Unusual Adverse Events Research Articles

Hematologic malignancies in Li-Fraumeni syndrome.

10613 Background: Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by mutations in the tumor suppressor gene TP53. Since its discovery, a growing list of cancers have been described in association with LFS, predominantly solid tumors. However, hematologic malignancies (HMs) cumulatively account for 4-10% of cancer diagnoses in LFS. In this study, we present the largest series of HMs in families with LFS with detailed clinical courses. Methods: This was a two-center retrospective observational cohort study conducted at the University of Utah and the University of Wisconsin-Madison with IRB approval. Cancer genetics clinic registries were reviewed to identify all families with LFS who also had a confirmed diagnosis of a HM. To meet criteria for LFS, the patient had to have a confirmed germline pathologic or likely pathologic TP53 variant. Patients with a TP53 variant of unknown significance (VUS) were also included if they met classical LFS testing criteria. Data was gathered by manual chart review of both the families’ histories and electronic health records. Results: Among the 121 families identified with LFS, 35 (29%) families had one or more HM. Of these, 17 individuals from 16 families (13%) had confirmed germline TP53 mutations. The most frequent HMs found were acute lymphoblastic leukemia (ALL) (n=6), non-Hodgkin lymphoma (NHL) (n=5), myelodysplastic syndromes (MDS) (n=3), and chronic lymphocytic leukemia (CLL) (n=2). Acute myeloid leukemia (AML), Langerhans cell histiocytosis (LCH), and chronic myeloid leukemia (CML) were each diagnosed once. Most cases were identified in adulthood (n=12, 71%). Of the 19 total HMs, the minority (n=5, 26%) were diagnosed post-cytotoxic therapy and only six (35%) individuals had received a diagnosis of LFS prior to HM diagnosis. The MDS/AML cohort (n=4) all exhibited bi-allelic inactivation of TP53. Two of these four patients achieved long term survival after matched-unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). All three patients who underwent MUD donor HSCT had immune-mediated adverse events. Conclusions: In this study we found a significantly higher incidence of HMs in LFS than previously described, with a predominance of lymphoid over myeloid malignancies. The majority of patients had excellent outcomes after standard of care therapy pointing towards more favorable outcomes for patients with LFS and HMs than previously reported. We also report several unusual immune-mediated adverse events in our patients indicating possible immunogenicity of some TP53 variants. Most patients did not have prior exposure to cytotoxic treatments and were diagnosed with the HM prior to their LFS diagnosis. We also show that 38% of individuals with an HM have multiple family members with an HM, consistent with a familial HM pattern. This underscores the importance of detailed family and personal histories in HM patients found to carry a somatic TP53 variant.

Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers

NV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine). Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations. Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication. The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study.

Unusual Adverse Events in a Patient With BRAF-Mutated Non–Small Cell Lung Cancer Treated With BRAF/MEK Inhibition

BRAF/MEK inhibition remains standard of care for treatment of BRAF-mutated non-small cell lung cancer (NSCLC). Although common adverse events (AEs) have been reported through clinical trials and ongoing clinical practice, only a handful of reports have detailed unusual adverse events associated with these medications. This report presents a patient with BRAF-mutated NSCLC treated with dabrafenib and trametinib who experienced 2 unusual AEs-Sweet syndrome and MEK-associated retinopathy-that responded to steroid treatment. The patient was able to continue BRAF/MEK inhibition through a coordinated multidisciplinary approach. This case highlights the importance for all clinicians to recognize unusual AEs associated with BRAF/MEK inhibition, particularly in the setting of expanded use for all BRAF V600E-mutated solid tumors.

Changing paradigms of hemophilia care across larger specialized treatment centers in the European region.

Introduction:In early 2021, the European Collaborative Haemophilia Network (ECHN) conducted a survey to determine whether the paradigms of care across the European region have changed with the introduction of novel therapies for people with hemophilia.Methods:We conducted a survey in 19 ECHN centers from 17 countries in the European region. The aim was to track recent changes in the hemophilia treatment landscape, determine the impact of these changes on hemophilia treatment centers and comprehensive care centers in the region, and to look into the future of care as applied to people with hemophilia. The survey was structured to include three key areas: demographics and organization; current challenges and opportunities; and future directions.Discussion:Our survey provides a snapshot of the current approach to hemophilia treatment that highlights a move toward preventive, rather than reactive care, but that also raises a number of key concerns related to costs and accessibility (particularly as related to novel therapies), time limitations for clinical research, and ongoing issues regarding human resources (particularly in terms of new doctors entering the field) and availability of laboratory resources as the use of novel therapies (some with unique modes of action and unusual adverse events, some with specialized monitoring requirements) becomes commonplace.Conclusion:While our survey suggests that specialized care will continue to play a central role in the management of hemophilia, the standards and protocols, as well as the centers themselves, will have to continue to evolve if they are to continue to provide the highest level of care. To meet this requirement, there is a clear need for engaging, ongoing education programs for healthcare professionals working in the field of hemophilia that can be adjusted to the changing landscape of hemophilia therapy and monitoring.

Rare Adverse Events with Programmed Death-1 and Programmed Death-1 Ligand Inhibitors: Justification and Rationale for a Systematic Review.

Immune checkpoint inhibitors are a new class of cancer drug that spawn unusual adverse events that generate unusual and sometimes unexpected adverse events. Despite databases that track such adverse events, there remains a need to also generate systematic reviews to capture side effects from such agents. We generated a systematic compendium of adverse event reports. Extensively reviewing the published literature of case reports and case series, we relied on the peer process to compile a resource for clinicians of rare adverse events associated with checkpoint inhibitors. We used this compendium as a platform to provide broad-based comments on the role of systematic reviews in gathering such adverse event data. This approach generated 265 types of rare adverse events that had been reported, the most frequent of which were autoimmune type I diabetes (n = 62), pneumonitis (n = 40), myocarditis (n = 39), and colitis (n = 36). More unusual adverse events were also catalogued. Some adverse events that initially seemed unusual turned out to be more frequently reported over time and thus lost their novelty-an important point which provides context for how adverse events should be viewed when new drugs become available. Additionally, in contrast to such resources as the FDA Adverse Event Reporting System (FAERS), this systematic review relied on peer-reviewed data-another important point which adds strength to such systematic reviews. This report provides a compendium of rare and usual adverse events, serves as a resource to cancer clinicians, and appears to be justified based on the reported findings.

SUN-LB112 Efficacy & Safety After Switchover to Remogliflozin in Indian T2DM Patients - a Real World Study

INTRODUCTON: Remogliflozin is new SGLT2i recently approved in India, but more economical than the previously available SGLT2i. It is prudent to evaluate its effectiveness & tolerability in comparison to other SGLT2i in real world setting. METHODS: In this observational retrospective study, medical data from EMR of tertiary care hospital in Kolkata was retrieved. The records of adult Type 2 diabetes mellitus (T2DM) patients who were on a dual therapy of Metformin plus SGLT2i (Canagliflozin, Dapagliflozin or Empagliflozin) for at least 6 months with adequate glycaemic control (HbA1c to target based on age & duration of diabetes) & subsequently switched over to Remogliflozin 100 mg twice daily because of economic reasons were screened. The day of switchover was considered as index day (Day 1) The patient records whose data was unavailable, metformin dose was altered during period of next 6 months, who had evidence of active UTI on index day, were receiving injectable anti-diabetic drugs or had recorded eGFR <45 mL/min were excluded. The effectiveness was assessed in terms of maintenance of HbA1c, FBS, PPBS, body weight after 3 & 6 months of treatment. The safety was assessed by adverse events recorded in medical records in terms of abnormal symptoms, signs or laboratory reported values during the observation period of 6 months & compared to equivalent period of 6 months before index day. The data was collected & analysed using appropriate statistical techniques. RESULTS: After screening, medical records of 50 adult T2DM patients (54% male) were found to be eligible. The mean baseline characteristics on Index day in terms of Age, HbA1c levels, FBS, PPBS, weight & BMI was 51.3±12.5 years, 6.8±0.4%, 108.7±8.1 mg/dL, 144.5±21.3 mg/dL, 65.5±5.7 kg & 25.8±2.8 kg/m2 respectively. After treatment period of 6-months with Remogliflozin-based regimen, the mean HbA1c, FBS, PPBS, -Body weight & BMI was 6.7±0.8%, 110.3±10.5 mg/dL, 138.5±12.7 mg/dL, 66.3±6.5 kg & 25.9±3.2 kg/m2 Mean change from baseline in HbA1c levels, FBS, PPBS, weight & BMI were-0.1±0.19%, -1.6±7.2 mg, -6.0±8.3 mg, +0.8±0.2kg, & +0.1±0.0.7 kg/m2 respectively. These change from baseline of all above parameters were not found to be statistically significant (P>0.05) No events of hypoglycaemia, disturbance in electrolytes or any unusual adverse events were reported. Combined incidence of UTI & genital Mycotic infection was similar during 6 month observation period as compared to 6 months prior to index day. (8% vs 6%) CONCLUSION: In real world clinical practice, replacement of ongoing SGLT2i with Remogliflozin was observed to provide consistent glycaemic control without any tolerability issues. Hence, novel SGLT2i Remogliflozin can be considered as equivalent alternative for SGLT2i based regimen in management of Indian T2DM patients

Nivolumab-related severe thrombocytopenia in a patient with relapsed lung adenocarcinoma: a case report and review of the literature

BackgroundImmune checkpoint inhibitor therapy has changed the standard drug therapy for relapsed or advanced non-small cell lung cancer; its efficacy is well-recognized by pulmonary physicians, oncologists, and thoracic surgeons. Nivolumab, one of the anti-programmed cell death 1 antibodies, was the first immune checkpoint inhibitor to be approved and is used as a standard second-line regimen for patients with non-small cell lung cancer irrespective of the expression of programmed cell death ligand 1. Programmed cell death 1 antibodies have been generally confirmed to be less toxic than conventional cytotoxic chemotherapy, although unusual immune-related adverse events such as type I diabetes mellitus, adrenal failure, and myasthenia gravis may occur with a very low incidence. A case of severe grade V immune-related thrombocytopenia after two courses of nivolumab as second-line therapy for relapsed non-small cell lung cancer is reported.Case presentationAn 82-year-old Japanese woman with relapsed lung adenocarcinoma was treated with nivolumab as second-line systemic therapy at our institute. Her laboratory data indicated thrombocytopenia suspected to be an immune-related adverse event following two courses of nivolumab. Subsequently, she developed a massive pulmonary hemorrhage and left cerebral infarction despite intensive treatment including systemic steroid therapy. Although there have been a few reports of thrombocytopenia caused by nivolumab, this is the first report of grade V thrombocytopenia following administration of nivolumab for relapsed non-small cell lung cancer.ConclusionA very difficult case of grade V immune-related thrombocytopenia after the administration of nivolumab as second-line therapy for relapsed lung adenocarcinoma was described. Immune-related thrombocytopenia is a rare adverse event, but it must be considered a possible complication because it may become critical once it has occurred.

1756PD - The ImmunoTOX multidisciplinary board: A descriptive study of collaborative management of immune-related adverse events

BackgroundThe adverse events generated by immunotherapies are characterized by their wide diversity, unpredictability and reversibility by steroid used, and requires a delicate management. A collaborative organization of immunological toxicology management called ImmunoTOX (iTox) has been set up at Gustave Roussy to support physicians in their routine practice. MethodsDescriptive study of all consecutive advice given by the ImmunoTOX committee at Gustave Roussy from Apr 6, 2016 to Jan 2, 2019. The iTox committee organizes a multidisciplinary meeting twice a month with organs specialists, oncologists, pharmacovigilants, radiologists, around prescribing physicians facing difficult to manage or unusual immune related adverse events (irAEs). ResultsThe iTox committee delivered 398 pieces of advice for 356 patients (207 men and 149 women) receiving immunotherapies. Patients received anti-PD1 (55%) or anti-PDL1 (6%) given in monotherapy, or in combination with anti-CTLA4 (11%), or in combination with targeted therapy (11%), or another immunotherapy regimen (17%). The queries patterns for advices questioned the causal link (37%), rechallenge over G≥3 (27%), or a complex clinical management (25%) or the possibility of initiating immunotherapy in a patient with comorbidities (10%). The iTox committee retained a causal link between the adverse event and immunotherapy in 273 of the 356 patients (77%). Of these 273 patients with irAEs, the grade of maximum severity was grade 1-2 in 112 (41%), grade 3-4 in 148 patients (54%), and irAE ultimately resulted in death in 13 (5%) patients. The organ categories mostly involved by requests were lung (21%), gastrointestinal (13%), liver (12%), musculoskeletal (10%) and neurological (8%). Over the study period, the 273 patients with irAEs led to 313 requests for advice that recommended systemic corticosteroids (n=193, 62%) or a second immunomodulatory agents (n=45, 14%). ConclusionsThese results should help cancer hospitals to further appreciate the current medical needs in their management of irAEs. By a specific management, patients with autoimmune comorbidities and rechallenge over G≥3 could be regarded as precautions for use and not absolute contraindications. Clinical trial identificationCommission Nationale de l’Informatique et des Libertés N°2098694v0. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureJ. Michot: Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Cellgene; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (institution): Abbvie; Honoraria (institution): Xencor. J. Soria: Full / Part-time employment: MedImmune. C. Massard: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Leadership role: Lilly. All other authors have declared no conflicts of interest.

FLT PET/CT imaging of metastatic prostate cancer patients treated with pTVG-HP DNA vaccine and pembrolizumab

BackgroundImmunotherapy has demonstrated remarkable success in treating different cancers. Nonetheless, a large number of patients do not respond, many respond without immediate changes detectable with conventional imaging, and many have unusual immune-related adverse events that cannot be predicted in advance. In this exploratory study, we investigate how 3′-Deoxy-3’-18F-fluorothymidine (FLT) positron emission tomography (PET) measurements of tumor and immune cell proliferation might be utilized as biomarkers in immunotherapy.MethodsSeventeen patients with metastatic castrate resistant prostate cancer were treated with combination pTVG-HP DNA vaccine and pembrolizumab. Patients underwent baseline and 12-week FLT PET/CT scans. FLT PET standardized uptake values (SUVs) were extracted from tumors, non-metastatic lymph nodes, spleen, bone marrow, pancreas, and thyroid to quantify cell proliferation in these tissues. Regional immune cell responses to pTVG-HP DNA vaccine were assessed by comparing FLT uptake changes in vaccine draining and non-draining lymph nodes. Cox proportional hazards regression was utilized to relate FLT uptake and other clinical markers (PSA and tumor size) to progression-free survival. Area under receiver operating characteristic (AUC) curves and concordance indices were used to assess the predictive capabilities of FLT uptake.ResultsChanges in FLT uptake in vaccine draining lymph nodes were significantly greater than changes in non-draining lymph nodes (P = 0.02), suggesting a regional immune response to vaccination. However, the changes in FLT uptake in lymph nodes were not significantly predictive of progression-free survival. Increases in tumor FLT uptake were significantly predictive of shorter progression-free survival (concordance index = 0.83, P < 0.01). Baseline FLT uptake in the thyroid was significantly predictive of whether or not a patient would subsequently experience a thyroid-related adverse event (AUC = 0.97, P < 0.01).ConclusionsFLT PET uptake was significantly predictive of progression-free survival and the occurrence of adverse events relating to thyroid function. The results suggest FLT PET imaging has potential as a biomarker in immunotherapy, providing a marker of tumor and immune responses, and as a possible means of anticipating specific immune-related adverse events.Trial registrationNCT02499835.

Widespread subacute cutaneous lupus erythematosus in a patient receiving checkpoint inhibitor immunotherapy with ipilimumab and nivolumab

Checkpoint inhibitor immunotherapy, including ipilimumab and nivolumab, is associated with numerous immune-related adverse events including dermatitis, pruritus, hepatitis, diarrhea, and hypophysitis. As the number of patients undergoing immunotherapy treatment increases, however, rare and unusual immune-related adverse events are observed. Many of these resemble known autoimmune phenomenon, such as subacute lupus erythematosus and myositis. Herein, we report a patient with metastatic serous ovarian carcinoma undergoing treatment with combination ipilimumab and nivolumab who developed subacute cutaneous lupus erythematosus (SCLE). Recent case reports have documented SCLE as a novel immune-related adverse event. In our case, she was able to successfully restart immunotherapy after a course of oral corticosteroids and maintenance oral hydroxychloroquine and topical corticosteroid therapy.

Conservative management of nivolumab-induced pericardial effusion: a case report and review of literature

BackgroundNivolumab is an immune checkpoint inhibitor targeting programmed death-1 protein and has been approved for the treatment of multiple advanced malignancies. Adverse effects of immune checkpoint inhibitors are distinct from conventional cytotoxic chemotherapy and can be life-threatening if left unrecognized. Here, we present a case of nivolumab-induced pericardial effusion successfully managed with high-dose corticosteroids.Case presentationA 70-year-old Caucasian female with a history of 50-pack-year cigarette smoking was diagnosed of recurrent adenocarcinoma of lung after initial surgery. She progressed through multiple lines of chemotherapy and was eventually started on nivolumab. She developed a large pericardial effusion, grade 3 by Common Terminology Criteria for Adverse Events v4.0, about 4 days after receiving first nivolumab treatment. She was treated with oral prednisone at 1 mg/kg daily with gradual resolution of pericardial effusion over 5 weeks while she still received nivolumab every 2 weeks. Prednisone treatment was eventually tapered off about 10 weeks from initial nivolumab treatment. However 1 week after stopping prednisone, she again presented with shortness of breath and bilateral ankle edema, imaging confirmed recurrent pericardial effusion measuring 2.8 cm. Nivolumab was stopped and patient was again started back on prednisone 1 mg/kg daily which resulted in complete resolution of pericardial effusion in 3 weeks. Nivolumab was resumed 1 week afterwards while patient was on tapering dose of prednisone. There was no recurrent pericardial effusion when she continued low-dose prednisone during the remaining course of nivolumab treatment.ConclusionsWith increasing use of immune checkpoint inhibitors, clinicians need to be aware of the unusual immune-related adverse events in order to provide timely management and effective patient care. To our knowledge, this is the first reported case of immune-related pericardial effusion from nivolumab successfully managed with high-dose corticosteroids. Furthermore, recurrent pericardial effusion was prevented by using low-dose corticosteroids as maintenance in order for patient to continue nivolumab treatment.

Incidence of hypophosphatemia in advanced cancer patients: a recent report from a single institution

Recent approval of molecular-targeted agents has contributed to improving the therapeutic outcomes of advanced cancer patients. However, they result in unusual adverse events that rarely occur with cytotoxic agents, such as hypertension, hypomagnesemia, and an acne-like rash. Although hypophosphatemia can be induced by various agents, some kinds of molecular-targeted agents are known to induce it. In addition, cancer survivors may be at a risk of hypophosphatemia. One hundred and seventy patients, who visited the Department of Clinical Oncology at Akita University from 1 April 2014 to 31 August 2016 were enrolled in this study after providing informed consent. Serum inorganic phosphorus levels were examined along with other routine clinical examinations. Correlation between the serum inorganic phosphorus level and other clinical data were also analyzed. Grade ≥2 severe hypophosphatemia (<2.5mg/dL of phosphorus) was detected in 49.4% of patients, and grade ≥3 (<2.0mg/dL of phosphorus) was observed in 22.9% patients. These results indicated that the presence of bone metastasis (p<0.001), history of bone-modifying agents (p<0.001) and molecular-targeted drugs (p=0.001), and time from the date of the first visit to the date of minimum serum phosphorus level (p<0.001) might correlate with hypophosphatemia. Multivariate logistic regression analysis showed that disease duration might be a risk factor (p=0.0466). As hypophosphatemia can be induced by various factors in advanced cancer patients, the serum phosphorus level of cancer patients at risk should be cautiously examined.

Safety Analysis of Adjuvant Chemotherapy with Docetaxel Administered with or without Anthracyclines to Early Stage Breast Cancer Patients: Combined Results from the Asia- Pacific Breast Initiatives I and II.

The Asia-Pacific Breast Initiatives (APBI) I and II registries were established to collect safety data for patients with early stage breast cancer receiving adjuvant docetaxel-based regimens in the Asia-Pacific region. Data from the two registries were combined to perform a safety analysis. Participants in the registry were women with early stage operable breast cancer with an intermediate or high risk of recurrence. These women received adjuvant chemotherapy that included docetaxel between 2006 and 2011. Adverse events (AEs) were recorded and analyzed. Data were collected from 3,224 patients from 13 countries. The mean dose intensity of docetaxel was 24.1, 22.7, 25.1 mg/m2/week among patients receiving docetaxel-based monotherapy, combination therapy and sequential therapy, respectively. Granulocyte colony-stimulating factor (G-CSF) was given with docetaxel to 41.8% of women and 20.6% of women receiving prophylactic antibiotics. Adverse events were reported in 86% of patients (anthracycline-containing regimens vs. non-anthracycline regimens; 87% vs. 80%). The most common adverse events were alopecia, nausea, neutropenia, vomiting, and myalgia. Adverse events NCI CTCAE ≥Grade 3 were reported in 45.4% of patients. Serious adverse events were reported in 13% of patients, of which 2.5% led to study discontinuation. Forty-six deaths (1.4%) were reported, with no significant difference between regimens. The safety parameters of adjuvant docetaxel therapy used to treat sequential Asian women were comparable to those reported in clinical trials evaluating the role of adjuvant docetaxel. No unusual adverse events linked to Asia-Pacific region patients were observed.

Evaluation of adverse drug reactions in HIV positive patients in a tertiary care hospital.

Context:The advancement and development of new drugs and treatment strategies increase the risk of unusual Adverse Events (AEs) in HIV patients.Aims:The objective of our study was to assess the incidence, types and nature of AEs in HIV positive subjects.Settings and Design:Patients with WHO stage IV disease irrespective of the CD4 cell count, or WHO stage III disease with a CD4 cell count <350 cell/cu. Mm, or, WHO stage I or II disease with a CD4 cell count of <200 cells/cu. mm, and on prior anti-retroviral therapy for not more than six months preceding the observation date, were included in the study. After initiation of therapy, the patients were examined for the occurrence any adverse events including the type and severity, or any other abnormal laboratory findings. Causality assessment of the adverse events was done using the Naranjo's scale.Results:Out of 327 patients studied prospectively, 43 patients developed AEs. Out of these, 23 (53.5%) were males and 20 (46.5%) were females. A total of 53 (16.21%) AEs were reported. Antitubercular drugs caused the maximum AEs (28.3%) followed by zidovudine (20.7%), nevirapine (15.0%) and efavirenz (5.6%). Stavudine, ethambutol, sulfamethoxazole and trimethoprim, and atazanavir were also responsible for 3.7% of AEs individually. Causality assessment done according to the Naranjo's scale revealed that 66.04% AEs were ‘probable’ and 33.96% were ‘possible’.Conclusions:Anemia, hepatitis and dermatological adverse effects are the most common AEs. Antitubercular drugs contributed significantly for the incidence of AEs in these patients. Frequency of AEs was slightly more in males compared to females.

Safety and efficacy of indigenous equine antithymocyte globulin along with cyclosporine in subjects with acquired aplastic anemia.

To confirm the safety and efficacy of an indigenous equine antithymocyte globulin (eATG) along with cyclosporine inIndian subjects with acquired aplastic anaemia. Subjects >2years old with acquired aplastic anaemia were enrolled at six hospitals between April 2011 and February 2013, after approval from respective Ethics Committees. Equine ATG at a dose of 40mg/kg/day was infused for 4days. Efficacy analysis defined a priori, was in subjects, who had completed eATG treatment and followed-up on day 90 and/or 180. Complete response (CR) was defined as-transfusion independent, haemoglobin ≥11g/dL, absolute neutrophil count (ANC) >1.5 10(9)/L and platelet ≥150 10(9)/L; partial response (PR) was transfusion independent, haemoglobin ≥8g/dL, ANC >0.5 10(9)/L and platelet ≥20 10(9)/L; non responders were transfusion dependent. Lymphocyte subsets (CD 2, 3, 4 and 8) in the blood were tested on days 0 (pre eATG infusion), 3, 5, 7, 14 and 21 after eATG. Of the 30 subjects (two children <12years old) enrolled, 19 completed day 90 and 18 completed day 180 visit. Of the remaining 11 subjects, two died on days 12 and 45 due to septicaemia and pneumonia, one was withdrawn after the first dose of eATG due to jaundice and eight were lost to follow-up. The median age was 30 (9-58) years and weight was 57 (26-84) kg. On day 90, 12 of 30 subjects responded (CR 1, PR 11) and 15 of 30 (CR 2, PR 13) on day 180. The most common adverse event was fever related to eATG infusion. There were two serious adverse events (acute renal failure, febrile neutropenia) and both recovered with treatment. There were no unusual adverse events noted during the study period. Blood T lymphocytes showed a mean decrease of 91% from baseline that recovered by day 21. We conclude that eATG is safe and in combination with cyclosporine showed overall response in 50% of enrolled subjects. The trial was registered with the clinical trial registry-india (Registration no. CTRI/2012/03/002498).

Select Articles Published on the Topic of Arrhythmia and Electrophysiogy in 2013

Select Articles Published on the Topic of Arrhythmia and Electrophysiogy in 2013

Acute Pancreatitis and Diabetic Ketoacidosis following L-Asparaginase/Prednisone Therapy in Acute Lymphoblastic Leukemia

Acute pancreatitis and diabetic ketoacidosis are unusual adverse events following chemotherapy based on L-asparaginase and prednisone as support treatment for acute lymphoblastic leukemia. We present the case of a 16-year-old Hispanic male patient, in remission induction therapy for acute lymphoblastic leukemia on treatment with mitoxantrone, vincristine, prednisone, and L-asparaginase. He was hospitalized complaining of abdominal pain, nausea, and vomiting. Hyperglycemia, acidosis, ketonuria, low bicarbonate levels, hyperamylasemia, and hyperlipasemia were documented, and the diagnosis of diabetic ketoacidosis was made. Because of uncertainty of the additional diagnosis of acute pancreatitis as the cause of abdominal pain, a contrast-enhanced computed tomography was performed resulting in a Balthazar C pancreatitis classification.

Efficacy and Safety of Docetaxel Combined With Oxaliplatin as a Neoadjuvant Chemotherapy Regimen for Chinese Triple-Negative Local Advanced Breast Cancer Patients

To determine the efficacy and toxicity of an oxaliplatin-based regimen as a neoadjuvant chemotherapy setting in triple-negative local advanced breast cancer (TNLABC) patients. Patients with stage IIIb or IIIc, chemotherapy-naive TNLABC receive docetaxel 75 mg/m day 1 and oxaliplatin 130 mg/m day 2, every 21 days for up to 4 cycles. The primary end point is pathologic complete response (CR), and the secondary end points are clinical response (including CR and partial response), disease-free survival, overall survival, and safety. Twenty-nine TNLABC patients were treated: 17(58.62%) had stage IIIB disease and 12 (41.38%) had stage IIIC disease. After neoadjuvant chemotherapy, there were 10 patients (34.48%) with pathologic CR (95% confidence interval, 21.51%-48.70%). Twenty patients responded (7 CR and 13 partial response) with a 68.97% total clinical response rate (95% confidence interval 57.51%-88.02%). Nearly 27.59% patients (8 patients) had disease progression after at least 2 cycles of chemotherapy, and only 1 patient (3.45%) had the disease stable, respectively. In the 29 treated patients, there were no unusual or unexpected adverse events in a total of 91 cycles for the chemotherapy setting. Common grade 3 or 4 hematologic toxicities were leukocytopenia, which occurred in 4 TNLABC patients (13.79%), and thrombocytopenia in 1 patient (3.45%). Grade 3 or 4 transaminase elevation occurred in 5 (17.24%) patients and grade 3 vomiting occurred in 1(3.45%) patient. One patient experienced grade 3 neurosensory toxicities. There are 5 reports (17.24%) of grade 3 fatigue. The results of this phase II clinical study suggest that docetaxel combined with oxaliplatin as a neoadjuvant chemotherapy regimen in TNLABC patients is active and well tolerated, and should be further investigated as a favorable treatment alternative for TNLABC patients. A large randomized prospective clinical study is warranted to confirm the results.

Totally Thoracoscopic Major Pulmonary Resections: An Analysis of Perioperative Complications

Reports of recent large series support the safety of video-assisted thoracoscopic major pulmonary resections (MPR). However, although their rate of postoperative complications is low, the real incidence of intraoperative complications is unknown. Clinical data from patients who underwent MPR through a full thoracoscopic approach between 2007 and 2012 were reviewed. Data were collected prospectively and analyzed retrospectively. A thoracoscopic MPR was attempted in 338 patients; 68.6% of the patients underwent a lobectomy and 31.4%, an anatomic segmentectomy. The mean operation time was 182 minutes (range, 80 to 300), and the mean intraoperative blood loss was 80 mL (range, 10 to 400 mL). Inhospital mortality rate was 0.3%. The overall complication rate was 32.8%. Intraoperative adverse events and conversion to open thoracotomy occurred in 2.7% and 5.6% of patients, respectively. Risk factors for conversion were preoperative forced expiratory volume of air in 1 second (p<0.001) and a fused fissure (p=0.001). A fused fissure (p=0.007) and surgical experience (p=0.022) were independent factors associated with a longer duration of operation. Major adverse events and reoperation occurred, respectively, in 8.9% and 3% of cases. Surgical complications were mostly vascular injury (n=9), laryngeal nerve palsy (n=5), chylothorax (n=3), and bronchus injury (n=1). On multivariate analysis, the only independent risk factors for major postoperative complications were smoking status and surgical experience. Although its overall rate of complications is low, a complete thoracoscopic approach might cause unusual adverse events. Surgeons must be aware of these complications to prevent them and anticipate their handling.

Immunogenicity and safety of three 2010–2011 seasonal trivalent influenza vaccines in Chinese toddlers, children and older adults

The 2009 influenza A(H1N1) pandemic strain was for the first time included in the 2010–2011 seasonal trivalent influenza vaccine (TIV). We conducted a double-blind, randomized trial in Chinese population to assess the immunogenicity and safety of the 2010–2011 TIV manufactured by GlaxoSmithKline and compared it with the counterpart vaccines manufactured by Sanofi Pasteur and Sinovac Biotech. Healthy toddlers (6–36 mo), children (6–12 y) and older adults (≥60 y) with 300 participants in each age group were enrolled to randomly receive two doses (toddlers, 28 d apart) or one dose (children and older adults). The immunogenicity was assessed by hemagglutination-inhibition (HI) assay. The solicited injection-site and systemic adverse events (AEs) were collected within 7 d after vaccination. All the three TIVs were well-tolerated with 15.1% of participants reporting AEs, most of which were mild. No serious AEs and unusual AEs were reported. Fever and pain were the most common systemic and injection-site AEs, respectively. The three TIVs showed good immunogenicity. The seroprotection rates against both H1N1 and H3N2 strains were more than 87% in toddlers after two doses and more than 95% in children and more than 86% in older adults after one dose. The seroprotection rates against B strain were 68–71% in toddlers after two doses, 70–74% in children and 69–72% in older adults after one dose. In conclusion, the three 2010–2011 TIVs had good immunogenicity and safety in Chinese toddlers, children and older adults and were generally comparable in immunogenicity and reactogenicity.