Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study.

BACKGROUND: Invasive fungal diseases (IFD) are life-threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases. OBJECTIVES: Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment. METHODS: Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non-Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software. RESULT: Thirty-five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1-540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD. CONCLUSIONS: The prevalence of IFD among chronic lymphocytic leukaemia/non-Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib-associated IFD.

Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia.

We report a case of invasive pulmonary aspergillosis in a patient taking ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat refractory chronic lymphocytic leukemia. We hypothesize that ibrutinib promoted this infection by suppressing innate immune responses against Aspergillus. Clinicians should be aware of potential Aspergillus infections in patients treated with this drug.

Overall survival analysis of adjuvant radiation versus observation in stage I testicular seminoma: a surveillance, epidemiology, and end results (SEER) analysis.

OBJECTIVE: The standard adjuvant treatment for men with stage I testicular seminoma remains controversial within the literature. We analyzed survival rates in men with stage I seminoma who underwent adjuvant radiation therapy (RT) or observation (OB) after orchiectomy. METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute from 1973 to 2003. The primary end points were overall survival (OS) and cause-specific survival (CSS). Multivariate Cox regression models were used to study the significance of clinical variables: age at diagnosis, laterality of primary disease, race, and radiation group. RESULTS: Of 6764 patients eligible for analysis, 5265 were treated with RT and 1499 with OB. After a median follow-up of 7.6 years, the 5-, 10-, and 20-year OS rates for the RT versus OB were 97.9 versus 95.0, 94.8 versus 92.2, and 83.5 versus 84.1 (P=0.0047), respectively. The CSS rates for the same time periods were 99.6 versus 98.7, 99.4 versus 98.7, and 99.2 versus 98.7 (P=0.0015), respectively. Adjuvant RT was associated with improved CSS on multivariate analysis with hazard ratio of 0.37 (confidence interval, 0.20-0.70; P=0.0023). CONCLUSIONS: Within this large US population analysis, adjuvant RT was associated with improved OS and CSS compared with OB for men with stage I testicular seminoma. Further studies are needed to determine whether modern RT techniques and field-size reductions may lead to greater improvements in the therapeutic ratio, in light of the trend toward chemotherapy as primary treatment.

A review of treatment modalities for vestibular schwannoma.

Vestibular schwannomas are benign intracranial tumors arising from the vestibular nerve. Treatment options include observation, stereotactic radiosurgery, fractionated radiotherapy, and microsurgery. We review the evidence describing efficacy and side-effect profiles of each of these modalities. This was accomplished by outlining the results of published meta-analyses and performing a systematic search of the literature for individual studies published between 2004 and June 2009. Without intervention, 29-54% of tumors will grow and 16-26% of patients require additional treatment, with 54-63% preserving functional hearing. With radiosurgery, only 2-4% require additional treatment and hearing preservation is accomplished in 44-66% of cases. Reviewing contemporary studies, it appears that reduced marginal doses may have decreased morbidity risks associated with radiosurgery without sacrificing efficacy. With fractionated radiotherapy, 3-7% will require additional treatment and hearing preservation is reported at 59-94% of patients, although long-term outcomes are not known. Microsurgery is an alternative for eligible patients, with fewer than 2% requiring additional treatment; however, the risk of hearing loss, facial neuropathy, and other morbidities is relatively high. There are significant limitations with comparing the efficacy and morbidity rates across interventions because of selection bias and confounding factors. Additional prospective comparative trials and randomized studies are needed to improve our understanding of the relative benefits of each modality.

Gamma knife radiosurgery for vestibular schwannomas: tumor control and functional preservation in 70 patients.

OBJECTIVE: We present the previously unreported outcomes of 70 patients treated with Gamma knife radiosurgery for vestibular schwannoma (VS), including comprehensive analysis of clinical outcomes and the effects of lower marginal doses. METHODS: We performed a retrospective study of patients treated for VS at Gamma knife of Spokane between 2003 and 2008. Endpoints measured include tumor control, hearing preservation, and facial nerve preservation, including the effect of tumor size and marginal dose. Statistical analysis was performed with Wilcoxon signed-rank test, paired Student t test, Mann-Whitney U test, Kendall's rank correlation, Fisher exact test, and Liddell's exact χ(2) test for matched pairs. RESULTS: With a mean follow-up of 26 months, 93.8% of tumors either shrank or remained static after receiving a mean marginal dose of 12.7 Gy. Tumor control was independent of marginal dose or tumor size. Hearing preservation was achieved in 64% of patients with serviceable function before the treatment. Hearing changes were independent of dose or tumor size. Preservation of good facial nerve function was achieved in 95% of patients. Post-treatment hydrocephalus occurred in 4.4% of patients, but no other significant morbidities were elucidated. CONCLUSIONS: In the treatment of VS, contemporary radiosurgical techniques and the use of marginal doses below 13 Gy offer excellent tumor control, at high rates relative to surgical intervention. These findings are independent of marginal dose and tumor size. Patients should be informed about the benefits and risks of radiosurgery and microsurgery before choosing an intervention. Further analysis of post-treatment outcomes should be encouraged as follow-up times increase and the treatment protocols continue to evolve.

Gamma knife radiosurgery for movement disorders: a concise review of the literature.

Medication is the predominant method for the management of patients with movement disorders. However, there is a fraction of patients who experience limited relief from pharmaceuticals or experience bothersome side-effects of the drugs. Deep brain stimulation (DBS) and surgical lesioning of the thalamus and basal ganglia are respected neurosurgical procedures, with valued success rates and a very low incidence of complications. Despite these positive outcomes, DBS and surgical lesioning procedures are contraindicated for some patients. Stereotactic radiosurgery with the Gamma Knife (GK) has been used as a lesioning technique for patients seeking a non-invasive treatment alternative and for medication-intolerable patients, who are unable to undergo DBS or lesioning due to comorbid medical conditions. Tremors of various etiologies are treated using GK thalamotomy, which targets the ventralis intermedius nucleus. GK thalamotomy produces favorable outcomes when treating tremors, with success rates ranging from 80-100%. In contrast, GK pallidotomy targets the internal globus pallidus, and is used in treating bradykinesia, rigidity, and dyskinesia. Although radiosurgery has proven beneficial for tremors, radiosurgical pallidotomy for bradykinesia, rigidity, and dyskinesia remains questionable, with mixed success rates in the literature that ranges from 0-87%. We suggest that GK thalamotomy be offered along with other neurosurgical approaches as a feasible treatment option to patients who prefer the non-invasive nature of radiosurgery and to those who are unqualified candidates for the neurosurgical alternatives. Also, we advise that patients with bradykinesia, rigidity, and dyskinesia be educated about the variability in the literature pertaining to GK pallidotomy before proceeding with treatment.

Gamma knife radiosurgery for essential tremor: a case report and review of the literature.

Approximately 5 million people in America are affected by essential tremors (ET), which are classified as a type of benign movement disorder. This disease manifests as tremors that usually occur in the hands, but they may also be present in the head, face, tongue, and lower limbs. Radiofrequency thalamotomy (RF) and deep brain stimulation (DBS) are common invasive procedures with proven track records that are used to treat ET. Although these procedures have high success rates, they still put patients at risk of potential side effects and are invasive by nature. Thalamotomy using the gamma knife (GK) also produces favorable outcomes in treating tremors, without the complications associated with invasive neurosurgery procedures. This report describes the presenting symptoms and extended treatment outcome for a patient with an advanced case of ET, who received GK thalamotomy treatment six years ago. Because of this non-invasive treatment, she regained the ability to paint and live with an improved quality of life. We also discuss and review the relevant literature regarding the risks and benefits of this treatment modality. GK thalamotomy is one effective option for the treatment of ET, and due to its noninvasive nature, it has a different risk profile than neurosurgery. We suggest that GK thalamotomy should be presented as one viable treatment option to all ET patients, and should be recommended to those who would be best served by less invasive treatment techniques.

Gamma Knife radiosurgery for vestibular schwannoma: case report and review of the literature.

Vestibular schwannomas, also called acoustic neuromas, are benign tumors of the vestibulocochlear nerve. Patients with these tumours almost always present with signs of hearing loss, and many also experience tinnitus, vertigo, and equilibrium problems. Following diagnosis with contrast enhanced MRI, patients may choose to observe the tumour with subsequent scans or seek active treatment in the form of microsurgery, radiosurgery, or radiotherapy. Unfortunately, definitive guidelines for treating vestibular schwannomas are lacking, because of insufficient evidence comparing the outcomes of therapeutic modalities.We present a contemporary case report, describing the finding of a vestibular schwannoma in a patient who presented with dizziness and a "clicking" sensation in the ear, but no hearing deficit. Audible clicking is a symptom that, to our knowledge, has not been associated with vestibular schwannoma in the literature. We discuss the diagnosis and patient's decision-making process, which led to treatment with Gamma Knife radiosurgery. Treatment resulted in an excellent radiographic response and complete hearing preservation. This case highlights an atypical presentation of vestibular schwannoma, associated with audible "clicks" and normal hearing. We also provide a concise review of the available literature on modern vestibular schwannoma treatment, which may be useful in guiding treatment decisions.

Effects of ionizing radiation on cellular structures, induced instability and carcinogenesis.

Ionizing radiation is perhaps the most extensively studied human carcinogen. There have been a number of epidemiological studies on human populations exposed to radiation for medical or occupational reasons, as a result of protracted environmental exposures due to radiation accidents, or after atomic bombings. As a result of these studies exposure to ionizing radiation has been unambiguously linked to cancer causation. While cancer induction is the primary concern and the most important somatic effect of exposure to ionizing radiation, potential health risks do not only involve neoplastic diseases but also somatic mutations that might contribute to birth defects and ocular maladies, and heritable mutations that might impact on disease risks in future generations. Consequantly it is important we understand the long-term health risks associated with exposure to ionizing radiation.