Clinical and Therapeutic Intervention of Hypereosinophilia in the Era of Molecular Diagnosis.

Hypereosinophilia (HE) presents with an elevated peripheral eosinophilic count of >1.5 × 109/L and is composed of a broad spectrum of secondary non-hematologic disorders and a minority of primary hematologic processes with heterogenous clinical presentations, ranging from mild symptoms to potentially lethal outcome secondary to end-organ damage. Following the introduction of advanced molecular diagnostics (genomic studies, RNA sequencing, and targeted gene mutation profile, etc.) in the last 1-2 decades, there have been deep insights into the etiology and molecular mechanisms involved in the development of HE. The classification of HE has been updated and refined following to the discovery of clinically novel markers and targets in the 2022 WHO classification and ICOG-EO 2021 Working Conference on Eosinophil Disorder and Syndromes. However, the diagnosis and management of HE is challenging given its heterogeneity and variable clinical outcome. It is critical to have a diagnostic algorithm for accurate subclassification of HE and hypereosinophilic syndrome (HES) (e.g., reactive, familial, idiopathic, myeloid/lymphoid neoplasm, organ restricted, or with unknown significance) and to follow established treatment guidelines for patients based on its clinical findings and risk stratification.

Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. RESULTS: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CONCLUSION: CAR-T demonstrates clinical efficacy for patients with RT.

Efficacy of CD19 directed therapies in patients with relapsed or refractory large b-cell lymphoma relapsing after CD19 directed chimeric antigen receptor T-cell therapy.

Outcomes are poor for patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL) post chimeric antigen receptor T-cell (CAR-T) therapy. Two CD19-directed therapies, tafasitamab- cxix plus lenalidomide (tafa-len) and loncastuximab tesirine (loncaT) are approved in R/R LBCL. The efficacy of these CD19 directed therapies in patients who relapse after CD19 directed CAR-T (CD19-CART) therapy is not well understood. We conducted a multi-center study of patients with R/R LBCL that received either tafa-len or loncaT at any timepoint for R/R disease after CD19-CART therapy. Fifty-three patients were included in this study with the median follow up of 56 (9.1-199) weeks from CAR-T infusion. Median number of systemic therapies pre-CAR-T therapy was 3 (range: 1-6); axicabtagene ciloleucel was the most utilized CAR-T product (n = 32,60%). Median time from CAR-T therapy to tafa-len or loncaT was 7.3 (1.2-38.2) months with median number of lines of therapy between CAR-T therapy and these regimens of 1 (0-5). Combined overall response rate and complete response rates were 27% and 10%, respectively. Median duration of response was 13.3 (2.1-56.7) weeks. In this real-world study, the use of currently approved CD19-directed therapies to treat R/R LBCL after CD19-CAR-T therapy showed limited clinical activity and duration of responses.

Successful treatment with carboplatin and paclitaxel in melanoma progression after immune-related adverse events.

The overall survival of melanoma patients has improved using antibodies targeting immune checkpoints (anti-PD-1, anti-CTLA-4 and anti-LAG-3). Systemic chemotherapy was administered in melanoma for many years with limited effectiveness. Here we report a case of a patient who experienced immune-mediated adverse effects from checkpoint blockade therapy and subsequently responded to chemotherapy. The patient presented with melanoma and paraneoplastic digital ischemia. She received a combination of ipilimumab/nivolumab and experienced G3 myocarditis, followed by melanoma progression after a steroid taper. This patient achieved a partial and durable response with platinum and taxane-based chemotherapy. This report suggests the possibility of a subset of patients who experience progression after immune-based side effects where chemotherapy may be effective in the modern age of melanoma treatment.

We describe a patient with a type of skin cancer called melanoma. At first, we tried to treat it with a medication that made the patient's body's defense system fight against it, but it caused problems with her heart so we had to stop it. Instead, we used another type of treatment called chemotherapy, which worked. The patient remains off therapy 4.5 years later. The lesson learned from this case is that chemotherapy is still helpful in certain situations. The initial treatment did not stop the melanoma growth. In addition, the patient had life-threatening toxicity.

Tisagenlecleucel: CAR-T cell therapy for adult patients with relapsed or refractory follicular lymphoma.

INTRODUCTION: Tisagenlecleucel (tisa-cel) is an anti CD19 CAR-T therapy that has demonstrated clinical activity in R/R large B-cell lymphoma and R/R B-cell acute lymphoblastic leukemia. It showed particularly high efficacy in R/R follicular lymphoma (FL) with a manageable toxicity profile. The pivotal ELARA study in R/R FL confirmed these findings and led to the FDA approval of tisa-cel in R/R FL after two lines of systemic therapies. AREAS COVERED: We start with an introduction of FL and the current treatment landscape with emphasis on the R/R setting. We review the role of CAR-T in R/R FL with focus on currently available products. We describe the ELARA study at a high level to give a perspective of the patient population that was treated. Finally, we discuss aspects related to product selection and whether bispecific antibodies will challenge the role of CAR-T in FL given their similar efficacy. EXPERT OPINION: Tisa-cel is a highly effective therapy for heavily pretreated R/R FL with a toxicity profile that is low grade and manageable. Durable remissions (including high-risk patients) are seen in the pivotal ELARA study. Clinicians should consider early referral of R/R FL patients for assessment and discussion.

Review of Current Systemic Therapy and Novel Systemic Therapy for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: This review aims to describe the systemic treatment options for pancreatic ductal adenocarcinoma and includes a summary of the current treatments as well as the ongoing clinical trials which may be efficacious in the treatment of this aggressive malignancy. METHODS: A literature review was performed using MEDLINE/PubMed between August 1996 and February 2023. The reviewed studies are categorized into these categories: current standard of care treatments, targeted therapies, immunotherapy and clinical trials. The current treatment modality for the treatment of advanced pancreatic cancer is mainly systemic chemotherapy. RESULTS: The introduction of polychemotherapy regimens including gemcitabine/nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, folinic acid and fluorouracil) has improved the clinical outcome of advanced pancreatic cancer. For further improvement in clinical outcomes, several novel approaches have been extensively studied in pancreatic cancer. The review discusses the current standard chemotherapy regimen and the novel treatment options in the field. CONCLUSIONS: While there are novel treatments being explored for metastatic pancreatic, it remains a debilitating and aggressive disease with high mortality that warrants continued efforts to advance therapeutic options.

Decoding the effects of spike receptor binding domain mutations on antibody escape abilities of omicron variants.

Recent times witnessed an upsurge in the number of COVID19 cases which is primarily attributed to the emergence of several omicron variants, although there is substantial population vaccination coverage across the globe. Currently, many therapeutic antibodies have been approved for emergency usage. The present study critically evaluates the effect of mutations observed in several omicron variants on the binding affinities of different classes of RBD-specific antibodies using a combined approach of immunoinformatics and binding free energy calculations. Our binding affinity data clearly show that omicron variants achieve antibody escape abilities by incorporating mutations at the immunogenic hotspot residues for each specific class of antibody. K417N and Y505H point mutations are primarily accountable for the loss of class I antibody binding affinities. The K417N/Q493R/Q498R/Y505H combined mutant significantly reduces binding affinities for all the class I antibodies. E484A single mutation, on the other hand, drastically reduces binding affinities for most of the class II antibodies. E484A and E484A/Q493R double mutations cause a 33-38% reduction in binding affinity for an approved therapeutic monoclonal antibody. The Q498R RBD mutation observed across all the omicron variants can reduce ∼12% binding affinity for REGN10987, a class III therapeutic antibody, and the L452R/Q498R double mutation causes a ∼6% decrease in binding affinities for another class III therapeutic antibody, LY-CoV1404. Our data suggest that achieving the immune evasion abilities appears to be the selection pressure behind the emergence of omicron variants.

QbD Approach towards Robust Design Space for Flutamide/PiperineSelf-Emulsifying Drug Delivery System with Reduced Liver Injury.

Flutamide which is used to treat prostate cancer and other diseases induces liver damage during and after the therapy. The aim of this study was to develop a flutamide/piperineco-loaded self-emulsifying drug delivery system (FPSEDDS) to inhibit flutamide-induced liver injury by utilizing piperine as a metabolic inhibitor. The development of SEDDS was carried out following a quality by design (QbD) approach. The risk assessment study was performed to identify critical quality attributes (CQAs) and critical material attributes (CMAs)/critical process parameters (CPPs). I-optimal mixture design was executed with three CMAs as the independent variables and CQAs as the dependable variables. The effectiveness of optimized SEDDS to circumvent flutamide-induced hepatotoxicity was assessed in mice. The numerical optimization suggested an optimal formulation with a desirability value of 0.621, using CQAs targets as optimization goals with 95% prediction intervals (α = 0.05). The optimal formulation exhibited the grade A SEDDS characteristics with the guarantee of high payloads in self-formed oily droplets. The design space was also obtained from the same optimization goals. All CQA responses of verification points were found within the 95% prediction intervals of the polynomial models, indicating a good agreement between actual versus predicted responses within the design space. These obtained responses also passed CQAs acceptance criteria. Finally, hematoxylin-eosin staining revealed the minimal flutamide-induced hepatotoxicity from the optimal SEDDS formulation as compared to the control and flutamide/piperine normal suspension. We demonstrate that the piperine containing optimized SEDDS formulation developed by QbD significantly reduces the flutamide-induced liver injury in mice.

Donor-derived Ehrlichiosis: 2 Clusters Following Solid Organ Transplantation.

Ehrlichiosis has been infrequently described as transmissible through organ transplantation. Two donor-derived clusters of ehrlichiosis are described here. During the summer of 2020, 2 cases of ehrlichiosis were reported to the Organ Procurement and Transplantation Network (OPTN) and the Centers for Disease Control and Prevention (CDC) for investigation. Additional transplant centers were contacted to investigate similar illness in other recipients and samples were sent to the CDC. Two kidney recipients from a common donor developed fatal ehrlichiosis-induced hemophagocytic lymphocytic histiocytosis. Two kidney recipients and a liver recipient from another common donor developed ehrlichiosis. All 3 were successfully treated. Clinicians should consider donor-derived ehrlichiosis when evaluating recipients with fever early after transplantation after more common causes are ruled out, especially if the donor has epidemiological risk factors for infection. Suspected cases should be reported to the organ procurement organization and the OPTN for further investigation by public health authorities.

Dietary Considerations for Inflammatory Bowel Disease Are Useful for Treatment of Checkpoint Inhibitor-Induced Colitis.

Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.

Evaluation of Presurgical Serum Cortisol Level in Patients Undergoing Major Maxillofacial Surgery.

BACKGROUND: Stress is an integral part of life. Anxiety levels may increase when it comes to being treated surgically due to road traffic accidents causing facial trauma, other pathologies or burns. The stress that is caused during a surgical procedure as well as during the treatment in debilitated patients or traumatic conditions is bound to cause disturbance in the metabolic and physiologic levels of cortisol. Therefore, a study was carried out to determine the cortisol levels just prior to surgery on the day of operation to quantify the stress levels and also aid in any preanesthetic medication changes for the patient undergoing maxillofacial surgery. AIM: To evaluate and compare pre-surgical serum cortisol levels in patients undergoing major maxillofacial surgery under general anaesthesia. OBJECTIVE: To evaluate the serum cortisol level of patient 3 days prior to surgery, on the day of surgery and to compare and evaluate the difference seen in both the obtained values. METHODS: A prospective, randomized, in- vivo study was carried out in the Department of Oral and Maxillofacial Surgery at a teaching dental hospital. A total of 32 patients were included in this study. Inclusion and Exculsion criteria was made along with pre-opertive assessment of the patient, informed consent was obtained from all patients involved in the study. Patient blood sample, at 8 am three days prior to surgery and on the day of surgery and sent for laboratory investigations. RESULT: Participants in this clinical study underwent treatment of various ailments like facial trauma, and miscellaneous pathologies like Dentigerous Cyst, Oral submucosa fibrosis, Osteomyelitis, Benign Tumor and Orthognathic surgery. The anxiety of the patients were assessed by serum cortisol level preoperatively and on the day of operation. A total of 32 patients, 26 male and 06 female were included in the study. There was statistically highly significant difference seen between the mean values obtained three days prior to surgery and on the day of surgery. CONCLUSION: We have concluded from this study that the serum cortisol level shows significant increase on the day of surgery. A future study can focus on association between increased levels of serum cortisol and postoperative wound healing where patients can be divided into two groups one receiving pre-operative stress reduction protocol and other not receiving the same.

A Fatal Case of Thrombotic Microangiopathy Without Schistocytosis and Absent Biochemical Markers of Hemolysis.

Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia with thrombocytopenia. In addition to the primary TMA syndromes, microangiopathic hemolytic anemia with thrombocytopenia can be seen in many systemic diseases. Transplant associated TMA (TA-TMA) affects patients following stem cell or solid organ transplant. A 48-year-old male who underwent autologous stem cell transplant for nonsecretory multiple myeloma was admitted to our hospital with worsening anemia, thrombocytopenia, renal dysfunction and hepatosplenomegaly. Initial blood work revealed rare schistocytes and normal lactate dehydrogenase and haptoglobin levels. He underwent an extensive workup looking for an infectious, inflammatory or malignant etiology but a definitive diagnosis could not be reached. Over his prolonged stay at the hospital, he suffered from multiorgan failure and eventually passed away. An autopsy revealed TMA involving all clinically affected organ systems and was deemed to be the cause of his demise. The absence of typical blood work suggestive of hemolysis does not rule out a diagnosis of TA-TMA. Knowledge of this rare disease entity will help physicians identify and treat this life-threatening condition early and effectively.

Comparing intra-oral wound healing after alveoloplasty using silk sutures and n-butyl-2-cyanoacrylate.

OBJECTIVES: The need for proper wound closure is of paramount importance after any intra-oral surgery. Various wound closure techniques have been described in literature using traditional non-absorbable suture materials. These include like synthetic absorbable sutures, surgical staples and tissue adhesives. Cyanoacrylates are among the most commonly used biocompatible tissue adhesives. To evaluate and compare intraoral wound healing using 3-0 silk sutures and n-butyl-2-cyanoacrylate after alveoloplasty. MATERIALS AND METHODS: A total of 20 patients requiring bilateral alveoloplasty in the same arch (upper or lower) were included in this study. Patients with any pre-existing pathology or systemic disease were excluded. After alveoloplasty was performed, the wound was closed using 3-0 braided silk sutures on one side, and using n-butyl-2-cyanoacrylate bio adhesive on the other side. Patients were evaluated based on the following parameters: time required to achieve wound closure; the incidence of immediate and postoperative hemostasis; the time to the use of the first rescue medication; the side where pain first arises; and the side where wound healing begins first. RESULTS: Compared to 3-0 silk sutures, cyanoacrylate demonstrated better hemostatic properties, reduced operative time, reduced postoperative pain and better wound healing. CONCLUSION: These data suggest that cyanoacrylate glue is an adequate alternative to conventional sutures to close the surgical wound after alveoloplasty, and better than are 3-0 silk sutures.

The use of Velscope to assess cellular changes occuring in oral premalignancy.

OBJECTIVES: To improve visualization of suspicious lesions of the oral mucosa and to assess the accuracy of Velscope in assessing cellular changes occurring in oral premalignancy for early diagnosis. MATERIALS AND METHODS: In this prospective, randomized in-vivo clinical study a total of 250 patients who gave history of chewing tobacco were screened. The selection of the site of biopsy was taken based on the area of loss of fluorescence identified by the Velscope within the lesion. Routine blood investigations were done. A biopsy was performed to confirm the findings of clinical examination. The data was collected and analysed. RESULTS: Among 200 patients only 110 underwent incisional biopsy. Of these only 89 patients showed neoplastic changes. Of the control biopsies, none of them showed any dysplastic changes. Out of 106 who exhibited speckling under autofluorescence, only 89 showed dysplastic changes whereas only 17 showed no dysplastic changes. Out of these 17 specimens, the histopathological diagnosis of 5 was coated tongue, 3 were pigmented lesions, 3 were geographic tongue and 2 were mucositis. Of the remaining 4, the histopathological diagnosis of 1 was oral submucous fibrosis, 1 was lichen planus and 2 were frictional keratosis. CONCLUSION: False positive findings are possible in presence of highly inflamed tissues, and it is possible that use of Velscope alone may result in failure to detect regions of dysplasia, but it has its use definitely to improve clinical decision making about the nature of oral lesions and aids in decisions to biopsy regions of concern. Use of the scope has allowed practitioners to identify the best region for biopsy. It is much better to occasionally sample tissue that turns out to be benign than to fail to diagnose dysplastic or malignant lesions. However, poor specificity is a major limitation for using it as a screening tool.

Chronic, Silent Microaspiration Masquerading as Interstitial Lung Disease.

Chronic, silent microaspiration is a common but underrecognized pathologic process in pulmonary medicine. The clinical presentation is variable and diagnosis can be challenging. We present the case of a 55-year-old woman with known emphysema, who was referred to us for progressive respiratory failure that was unresponsive to therapy. The patient had 9 hospital admissions in the preceding 5 months and was treated with multiple courses of antibiotics and systemic steroid therapy for a diagnosis of cryptogenic organizing pneumonia. The steroid therapy was complicated by 51 pounds of weight gain. She had conversational as well as profound exertional shortness of breath. Physical examination revealed a woman in moderate distress and bilateral diffuse wheezing and rhonchi. Computed tomography of the chest revealed areas of bronchocentric consolidation and bronchial wall thickening in the bilateral lower lobes. She underwent surgical lung biopsy and the histopathology was consistent with chronic aspiration pneumonia.

Comparison of minimally invasive versus conventional open harvesting technique for iliac bone graft in secondary alveolar bone grafting in cleft palate patients: a systematic review.

This study evaluated and compared the donor site morbidity following minimally invasive and conventional open harvesting of iliac bone for secondary alveolar bone grafting in cleft palate patients. A thorough electronic search of PubMed, Google Scholar, EMBASE, and an institutional library and manual search of various journals was done; Inclusion criteria: 1) full-text articles using a minimally invasive or conventional open harvesting technique for iliac bone for secondary alveolar grafting in cleft palate patients and 2) articles published between January 1, 2001 and June 30, 2017 and Exclusion criteria: 1) articles published in languages other than English, 2) case reports, case series, animal studies, in vitro studies, and letters to the editor, and 3) full-text article unavailable even after writing to the authors. Preliminary screening of 274 studies excluded 223 studies for not meeting the eligibility criteria. Of the remaining 51 studies, 19 were removed for being duplicates. Of the remaining 32 studies, 15 were excluded after reading the abstract. Of the 17 studies that were left, 2 were excluded because they were in a language other than English, and 2 were excluded because the study group did not mention cleft palate patients. Thus, 13 studies providing results for a total of 654 patients were included in this qualitative synthesis. Minimally invasive bone graft harvest techniques are better than the conventional open iliac bone harvest method because they offer shorter operative time, decreased requirement for pain medications, less pain on discharge, and a shorter hospital stay.

An in vivo study comparing efficacy of 0.25% and 0.5% bupivacaine in infraorbital nerve block for postoperative analgesia.

BACKGROUND: Pain is an unpleasant sensation ranging from mild localized discomfort to agony and is one of the most commonly experienced symptoms in oral surgery. Usually, local anesthetic agents and analgesics are used for pain control in oral surgical procedures. Local anesthetic agents including lignocaine and bupivacaine are routinely used in varying concentrations. The present study was designed to evaluate and compare the efficacy of 0.25% and 0.5% bupivacaine for postoperative analgesia in infraorbital nerve block. METHODS: Forty-one patients undergoing bilateral maxillary orthodontic extraction received 0.5% bupivacaine (n = 41) on one side and 0.25% bupivacaine (n = 41) on the other side at an interval of 7 d. The parameters evaluated for both the bupivacaine concentrations were onset of action, pain during procedure (visual analog scale score [VAS]), and duration of action. The results were noted, tabulated, and analyzed using the Wilcoxon signed rank test. RESULTS: The onset of action of 0.5% bupivacaine was quicker than that of 0.25% bupivacaine, but the difference was not statistically significant (P = 0.306). No significant difference was found between the solutions for VAS scores (P = 0.221) scores and duration of action (P = 0.662). CONCLUSION: There was no significant difference between 0.25% bupivacaine and 0.5% bupivacaine in terms of onset of action, pain during procedure, and duration of action. The use of 0.25% bupivacaine is recommended.

Measurement of cerebrospinal fluid ACE level in aseptic meningitis: diagnostic?

Neurosarcoidosis (NS) is a rare disease, affecting only 3%-10% of patients with sarcoidosis. The clinical presentation can be protean and often represents a diagnostic challenge. Cerebrospinal fluid (CSF) ACE level has poor sensitivity, but high specificity for establishing a diagnosis of NS. We present a case of NS in a middle-aged African American woman who presented with dysphagia and dysphonia. An extensive radiological workup was negative for structural brain disease. CSF studies demonstrated lymphocyte predominant pleocytosis with an elevated ACE level. A diagnosis of possible neurosarcoidosis was made. She responded to systemic steroid therapy with complete resolution of her symptoms over the next five months. In the appropriate clinical setting, an elevated CSF ACE level could be of paramount importance for making a diagnosis of NS.

A Case of Acute Life-Threatening Pulmonary Hemorrhage from Synthetic Cannabinoid Abuse.

We report a case of alveolar hemorrhage secondary to inhalation of synthetic cannabinoid. The patient developed hemoptysis and respiratory failure 48 hours after the episode. Alveolar hemorrhage from synthetic cannabinoid use is a rare entity that has been reported only thrice previously. The unique feature of this case was that the initial urine and blood toxicology screens were negative for cannabinoids and the diagnosis was confirmed via detection of serum metabolites of a synthetic cannabinoid.