (EUS-FNA) may be an accurate method for diagnosing sarcoidosis. However, these data were obtained in a small selected group of patients with a very high pretest probability of sarcoidosis. This retrospective study reports on the use of EUS-FNA in an unselected group of patients with mediastinal lymphadenopathy of unknown origin. METHODS: The EUS database of a single tertiary referral centre was reviewed for patients who underwent EUS-FNA for mediastinal lymphadenopathy of unknown origin. Clinical presentation and imaging studies of each case were carefully reviewed and the diagnosis "sarcoidosis" or "no sarcoidosis" attributed if possible. The diagnoses were compared with the result of EUS-FNA. RESULTS: One hundred and twenty four patients were investigated. In 35 cases EUS-FNA identified granulomas (group 1); in the other 89 cases (group 2) no granulomas were detected. The definite diagnoses in group 1 were sarcoidosis (n = 25), indefinite (n = 7), no sarcoidosis (n = 3). The definite diagnoses in group 2 were sarcoidosis (n = 3), indefinite (n = 9), no sarcoidosis (n = 77). Of the 77 cases with no sarcoidosis, 44 were diagnosed with other diseases. The other 33 showed non-specific changes in the FNA and sarcoidosis was excluded by negative non-EUS pathology (n = 17) and clinical presentation. The sensitivity and specificity for EUS-FNA were 89% (95% CI 82 to 94) and 96% (95% CI 91 to 98), respectively, after exclusion of the indefinite cases in both groups. CONCLUSIONS: EUS-FNA is an accurate method for diagnosing sarcoidosis in an unselected group of patients with mediastinal lymphadenopathy. The reported sensitivity and specificity must be appreciated in the context of the difficult and often incomplete clinical diagnosis of sarcoidosis.

Endoscopic ultrasonography in the diagnosis and staging of neoplasms of the head and neck.

BACKGROUND AND STUDY AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a minimally invasive and highly accurate method of detecting mediastinal lymph-node metastases in gastrointestinal and lung cancer. Little information is available regarding the use of EUS-FNA to stage tumors in the head and neck region. This study reports experience with EUS in the diagnosis and staging of these tumors and their mediastinal spread. PATIENTS AND METHODS: The records of patients who underwent EUS for diagnosis and/or staging of head and neck tumors were reviewed. Referral criteria were suspected invasion of the esophagus by a lower-neck mass on cervical computed tomography (CT) or magnetic resonance imaging (MRI), or mediastinal lymphadenopathy > 10 mm on a chest CT. RESULTS: Thirty-two patients (23 men, nine women; mean age 65 years, range 44 - 80) were referred and underwent 35 EUS examinations. In one patient, EUS was not possible due to a benign esophageal stricture. In 17 patients with suspected esophageal invasion on CT scans, EUS demonstrated invasion of the esophagus in four cases and of the pleura in one; 12 tumors showed no visible invasion of adjacent structures. The other 17 examinations were carried out for suspected mediastinal metastatic disease. In eight cases, EUS-FNA confirmed metastatic disease, whereas only benign changes were shown in the other nine cases. EUS-FNA also provided the first tissue diagnosis in two primary tumors and identified malignancy in one patient with no CT suspicion of positive mediastinal lymph nodes. EUS avoided the need for more invasive investigations in all patients with mediastinal lymphadenopathy, and it changed the management in 12 of the 17 patients (71 %) with suspected esophageal invasion and in eight of the 17 patients (47 %) with suspected mediastinal disease. CONCLUSIONS: EUS with FNA provides a viable approach to the diagnosis and staging of tumors in the head and neck region when there is a suggestion of esophageal invasion on CT or MRI, or enlarged mediastinal lymph nodes. EUS with FNA may avoid the need for mediastinoscopy or other more invasive techniques for staging of these neoplasms.

Blood safety in the age of AIDS.

This series of essays was developed as part of FASEB's efforts to educate the general public and the legislators whom it elects about the benefits of fundamental biomedical research--particularly how investment in such research leads to scientific progress, improved health, and economic well-being. "Blood safety in the age of AIDS" examines the effects of the AIDS epidemic on the safety of the blood supply. Just as a pebble tossed in a lake sends out ripples that last long after the pebble sinks, the discovery more than a decade ago that the AIDS virus was in the blood supply is still having repercussions on research and transfusion practices. New screening tests for blood and new ways of using one's own blood during surgery are among the steps that have made blood transfusions much safer. Meanwhile, researchers continue tracking down new threats and devising ways to circumvent them.

Stimulation of UV-induced DNA excision repair by chemotherapeutic drugs in cancer patients.

We have used a monoclonal antibody specific for UV-induced 6-4 photoproducts in an ELISA assay to determine the kinetics of loss of antigenicity from the DNA of lymphocytes obtained from four groups of people; normal controls and cancer patients who had either received chemotherapy, hormone therapy or no treatment at all. This result was confirmed on a matched pairs analysis of 12 breast cancer patients sampled before and after chemotherapy. We conclude, that chemotherapeutic treatment with alkylating agents modulate the capacity of UV-induced DNA-repair in human lymphocytes in a yet unknown way.

Pulmonary coin lesions caused by Dirofilaria immitis.

The dog heartworm Dirofilaria immitis has been diagnosed by thoracotomy as the etiology of neoplastic-appearing nodules in two patients in the Peoria, Illinois area. This brings the total number of reported cases of human pulmonary dirofilariasis to approximately 81 in the United States. The major concern of this benign disease is that in making the diagnosis the patients undergo the risk of surgery because of the presumed preoperative diagnosis of cancer. Greater awareness of this disease is needed as the geographic distribution of human pulmonary dirofilariasis expands in this country.