Challenging Diagnosis Research Articles

Rasmussen encephalitis: A challenging diagnosis in children

Rasmussen encephalitis: A challenging diagnosis in children

Probabilistic computer‐aided diagnosis of Alzheimer’s disease and frontotemporal dementia based on MRI and biochemical markers

AbstractBackgroundOne of the clinical problems for biomarkers' clinical use is the ability to differentiate between Alzheimer’s disease (AD), frontotemporal dementia (FTD), and healthy subjects (CTR). This clearly challenges diagnosis and prognosis. We implemented a ML algorithm that provides individual probabilistic diagnoses for these dementias based on magnetic resonance imaging (MRI) and we correlated the results with biochemical markers.MethodWe studied 3T‐T1w MRI of 432 subjects. A subset of these participants had cerebrospinal fluid (CSF) and plasma biomarkers (Table 1). We obtained regional subcortical gray matter volumes and cortical thickness measures using Freesurfer. We implemented a calibrated classifier with a Support Vector Machine with only the MRI data. We tested paired‐wise classification and classification across the 3 groups. We obtained individual probabilities associated with group correspondence. We studied the correlation between these probabilities and CSF and plasma biomarkers. For this, we subdivided the groups into true‐group (subjects with classification according to clinical diagnosis) and false‐group (subjects which did not coincide with clinical diagnosis). Finally, we implemented a permutation test to find the importance of each region in the classification.ResultWe obtained accuracies of 90.7 ± 6.7% in the CTR vs AD classification, 88.6 ± 4.5% for CTR vs FTD, 79.3 ± 8.8% for AD vs FTD, and 79.9 ± 5.1% when discriminating the 3 groups. We obtained a significant positive correlation for plasma p‐tau181 for the false‐AD in the comparison AD vs CTR (Figure 1). The correlation of the false‐CTR was significantly positive for the CSF and plasma NfL. Finally, in the AD vs FTD, the true‐FTD had a significant negative correlation with CSF NfL. The other biochemical biomarkers did not provide additional information. The most important regions for classification are shown in Figure 2.ConclusionThe ML algorithm gave high accuracies. Within wrongly classified AD patients, probabilities correlated positively with plasma p‐tau181, suggesting hidden pathological processes associated with subjects clinically classified as CTR. Finally, the group probability within well‐classified FTD patients in comparison with AD negatively correlated with CSF NfL. We suggest that this approach can be used as a tool to try to develop personalized diagnoses.

S141 Mucinous Carcinoma Arising Within Perianal Fistula in a Crohn’s Patient: A Challenging Diagnosis That Often Fails Biopsy Detection

S141 Mucinous Carcinoma Arising Within Perianal Fistula in a Crohn’s Patient: A Challenging Diagnosis That Often Fails Biopsy Detection

Thymoma Involved by Small Lymphocytic Lymphoma (SLL): A Rare and Challenging Diagnosis

Abstract Introduction/Objective Thymoma is a malignant neoplasm arising from the epithelial cells of the thymus. It usually affects patients between the fourth and sixth decades of life. There is a strong association of thymoma with myasthenia gravis and other paraneoplastic syndromes Thymic epithelial tumors are the most common tumors of the anterior mediastinum; however, lymphomas frequently present as mediastinal masses. Concurrent thymoma and lymphoma affecting the thymus is very rare. Methods/Case Report A 79-year-old woman with a history of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) presented with night sweats and weight loss. Chest CT revealed small pulmonary nodules, a 3.3 x cm anterior mediastinal mass and enlarged hilar lymph nodes. Fine needle aspiration (FNA) of the mass revealed a mixture of lymphocytes and epithelial cells. Flow cytometry showed a monoclonal B-cell population, and double CD4/CD8-positive T-cells consistent with thymocytes. Core biopsy showed scattered neoplastic epithelial cells interspersed among densely packed small lymphocytes. Scattered and small clusters of epithelial cells were highlighted by the CK AE1/3 immunostain. CD3 and PAX5 showed the thymocytes and infiltrating B-cells, respectively. Based on cytomorphologic, flow cytometric, histopathologic, and immunohistochemical findings, the diagnosis of thymoma, type B2 involved by SLL was rendered. Results (if a Case Study enter NA) N/A Conclusion A multimodality diagnostic work-up integrating cytomorphology, flow cytometry and immunohistochemistry allowed recognizing this unusual association.

Thoracic SMARCA4-deficient undifferentiated tumor: A rare entity and challenging diagnosis

Abstract Introduction/Objective Thoracic SMARCA4-deficient undifferentiated tumor is a high-grade malignant neoplasm that frequently shows undifferentiated morphology and deficiency of SMARCA4. There is limited data in literature for this entity. The purpose of this report is to describe a case of this entity and to emphasize the importance of keep this entity in mind when dealing with poorly differentiated thoracic / lung tumors. Methods/Case Report A 49-year-old female with 7.5 pack years smoking history presented with a right shoulder pain. A chest x-ray showed rounded density in the right lung apex. This was followed by a CT chest which revealed a 5.6 cm mass with local destruction of the adjacent right third rib suggestive of a chest wall invasion. Also, hilar and paratracheal lymphadenopathy were noted. Subsequently the patient underwent a right upper lobe biopsy which showed diffuse discohesive sheets of moderately pleomorphic large epithelioid cells with vesicular chromatin, focal rhabdoid morphology, frequent mitoses, and extensive necrosis. Immunochemical staining showed the tumor cells to be positive for Cam 5.2, pancytokeratin (focal, weak), synaptophysin, p53 and TTF-1 (focal, weak) and negative for Napsin, SOX-10, CD45, chromogranin, INSM1, p40, CK7, and CK20. Ki-67 proliferation index was 40-50%. Tumor cells had intact expression of RB and were negative BRG1 (SMARCA4). Therefore, diagnosis of thoracic SMARCA4- deficient undifferentiated tumor was rendered. Next generation sequencing showed pathogenic variants in TP53, CDKN2A, and APC genes and likely pathogenic variants in ATR, SMARCA4, and BCOR genes. The patient received carbotaxol and radiation therapy and is alive with metastatic disease 4 months after initial diagnosis. Results (if a Case Study enter NA) NA Conclusion SMARCA4-deficient undifferentiated tumor is an aggressive malignancy that shows undifferentiated histology with frequent synaptophysin positivity and negativity for other neuroendocrine markers. Pathologists need to keep this entity in their differential when dealing with poorly to undifferentiated thoracic / lung tumors and appropriate immunohistochemical staining can clinch the diagnosis.

Primary Central Nervous System ALK-Negative Anaplastic T-Cell Lymphoma is a Challenging and Uncommon Diagnosis

Abstract Introduction/Objective Primary central nervous system lymphoma (PCNSL) accounts for only 1% of all lymphomas and 6% of all tumors in the central nervous system. Most of these lymphomas are B-cell types, while T-cell types are less common. Anaplastic T-cell lymphoma with ALK-negative is the least common form of anaplastic T-cell lymphoma. It has a similar morphology but is more aggressive than ALK-positive variant. Smaller numbers of ALK-negative PCNSL have been reported. Herein, we report a case of cerebellar ALK-negative anaplastic T-cell lymphoma (ATCL) not only because of the unique location but also to highlight this entity to be considered in future diagnosis to avoid delay or misdiagnosis. Methods/Case Report A 58-year-old woman with no significant past medical history presented with headaches, aphasia, confusion, short memory loss, and loss of control over her body. She had had similar episodes more than three months before. MRI demonstrated extensive enhancement of the leptomeningeal, pial, and pachymeningeal surfaces. Moreover, there are nodular mass-like areas along the cerebellar folia. Left suboccipital craniotomy with biopsy of left cerebellar lesion was performed. Histopathological examination revealed numerous large, atypical lymphocytes characterized by large-size, ovoid to irregular to lobated nuclei, vesicular chromatin, and vacuolated cytoplasm. These cells react positive to CD3, CD30, CD43, CD2, CD7CD56, and negative to ALK1, CD8, CD20, PAX5, CD5, CD10, CD15, CD34, CD138, EMA, p63, TdT, GFAP, CAM5.3, synaptophysin, SOX10, and EBER in situ hybridization. No ALK separation is observed by FISH; however, three copies of the ALK gene are found on chromosome 2p23. ALK-negative ATCL was diagnosed based on all these findings. Results (if a Case Study enter NA) N/A Conclusion Primary central nervous system lymphoma (PCNSL) is extremely rare, and most lymphomas are B-cell types. Anaplastic T-cell lymphomas, ALK-negative lymphoma is a rare and most aggressive variant of T-cell lymphoma. Reporting this tumor is crucial to avoid delay or misdiagnosis.

Primary Endometrial Carcinoma with Signet Ring Cells: A Rare and Unusual Entity

Abstract Introduction/Objective The presence of signet ring cells in an endometrial tumor is suggestive of metastasis, as primary tumors with this morphology are extremely rare. As a result, primary tumors are a diagnosis of exclusion, defined by the presence of signet-ring cells usually associated with mucinous endometrioid carcinoma without clinical or radiographic evidence of metastases from breast, stomach, or colon. Methods/Case Report A 64-year-old woman presented with vaginal bleeding. Ultrasound showed a large, heterogenous uterine mass that was diagnosed as poorly differentiated carcinoma on biopsy. Serum CEA was elevated, and CA-125 was normal. Hysterectomy with salpingo-oophorectomy showed a minor endometrial component of grade 3 endometrioid carcinoma and a predominant component of poorly differentiated carcinoma with signet ring cells. The myoinvasive component consisted of the signet ring cells with pools of acellular mucin. Extensive lymphovascular invasion was noted. Cervix, adnexa, and lymph nodes were free of disease. The signet ring cells were positive for CK7, CK20, and CDX2, and negative for ER and Pax-8. The endometrioid component was positive for ER, Pax-8, and CK7, and negative for CK20 and CDX2. E-cadherin staining was lost in the myoinvasive component of the tumor. Loss of MLH1 and PMS2 nuclear expression was seen, and MLH1 promoter methylation was detected in both components of the tumor. Subsequent colonoscopy and imaging did not reveal any other disease sites. Based on histology, pattern of uterine involvement, and lack of extrauterine disease, a diagnosis of primary poorly-differentiated endometrial adenocarcinoma with signet ring cell features was made. The patient was treated with adjuvant chemotherapy and is currently being followed. Results (if a Case Study enter NA) NA Conclusion We present a rare case of primary signet ring carcinoma of the uterus, a challenging diagnosis made after extensive work-up to rule out metastases. Of the previous 9 reported cases, only one was similar to our tumor with distinct endometrioid and signet ring components. Although these primary endometrial tumors are unified by the presence of signet ring cells, there is considerable immunohistochemical heterogeneity. Some reports suggest the signet ring cells have a Mullerian phenotype, while others, including our case, suggest a gastrointestinal phenotype. In presenting this case, we hope to contribute to this entity’s characterization and bring further awareness that the presence of signet ring cells does not exclude a uterine primary.

Congenital duodenal web causing partial obstruction with recurrent vomiting and abdominal distention in a toddler boy: a case report

BackgroundThe duodenal web is a thin, elongated, web-like structure that is one of the factors contributing to duodenal obstruction. Only 100 cases have been reported in the literature. We present a 2.5-year-old cachectic Afghan child who did not have any overt signs and symptoms of intestinal obstruction, like recurrent vomiting, abdominal distention, and weight loss. The web was discovered near the intersection of the third and fourth portions, which is an uncommon location for the duodenal web. The late presentation of congenital duodenal web with partial obstruction is rare but well-known and has been reported in this case.Case presentationA 2.5-year-old cachectic Afghan child who had recurrent vomiting and experienced abdominal distention was brought to Maiwand Teaching Hospital from the Jabelsuraj region of Parwan province. The patient was suffering from unusual signs and symptoms like recurrent vomiting, abdominal distention, weight loss, and constipation. The diagnosis of these anomalies was established by a detailed history, clinical features, and abdominal CT scan. In the computerized tomography scanning (CT-Scan) image reported, there was a web with stenosis and partial obstruction in the distal aspect of the third-to-fourth portion of the duodenum. After preoperative stabilization, the child was taken for surgery. The abdomen was opened by a right upper abdominal transverse incision. After web resection and duodenoplasty, the patient was shifted to the recovery room in satisfactory condition. The child was allowed to feed after 8 days, which he tolerated well.ConclusionCongenital duodenal web with partial obstruction is typically observed in the second and third years of life. It is suspected in patients with recurrent vomiting, abdominal distention, weight loss, and constipation. Partial obstruction may not have an overt presentation, making it a challenging diagnosis for general practitioners. Abdomen X-ray and CT scan usually confirm the diagnosis, and successful surgical intervention is recommended.

Ocular involvement in pediatric Behçet’s disease: is it different than in adults? (a short case series and mini review)

BackgroundPediatric Behçet’s disease (PBD) is rarer than BD and can be a challenging diagnosis as clinical picture may be incomplete. As in adult patients, sight-threatening ocular manifestations may lead to diagnosis. In this study, we aimed to report a series of cases of PBD with ocular manifestations and provide a review of the literature.MethodsRetrospective case series of PBD patients with ocular manifestations. Demographic, ophthalmological and systemic data at presentation and during follow-up were collected and analyzed.ResultsFour patients, aged 13.0 ± 2.9 years (9–16) were included. Posterior uveitis with retinal vasculitis, papillitis and macular edema was present in all patients, with associated anterior uveitis in 2 cases. Other features included occlusive vasculitis (2/4) and necrotizing retinitis (2/4). All patients were improved by systemic treatments except one patient with severe bilateral optic neuropathy. Ocular manifestations were the presenting symptoms in 3/4 cases.ConclusionOcular manifestations and systemic associations of PBD are comparable to those encountered in adult patients. The lack of complains in pediatric patients may lead to a longer diagnosis delay, especially in unilateral uveitis. Aggressive and long-term treatment is mandatory to prevent vision loss and recurrences.

Juvenile Bullous Pemphigoid with Similarity Clinical Features to Chronic Bullous Disease of Childhood

Introduction: Autoimmune bullous disease (ABD) is a specific autoimmune skin disease characterized by subepidermal vesicles and bullae. In pediatrics, there is an autoimmune bullous disease controversy with clinical clusters of jewel on Chronic bullous disease of childhood (CBDC) but dominant IgG autoantibodies. A similar clinical presentation challenges diagnosis; thus, supporting studies on direct immunofluorescence (DIF) as a specific autoantibody factor are necessary. Case: A 10-year-old boy with clinically tense-walled blisters with or without an erythematous base is itchy all over his body, with a predominance of palmoplantar, neck, inguinal, and axillary, presented by erosions, crusts, and a partial cluster of jewels lesion with mucosal involvement. A complete blood count shows leukocytosis and eosinophilia. Hematoxylin-eosin (HE) staining revealed a subepidermal cleft with eosinophil predominance, while direct immunofluorescence (DIF) revealed IgG deposits in the basal membrana and intercellular parts of the basal stratum. Discussion: Histopathology reveals subepidermal blisters of eosinophil dominance, and direct immunofluorescence (DIF) examination reveals IgG autoantibody deposit dominance, verifying the diagnosis of juvenile bullous pemphigoid. Given that BP180 (BPAG2) is one of the autoantigens involved, there may be similarities between the histology and clinical presentation of Bullous pemphigoid (BP) and CBDC. Conclusion: Autoimmune bullous diseases are difficult to differentiate clinically, histological studies and direct immunofluorescence are necessary to make a diagnosis.

Esophageal Plexiform Fibromyxoma: An Extremely Rare Localization

Plexiform fibromyxoma (PFM) is a rare gastrointestinal tumor, primarily found in the stomach. Esophageal PFM is exceptionally rare. We describe a case of a mid-20s woman with respiratory and swallowing difficulties, revealing a 105x65 mm upper thoracic esophageal submucosal tumor during endoscopy. Biopsy lacked histological evidence of gastrointestinal stromal tumors (GISTs). Post-tumor removal histopathology showed a spindle tumor with plexiform architecture and myxoid-vascular stroma. Immunohistochemistry revealed vimentin and alpha-smooth muscle actin expression, while desmin, c-kit, DOG1, and CD34 were absent, confirming PFM. No recurrence or metastasis appeared during a 6-month follow-up. This case underscores the extreme rarity of esophageal PFM, emphasizing the need for precise diagnostic tools to navigate challenging differential diagnosis.

Challenging diagnoses of tetraploidy/diploidy and trisomy 12: utility of first-tier prenatal testing methods.

Introduction: Chromosome mosaicism and low-grade mosaicism present a challenge for diagnosis in the era of SNP array and NGS. Tetraploidy is a rare numerical chromosomal abnormality characterized by the presence of four copies of each chromosome. The prevalence of tetraploidy/diploidy mosaicism cases is extremely rare in the human population. Accurate estimates of the frequency of this chromosomal anomaly are lacking due to its classification as an extremely rare and difficult-to-detect condition. Methods: In this report, we describe two cases involving challenging diagnoses of tetraploidy/diploidy and trisomy 12. We utilized advanced genetic testing techniques, including SNP array, to examine the chromosomal abnormalities in these cases. We compared the results from SNP array to conventional G band karyotyping to assess the utility of first-tier prenatal testing methods. Results:Our analysis revealed two cases of tetraploidy/diploidy and trisomy 12 with atypical presentations. SNP array analysis provided higher resolution and more precise information about the chromosomal anomalies in these cases compared to conventional G band karyotyping. Additionally, the prevalence of tetraploidy/diploidy mosaicism was confirmed to be extremely rare in the population. Discussion: Low-level mosaicism is difficult to diagnose, and in many cases, it has traditionally been identified through techniques such as G band karyotype or FISH. Microarray has become an invaluable diagnostic tool for detecting chromosomal abnormalities, offering high-resolution insights. However, it may not always be able to detect rare occurrences of tetraploidy or tetraploidy/diploidy mosaicism. As a result, it is recommended to perform a G band karyotype analysis after obtaining a negative microarray result before considering other diagnostic methods with a potentially higher yield of diagnosis. For the detection of low-level mosaicism, combined diagnostic methods should be considered. The diagnosis of mosaicism is a multistep process that can be time-consuming, often requiring the application of more than one diagnostic technique. This approach is crucial for accurate diagnosis and comprehensive patient care. Further research is warranted to better understand the underlying mechanisms of these rare chromosomal anomalies and to develop more effective diagnostic strategies for challenging cases.

Chronic Recurrent Multifocal Osteomyelitis: A Challenging Diagnosis in The Pediatric Age Group and The Role of Imaging: Sharing A Rare Clinical Experience from Ethiopia, East Africa

Chronic recurrent multifocal osteomyelitis, which was originally described as chronic non-bacterial osteomyelitis is an autoinflammatory bone disorder of idiopathic origin affecting the metaphyseal portion of long bones at multiple sites. This disease entity, which was previously considered to be rare; is now showing a higher incidence according to recent studies. The disease affects children in the age range of 8-11 years and affects females more than males. It is characterized by clinical symptoms persisting more than six months with remissions and episodic exacerbations. Here we present a case of a 12- and half year-old girl who had multiple painful swellings with tenderness in her extremities and clavicle over a 4-year period which exacerbated over the last 18 months prior to diagnosis.

HSV-2 Associated Meningitis Case: A Challenging Diagnosis in An Immunocompetent Woman

Herpes simplex virus type-2 (HSV-2) associated aseptic meningitis is rarely seen in healthy individuals. Herein, we report a rare case of meningitis, associated with HSV-2, without the presence of genital lesions. A healthy, 40-year-old female was presented to the emergency service with unremitting headache, vomiting and nausea. Her cerebrospinal fluid (CSF) revealed elevated protein level of 308,2 mg/dL, high leukocyte cell count of 1,118,000 cells/µL with 98% lymphocytes and 2% polymorphonuclear neutrophils (PMNs). The bacterial culture and gram staining of CSF were negative. Real-time quantitative polymerase chain reaction (RT-qPCR) CSF analysis indicated the presence of HSV-2. The cranial MRI revealed meningeal contrast enhancement. The patient was administered acyclovir for 10 days during her hospital stay and she was discharged without any neurological sequela. The patient has a history of herpes infection. This case report shows that HSV-2 meningitis can occur in immunocompetent individuals via re-activation and should always be considered by the clinicians even in the absence of genital lesions.

Follicular cholangitis: a rare cause of benign biliary stricture

Introduction: The differential diagnosis of focal biliary strictures comprises both malignant and benign conditions. We report a rare case of follicular cholangitis presenting with segmental stricture of the left hepatic duct. Case description: An asymptomatic 59-year-old male with no past medical history presented with dilation of the left intrahepatic bile ducts revealed as an incidental finding on an abdominal ultrasound. Blood examinations showed only a slightly elevated gamma- glutamyl transferase (gammaGT) value, while carbohydrate antigen 19-9 (Ca 19-9) and serum immunoglobulin G4 (IgG4) were within normal range. Abdominal computed tomography and magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) scans revealed a high grade focal intrahepatic stricture of the left hepatic duct (FIHS type III) with proximal dilatation. Given that a diagnosis of cholangiocarcinoma could not be ruled out, the patient was referred for a left hepatectomy with regional lymph node dissection. Histological analysis showed a lymphoplasmacytic infiltration of the left hepatic duct with fibrosis and follicle formations in the submucosa, findings consistent with follicular cholangitis. The postoperative course was uneventful and there is no evidence of recurrence 8 months after the surgery. Discussion: The clinical and imaging presentation of follicular cholangitis is very similar to cholangiocarcinoma, rendering it a challenging diagnosis preoperatively. Conclusion: The approach to these cases should be primarily surgical. Even though it is very rare -- our report is the 13th case reported worldwide -- follicular cholangitis should be included in the differential diagnosis of focal biliary strictures.

Abstract 18349: The Impact of Concomitant Mitral Regurgitation on Aortic Valve Intervention Outcomes in Paradoxical Low-Flow Low-Gradient Severe Aortic Stenosis

Background: Patients with paradoxical low flow low gradient severe aortic stenosis (LFLGAS) exhibit low transvalvular flow rates due to reduced stroke volumes, while maintaining preserved left ventricular ejection fraction (LVEF). The presence of mitral regurgitation (MR) adds complexity to this already challenging diagnosis, by further lowering flow rate. However, the impact of aortic valve intervention in this patient population remains uncertain. Methods: A total of 1178 patients were included from an institutional echo database with adjudicated aortic valve area (AVA <1.0 cm2), transaortic gradients (mean gradient< 40 mmHg) and low flow rate (Q ≤210 ml/sec), to confirm the diagnosis of LFLGAS and preserved LVEF (>50%). Subgroups were formed based on the presence of severe MR and subsequent surgical and transcatheter aortic valve intervention (SAVR/TAVR). Patients who underwent mitral valve intervention were censored. All-cause mortality was assessed as the primary outcome. Results: Patients with severe MR had significantly lower flow rates compared to patients w/o severe MR (166.5 ± 26.3 vs 174.7 ± 25, p=0.006). During a median follow up of 1.3 years, 745 deaths (62.2%) were identified, with a cumulative incidence significantly lower in the intervention groups (Figure). After multivariate propensity adjustment for age, sex, aortic valve area and comorbidities, aortic valve intervention showed a significant reduction in mortality risk in both intervention groups, which was more pronounced in the severe MR group compared to patients w/o severe MR (AdjHR 0.334, p=0.015 vs 0.436, p<0.001, p for interaction =0.24). Conclusions: In paradoxical low-flow low-gradient severe aortic stenosis, aortic valve intervention results in a survival benefit, especially among patients with concomitant severe MR. Our findings highlight the importance of recognizing severe MR as a flow-diverting lesion that can impact outcomes in LFLGAS.

Abstract 15984: Toxic Twist: A Case of Bupropion Induced Brugada Syndrome

Introduction: Brugada syndrome is an inherited sodium channel pathology typically diagnosed by ECG findings. The condition can also be triggered by electrolye imbalances, fever and medications. It can result in ventricular tachycardia or fibrillation which can lead to sudden cardiac death. Therefore, it is vital to recognize the Brugada pattern on ECG and identify the potential triggers. Case Presentation: 36-year-old woman with past medical history of depression and prior suicidal attempt presented to emergency department with altered mental status secondary to intentional overdose of bupropion. Vitals were HR 118 beats per minute, BP 160/95 mmHg, RR 14 and SpO2 100% on room air. Physical examination was significant for tachycardia and lethargy. Laboratory values were significant for K + :3.3 mEq/L , HCO3 - :20 mEq/L , anion gap: 15, lactic acid: 5.5 mmol/L, ABG pH: 7.3. ECG on admission showed sinus tachycardia with rate of 121 and prolonged QTc 488 ms. Patient was monitored with serial ECGs given concern for Qtc prolongation. Later in the hospital course, ECG showed coved ST segment elevation in V1-V2 followed by a negative T wave. Echocardiogram was without structural abnormalities with EF of 55-60%. ICD placement was not indicated given this condition was drug induced with type 1 Brugada pattern and there was no family or personal history of syncope, arrhythmia or sudden cardiac death. Patient’s medication regimen was optimized with discontinuation of bupropion which was contraindicated in Brugada syndrome and avoidance of medications with sodium channel blocking effects was emphasized. Discussion: Brugada syndrome is a rare but potentially fatal condition. It becomes more challenging diagnosis in the absence of personal or familial cardiac history. It is very important to consider medications as a possible trigger for the condition given the management differs from inherited type and it does not generally require ICD placement.

Overcoming adnexal torsion: Whirlpool sign

Ovarian torsion or adnexal torsion is an acute gynecologic disorder involving complete or partial rotation of the ovarian vascular pedicle. The majority occurs in young women and is mainly associated to an underlying ovarian mass. It remains a challenging diagnosis and imaging plays a pivotal role for timely and accurate diagnosis [1]. In fact, clinical presentation is nonspecific, most patients present with acute abdominal or pelvic pain, either intermittent or persistent with possible nausea and vomiting.

Rare Invasive Fungal Infections in Hematologic Patients: A Large Unicentric Series

Introduction: Invasive fungal infections (IFI) are a major cause of infectious mortality in immunocompromised hematologic patients. While Candida spp and Aspergillus spp account for most cases, IFI by so-called “rare” fungi (about 1% of all IFI) are clinically relevant, with challenging diagnoses (including difficult phenotypic identification and misinterpretation as contaminants) and insufficient data on antifungal susceptibility to guide treatment guidelines. International efforts to record the epidemiology of these rare IFIs are fundamental to help overcome the lack of data that hinders successful diagnosis and treatment. Methods: We reviewed all fungal infections diagnosed in our Hematology Department in adults (18 years and over) from 06.01.2006 to 03.31.2023, selecting cases with identification of rare fungi by mycologic methods. The date of “Diagnosis” (Dx) was that of collection of the first positive sample. Results: A total of 67 patients (pts, 52.2% male) with a median age of 63.6 years (mean: 59.2, range: 23.2-90.0) were included; 68.7% had acute leukemias - 89.4% of which myeloid (AML), 13.0% lymphoblastic, 4.4% promyelocytic and 2.2% of ambiguous lineage - and 4.5% had myelodysplastic syndromes; 20.9% had a chronic lymphoproliferative disease, 3.0% had aplastic anemia and 3.0% had plasma cell dyscrasias. There was an average of 4 cases of rare IFI per year (range: 0-9), with a peak in 2017 (13.4% of total); 50.8% of all infections diagnosed over the nearly 17 years of the study occurred in the 5 years between 2013-2017, a period of renovation work in our hospital. Time to Dx ranged from 0 (collection on the day of hospitalization) to 98 days (mean: 25.4; median: 22 days). Identification of the fungus took a median of 5 days (mean: 5.6, range: 2-16 days) from the time of collection. In 8 patients (12.9%), the lab report with a fungal identification was released post-mortem; in these pts, results were available a median of 3.5 days after exitus (mean: 5.4, range: 1-13 days). In 79.1% of pts, a yeast was isolated (68.7% Geotrichum-like), while in 20.9% a filamentous fungus was identified (3.0% Mucorales). The most frequent genera were Geotrichum (62.7%), Saprochaete (5.8%), Fusarium and Alternaria (4.5% each). Cryptococcus, Trichosporon and Penicillium accounted for 3% of infections each, with 9 additional species identified in single pts. Fungemia was found in 58.2% of pts (in peripheral blood in 52.2%; in central access blood in 38.8%; in both in 32.8%). Pulmonary isolates were obtained in 26.9% of pts (in sputum in 19.4%; in bronchial aspirate or lavage in 10.4%; in both in 3.0%). Urinary isolates were found in 6.0% of pts; 13.4% had fungi in other biologic samples. The median overall survival was 20 days; 32.6% of pts died within a week of Dx, 45.6% within the first fortnight and 60.9% within the first month; 26.1% died between 1 and 3 months from Dx; and 13.0% died over 3 months after Dx. At the time of the study, 5 pts (7.5% of the cohort) were still alive, all with yeast infections; survivors had evidence of fungemia in 20% of cases and pulmonary involvement in 60%. Discussion: In our large clinical series, AML was responsible for nearly 2/3 of cases of rare IFI, reflecting its overall increased risk for IFI. The rarity of these agents was highlighted by the fact that our tertiary hematology center, serving a population of 2.3 million, had an average of 4 cases of rare IFI per year; yearly variations were in part accounted for by construction work (which releases fungal spores). Dx varied from the day of admission to over 3 months into hospitalization, reflecting a range from community-acquired to nosocomial infections; the average pt had been in hospital for 3 weeks by the time they were diagnosed. There were 4-fold more yeast infections than filamentous fungi, with Geotrichum and related yeasts accounting for 2/3 of cases. Fungemia was present in over half of patients, and pulmonary infiltrates in 1/4, a proportion that was reversed in survivors. Fungal identification took up to a fortnight, and over 10% of patients were dead before a Dx was established, not benefiting from directed treatment. The high lethality of these infections was underlined by the fact that 1/3 died within a week of Dx, with a median OS of 3 weeks. About 1/10 of pts died more than 3 months from Dx, with progressive hematologic disease being the most likely cause of death in that pt subset; less than 10% of the cohort is currently alive, and in remission.

Pirtobrutinib in Richter Transformation: Updated Efficacy and Safety Results with 18-Month Median Survival Follow-up from the Phase 1/2 BRUIN Study

Background:Richter transformation (RT) occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL), typically presents as an aggressive diffuse large B-cell lymphoma (DLBCL) and is associated with poor survival. RT has no approved standard therapy; and clinical trial enrollment is the preferred first line of therapy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, that inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval. Pirtobrutinib demonstrated durable overall response rates (ORR) and was well tolerated in patients (pts) with poor-prognosis B-cell malignancies regardless of prior therapy. Here we provide updated safety and efficacy of pirtobrutinib in RT pts from the phase 1/2 BRUIN trial (NCT03740529). Methods: Pts with previously treated, histologically confirmed RT were eligible in the global, multicenter, phase 1/2 BRUIN study. Pts with untreated RT became eligible after Amendment 10. All but one patient received the recommended phase 2 dose of 200 mg daily. Key endpoints included investigator-assessed ORR, DoR per Lugano 2014 criteria, OS, and safety. A data cut of 05 May 2023 was utilized. To assess clonal relationship, IGH rearrangement studies were done on tissue biopsies with RT involvement, and baseline blood or bone marrow (BM) samples with CLL involvement. Results: Among all pts with RT (N=82) the median age was 67 (range, 26-95) and the median total number of lines of prior systemic therapy was 4 (range, 0-13). Pts with prior treatment had a median of 2 CLL-directed therapies and 2 RT-directed therapies. Eight pts did not have a previous line of RT-directed therapy, and 1 patient received neither RT- nor CLL-directed therapy. Common prior RT- and CLL-directed therapies (RT, CLL) included: chemotherapy (76%, 52%), cBTKi (34%, 62%), anti-CD20 antibody (78%, 66%), BCL2i (38%, 49%), stem cell transplant (SCT; 6%, 7%), and CAR-T (11%, 4%). Of 29 pts with bone marrow screening, 41.4% had CLL alone present in BM, 13.8% had DLBCL present and 24.1% had both CLL and DLBCL present. For 39 pts with available PET data, the median SUVmax was 19.1 (range, 2.6-41.2). For all 82 pts, the ORR was 50.0% (95% CI, 38.7-61.3) including complete (13.4%, n=11) and partial (36.6%, n=30) responses. For 61 pts who received prior cBTKi therapy, the ORR was 45.9% (95% CI 33.1-59.2). Among 28 pts with an RT-directed cBTKi and 51 pts with prior CLL-directed cBTKi, the ORR was 42.9% (95% CI, 24.5-62.8) and 43.1% (95% CI, 29.3-57.8), respectively. In 50 pts who discontinued prior cBTKi due to disease progression, the ORR was 42.0% (95% CI, 28.2-56.8). At median follow-up time of 9.7 months, the median DoR for all 82 RT pts was 7.4 months (95% CI, 3.1-19.1) and the estimated rate at 12 months was 45.9% (95% CI, 28.3-61.8). The median time on treatment for the 41pts who responded to treatment was 8.3 months. Eight pts stopped pirtobrutinib to pursue curative-intent allogeneic SCT and DoR was censored at the last preceding disease assessment. At a median survival follow-up of 18.3 months, the median OS for the entire RT cohort was 12.5 months (95% CI, 6.9-20.5). At 18 months, the OS rate was 44.3% (95% CI, 32.5-55.4). Frequent treatment-emergent adverse events (TEAE) in the RT cohort (n=82) were neutropenia/decreased neutrophil count (29.3%, n=24), fatigue (24.4%, n=20) and diarrhea, dyspnea, thrombocytopenia, and pyrexia (18.3% each, n=15). Common grade ≥3 TEAEs were neutropenia/decreased neutrophil count (23.2%, n=19), thrombocytopenia (11.0%, n=9), plus anemia and sepsis (9.8% each, n=8). Any grade hypertension (3.7%, n=3) or atrial fibrillation (1.2%, n=1) were infrequent. Three pts (3.7%) had treatment-related AEs leading to dose reductions, but no pt had a treatment-related AE leading to pirtobrutinib discontinuation. Analyses of clonality will be presented. Conclusions: Continued follow-up from BRUIN demonstrates encouraging response and OS in pts with RT. Pirtobrutinib remains well-tolerated with low rates of discontinuation and manageable safety profile. While RT remains a challenging diagnosis, pirtobrutinib represents a potential treatment option that warrants further investigation.