Malignant Causes Research Articles

A Unique Case of Bilateral Chylothorax in a Patient Treated with Dasatinib for CML

We describe an interesting case of an elderly woman with CML who presented with bilateral recurrent effusion. Pleural fluid analysis revealed lymphocytepredominant exudative pleural fluid negative for malignant cells. She was started on antitubercular medications on an empirical basis with no improvement. On re-evaluation with repeat fluid analysis, the fluid from both sides turned out to be chylothorax. Infectious, malignant causes were ruled out. She was on Dasatinib for 2 years before she developed effusion. A diagnosis of drug-induced effusion was made and the offending drug was withheld. Her effusion cleared and pleurodesis was done bilaterally. She remains clinically and radiologically better on follow-up to date.

Semiquantitative 18F-FDG PET/CT in monitoring glucocorticoid response of immunoglobulin G4-related effusive constrictive pericarditis: a case report

BackgroundImmunoglobulin G4 (IgG4)-related effusive constrictive pericarditis (ECP) is a rare manifestation of IgG4-related disease (IgG4-RD). It can lead to persistent pericardial fibrosis, resulting in cardiac tamponade, diastolic dysfunction, and heart failure. Glucocorticoids are the primary treatment for effectively reducing inflammation and preventing fibrosis. However, guidelines for monitoring treatment response are lacking and tapering glucocorticoid therapy for specific target organs remains a challenge. Recent studies on IgG4-RD have demonstrated that semiquantitative measurements of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the main involved organs in positron emission tomography/computed tomography (PET/CT) scanning are correlated to disease activity. We present a case of IgG4-related ECP to demonstrate the usefulness of 18F-FDG PET/CT for diagnosing and treatment follow-up of IgG4-related ECP.Case presentationHerein, a 66-year-old woman diagnosed with IgG4-related ECP presented with breathlessness, leg swelling, rales, and fever. Laboratory tests revealed markedly elevated levels of C-reactive protein, and transthoracic echocardiography revealed constrictive physiology with effusion. High IgG4 levels suggested an immune-related pathogenesis, while viral and malignant causes were excluded. Subsequent pericardial biopsy revealed lymphocyte and plasma cell infiltration in the pericardium, confirming the diagnosis of IgG4-related ECP. 18F-FDG PET/CT revealed increased uptake of 18F-FDG in the pericardium, indicating isolated cardiac involvement of IgG4-RD. Treatment with prednisolone and colchicine led to a rapid improvement in the patient’s condition within a few weeks. Follow-up imaging with 18F-FDG PET/CT after 3 months revealed reduced inflammation and improved constrictive physiology on echocardiography, leading to successful tapering of the prednisolone dose and discontinuation of colchicine.ConclusionThe rarity of IgG4-related ECP and possibility of multiorgan involvement in IgG4-RD necessitates a comprehensive diagnostic approach and personalized management. This case report highlights the usefulness of 18F-FDG PET/CT in the diagnosis and treatment follow-up of isolated pericardial involvement in IgG4-RD.

Identification and verification on prognostic index of glioblastoma immune-related lncRNAs.

Glioblastoma (GBM) is the most common cause of primary brain malignancy. Recently, many immune-related long noncoding ribonucleic acids (ir-lncRNAs) are indicated to be closely related to the regulation of the immune microenvironment and immune cell infiltration of GBM. Through the joint analysis of multiple public databases, key ir-lncRNAs in GBM were screened. The ir-lncRNAs were used to construct risk-scoring models and promote the development of novel GBM biomarkers. In this study, we performed a three-way Venn analysis combined with a least absolute shrinkage and selection operator (LASSO) regression analysis on all lncRNAs in The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and Imm-Lnc datasets, and identified 10 ir-lncRNAs. Multivariate Cox analysis was used to calculate the coefficient and construct a risk-scoring model. By plotting calibration curves and receiver operating characteristic (ROC) curves, the model showed excellent prediction results. Based on the Tumor Immune Estimation Resource (TIMER) database, the correlation analysis showed that 10 ir-lncRNAs risk scores were related to immune cell infiltration. The enrichment analysis was subsequently performed, which showed that these ir-lncRNAs played an important role in the progression of GBM. Among the 10 lncRNAs, we found that AL354993.1 was highly expressed in GBM, had not been reported, and was shown to be closely related to GBM progression. In conclusion, the 10 ir-lncRNAs have the potential to predict the prognosis of GBM patients and may play a vital role in the progression of the disease.

Superior Vena Cava Syndrome Associated with Left Subclavian Thrombosis Secondary to Anaplastic Thyroid Carcinoma: A Case Report

Superior vena cava syndrome results from obstruction of the venous flow or the return of the superior vena cava. Increased venous pressure in the upper body causes edema of the face, neck, and upper extremities occasionally accompanied by vessel distension, cyanosis, cough, dyspnea, stridor, and dysphagia. Cerebral edema causes headaches, confusion, coma, and even death. Lung cancer and non-Hodgkin lymphoma are the most frequent malignant causes (85%) of superior vena cava syndrome, and thyroid cancer is a rare cause (< 5%).

Prognostic Factors of Adult Hemophagocytic Lymphohistiocytosis and Clinical Utility of HLH-2004 Diagnostic Criteria and HScore: A Real-World Multicenter Study from Thailand

Introduction: Adult hemophagocytic lymphohistiocytosis (HLH) is a rare disease with a dismal prognosis. Early diagnosis and prompt management are necessary for improved outcomes. Methods: This multicenter retrospective study investigated the etiologies, survival, and prognostic factors of HLH, including the utility of HLH-2004 criteria and HScore in real-life clinical practice. Results: A total of 147 HLH patients were identified by using a combination of hemophagocytosis identification in bone marrow and the HLH-related international classification disease-10. A total of 116 (78.9%) patients fulfilled the HLH diagnosis by HScore, while 91 (61.9%) patients fulfilled 5 of 8 HLH-2004 criteria. In Thailand, the clinical application of HLH-2004 criteria needed to be reduced from 8 to 6 due to a lack of sCD25 and natural killer cell activity tests. Using the adapted HLH-2004 with a cutoff value of 4 resulted in 132 (89.9%) cases meeting the diagnostic criteria. Among these 132 confirmed HLH patients by using adapted HLH-2004, HLH was triggered by infection (29.5%), autoimmune disease (12.9%), malignancy (40.9%), and unknown cause (16.7%). Median overall survival of HLH patients was extremely short (67 days). Ferritin >6,000 μg/L, HLH from infection, malignancy, and unknown etiology were demonstrated as independent prognostic factors for inferior survival (hazard ratio [HR] 2.47; 95% confidence interval [CI] 1.39–4.37, HR 4.69; 95% CI 1.38–15.92, HR 6.09; 95% CI 1.84–20.14, and HR 6.02; 95% CI 1.64–22.05, respectively). Conclusion: Ferritin is a helpful biomarker for HLH diagnosis and prognostic prediction. Autoimmune disease-triggered HLH has favorable outcomes. Future prospective study is required to verify the use of the adapted HLH-2004 criteria.

Identification of dysregulation of sphingolipids in retinoblastoma using liquid chromatography-mass spectrometry

Retinoblastoma (RB) is a rare ocular cancer seen in children that counts for approximately 3% of all childhood cancers. It is found that mutation in RB1, a tumour Suppressor Gene on chromosome 13 as the cause of malignancy. Retinoblastoma protein is the target for ceramide to cause apoptosis. We studied lipidomics of two RB cell lines, one aggressive cell line (NCC–RbC-51) derived from a metastatic site and one non aggressive cell line (WERI-Rb1) in comparison with a control cell line (MIO-M1). Lipid profiles of all the cell lines were studied using high resolution mass spectrometer coupled to high performance liquid chromatography. Data acquired from all the three cell lines in positive mode were analyzed to identify differentially expressed metabolites. Several phospholipids and lysophospholipids were found to be dysregulated. We observed upregulation of hexosyl ceramides, and down regulation of dihydroceramides and higher order sphingoglycolipids hinting at a hindered sphingolipid biosynthesis. The results obtained from liquid chromatography-mass spectrometry are validated by using qPCR and it was observed that genes involved in ceramide biosynthesis pathway are getting down regulated.

Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection.

Kaposi's sarcoma herpesvirus (KSHV) is a leading cause of malignancy in AIDS and current therapies are limited. Like all herpesviruses, KSHV infection can be latent or lytic. KSHV latency-associated nuclear antigen (LANA) is essential for viral genome persistence during latent infection. LANA also maintains latency by antagonizing expression and function of the KSHV lytic switch protein, RTA. Here, we find LANA null KSHV is not capable of lytic replication, indicating a requirement for LANA. While LANA promoted both lytic and latent gene expression in cells partially permissive for lytic infection, it repressed expression in non-permissive cells. Importantly, forced RTA expression in non-permissive cells led to induction of lytic infection and LANA switched to promote, rather than repress, most lytic viral gene expression. When basal viral gene expression levels were high, LANA promoted expression, but repressed expression at low basal levels unless RTA expression was forcibly induced. LANA's effects were broad, but virus gene specific, extending to an engineered, recombinant viral GFP under control of host EF1α promoter, but not to host EF1α. Together, these results demonstrate that, in addition to its essential role in genome maintenance, LANA broadly regulates viral gene expression, and is required for high levels of lytic gene expression during lytic infection. Strategies that target LANA are expected to abolish KSHV infection.

A starry sky image result in a patient with active bleeding due to malignancy cause.

Hemostatic powders (HP) are increasingly used to address limitations in conventional endoscopic techniques for gastrointestinal bleeding. HP is a relatively recent addition to the arsenal of hemostatic endoscopic procedures (HEPs) for gastrointestinal bleeding (GIB) due to benign and malignant lesions, which all life-threatening conditions. HP acts as a mechanical barrier and/or promotes platelet activation and coagulation cascade. Malignancy causes comprise 1-5% of all non-variceal upper gastrointestinal bleeding (NVUGIB). UI-EWD (NexPowder) is composed of oxidized dextran and succinic anhydride, which is converted to an adhesive hydrogel upon contact with moisture. The resulting hydrogel cross-links within itself and with adjacent tissue to create a mechanical barrier to promote hemostasis. As it does not require clot formation to achieve hemostasis, UI-EWD does not require active bleeding. This provides it a potential role in prophylaxis, such as post-procedure or following primary hemostasis achieved with conventional endoscopic techniques. While UI-EWD is the newest development in hemostatic powders for clinical use, initial results are promising. We report the case of a 51-year-old male with epidermoid esophageal stenosing carcinoma recently diagnosed and locally advanced. Started treatment concurrent chemotherapy and radiotherapy, being necessary a nasogastric tube for parenteral nutrition. Our patient came to the emergency unit due to hematemesis which came from a pressure ulcer with active bleeding shown in gastroscopy exploration, withdrawing the tube and spraying onto the surface of the bleeding site UI-EWD until the bleeding lesion was completely covered with the powder, doing successful hemostasis confirmed by hemostasis until 5 minutes after the endoscopic treatment. HP is highly effective in patients with NVUGIB when used either in combination with or as rescue therapy. Rapid development of hemostatic powders and growing clinical expertise has established these agents as a valuable strategy in gastrointestinal bleeding.

Pattern and outcome of paediatric pleural effusion seen at Usmanu Dafodiyo University Teaching Hospital, Sokoto: A 5-year retrospective study

Background: Pleural effusion is an abnormal accumulation of fluid in the pleural cavity which present with spectrum of clinico-aetiological manifestations often requiring multidisciplinary approach.
 Objectives: This study set out to determine the prevalence, aetiology, clinical presentation, treatment modalities and outcome of pleural effusion in children.
 Materials and Methods: This was a retrospective study where records of children with diagnosis of pleural effusion admitted at UDUTH, Sokoto were obtained between January 2017 and December 2022 and reviewed. Diagnosis was based on clinical presentation and radiological confirmation of pleural effusion. Data was analyzed with SPSS version 20.0.
 Results: A total of 49 cases were retrieved. The prevalence of pleural effusion was 0.54% (9,056). It was more prevalent in males with ratio of 2.5:1 (χ² = 9.833, P = 0.007). The median age was 9 years (IQR 7). The most common cause of pleural effusion was pneumonia 26 (53.1%) followed by tuberculosis 16 (32.6%), malignancy 3 (6.1%), cardiac and renal causes accounted for 2 (4.1%) each. Cough (100.0%), difficulty in breathing (100.0%), tachypnea (100.0%), respiratory distress (100.0%), and desaturation (98.0%) were the common presentations. Most (77.5%) of them presented with right sided pleural effusion. The majority (93.9%) had closed thoracostomy tube drainage. The outcome showed majority (83.7%) of the cases been discharged, with a median duration of hospital stay of 22days (IQR 17). However, mortality rate for the malignant causes was 100.0%.
 Conclusion: Infections were the major cause of paediatric pleural effusion with relatively good outcome. Surgical intervention and multidisciplinary team approach are needed to reduce the morbidity and mortality in patients with pleural effusion especially for the malignant causes.

Optimizing diagnostic success for vitreoretinal lymphoma

Aims/Purpose: To determine the diagnostic yield and pathological entities in a retrospective cohort of diagnostic vitrectomy patients.Methods: A retrospective cohort of diagnostic vitrectomy samples submitted to a tertial referral hospital pathology laboratory was identified by database search. The specimen submission protocol for this cohort consisted of two components: (i) intraoperative preparation of a neat vitreous aspirate as well as submission of the casette washings in RPMI and (ii) laboratory triage of each sample for microbiology culture, flow cytometry, cytological assessment and cell block preparation.Results: A total of 133 diagnostic vitrectomy samples were submitted between November 2015 and January 2022 (mean age 74 years, 0.8 M:F). A diagnostic report resulted in 132 (99.2%) of cases. Benign diagnoses (infectious and non‐infectious vitritis, degenerative or reactive changes, haemorrhage) were found in 88 of the cases (66.1%), while 20 cases (15%) were malignant. Of the malignant diagnoses, 18 (13.5%) were vitreoretinal lymphoma (17 diffuse large B cells; 1 T cell) by cytology and flow cytometry. The other two malignant diagnoses consisted of metastatic adenocarcinoma and metastatic cutaneous melanoma. 24 cases (18%) were classified as atypical, consisting of a lymphocytosis without demonstrable clonality by flow cytometry.Conclusions: This intraoperative and laboratory protocol maximizes the sample for all diagnostic tests required to discern infectious, inflammatory and malignant causes of increased vitreous cellularity. Importantly, the protocol allows for immunophenotyping of vitreoretinal lymphoma by flow cytometry and immunohistochemistry to WHO classification standards, essential for treatment and surveillance decision‐making.

Constitutional mismatch repair deficiency syndrome as a cause of numerous malignancies in a teenage patient - a case report

Constitutional mismatch repair deficiency syndrome as a cause of numerous malignancies in a teenage patient - a case report

SIMULTANEOUS SURGICAL MANAGEMENT OF CONGENITAL BICUSPID AORTIC VALVE AND GASTRIC CANCER: A CASE REPORT

Relevance: Gastric cancer is the second leading cause of malignancies of the gastrointestinal tract and the fifth leading cause in overall cancer statistics. Diseases of the cardiovascular system are the leading cause of death worldwide. A high prevalence of both diseases increases the chances of their co-morbidity.
 The study aimed to present a case where a patient undergoes two simultaneous procedures for two diseases and discuss possible surgical tactics, advantages, and disadvantages.
 Methods:
 Results: In this case report, we present simultaneous surgical procedures performed on a 49-year-old male with a history of congenital bicuspid aortic valve and gastric cancer, found incidentally on upper gastrointestinal (GI) endoscopy. Since the patient was a good fit, he qualified for simultaneous surgery on the heart and abdomen.
 The surgery results were good, and the patient was discharged 8 days after surgery.
 Conclusion: Performing simultaneous surgery for both the abdomen and heart can be a safe procedure that allows people with malignant diseases to receive adjuvant therapy faster by minimizing the interval between surgeries.

Non-Smoker’s Cancer- Human Papilloma Virus (HPV) Induced Head & Neck Squamous Cell Carcinoma (HNSCC)

Head and neck squamous cell carcinoma is recognized as 6th most common cancer worldwide. Etiological factors are generally cigarettes, alcohol consumption also tobacco products such as ghutka, pan masala and betel quid also triggers the development of OSCC. Among several causes of cervical malignancies which the second most carcinoma is the world, infection with some types of human papilloma virus (HPV) is thought to be the greatest cervical cancer risk factor. Over 150 subtypes of HPV have been identified; from which more than 40 types of HPVs are typically transmitted through sexual contact and infect the anogenital region and oral cavity. HPV is suspected as the principle causative factor for oral malignancy in non smoker and non-alcoholic patients. It was also reported to be associated with Head and neck squamous cell carcinoma in 1995. The recently introduced vaccine for HPV infection is effective against certain subtypes of HPV which are associated with cervical cancer, genital warts, and some less common cancers, including oropharyngeal cancer. The value of HPV vaccination for oral cancer prevention is still controversial and hypothetical; some evidence also supports the possibility that HPV vaccination may be preventive factor in reducing the incidence of oral cancer.

SIMULTANEOUS SURGICAL MANAGEMENT
 OF CONGENITAL BICUSPID AORTIC VALVE
 AND GASTRIC CANCER:
 A CASE REPORT

Relevance: Gastric cancer is the second leading cause of malignancies of the gastrointestinal tract and the fifth leading cause in
 overall cancer statistics. Diseases of the cardiovascular system are the leading cause of death worldwide. A high prevalence of both
 diseases increases the chances of their co-morbidity.
 The article aimed present a case where a patient undergoes two simultaneous procedures for two diseases and discuss possible
 surgical tactics, advantages, and disadvantages.
 Results: In this case report, we present simultaneous surgical procedures performed on a 49-year-old male with a history of congenital bicuspid aortic valve and gastric cancer, found incidentally on upper gastrointestinal (GI) endoscopy. Since the patient was a
 good fit, he qualified for simultaneous surgery on the heart and abdomen.
 The surgery results were good, and the patient was discharged 8 days after surgery.
 Conclusion: Performing simultaneous surgery for both the abdomen and heart can be a safe procedure that allows people with
 malignant diseases to receive adjuvant therapy faster by minimizing the interval between surgeries.

OBSTRUCTIVE JAUNDICE: ETIOLOGY AND PATTERN OF PRESENTATION

Surgical jaundice mainly occurs due to obstruction in any duct from the liver to the gall bladder and then the small intestine. It can be divided into intra-hepatic or extra-hepatic causes. Biliary stones, iatrogenic or ischemic biliary stricture, pseudo-pancreatic cysts, carcinoma of the head of the pancreas, and periampullary carcinomas are common pathologies of obstructive jaundice. Common bile duct stones account for 10-15% of biliary stone disease and are the most common cause of obstructive jaundice. Obstructive jaundice presents with a wide range of associated features. Ultrasonography, MRCP, and ERCP are the primary diagnostic tools for diagnosing and managing obstructive jaundice, in addition to blood tests. This study aims to determine the pattern of presentation and causes of obstructive jaundice. This observational, retrospective study was conducted in general surgery and surgical oncology unit 2 of Sheikh Zayed Hospital, Lahore. The study lasted from January 2022 to April 2023. A non-probability convenience sampling technique was used. A total of 55 patients with obstructive jaundice were presented in the study area in a defined period, which included 17 (30.90%) males and 38 (69.09%) females. The mean age was 49 years, with age ranges from 28 years to 80 years. 13 (23.66%) patients were found to have malignant disease, whereas 42 (76.33%) patients presented with benign disease. The most common malignant cause of obstructive jaundice was carcinoma head of the pancreas (10.90%), whereas the least common causes were cholangiocarcinoma (1.82%), carcinoma gall bladder (1.82%) and malignant biliary stricture (1.82%). The most common benign cause and overall most common cause of obstructive jaundice was choledocholithiasis (32.73%), followed by referred biliary injuries (18.18%). The most common clinical feature presented in benign causes of obstructive jaundice was jaundice (100%), followed by itching (71.4%) and abdominal pain (64.28%). The most common clinical feature in malignant causes of obstructive jaundice was jaundice (100%), followed by loss of appetite (84.61%) and weight loss (84.61%). Female was the most common gender presented with obstructive jaundice. The most common benign cause of obstructive jaundice was Choledocholithiasis, while the most malignant cause was carcinoma head of the pancreas.

Screening for HPV-Related Oropharyngeal Cancer in Gay and Bisexual Men: Acceptability and Predicting Possible Use of "Oral Selfies" by Smartphone as a Secondary Prevention Approach.

Oropharyngeal cancers (OPCa) caused by HPV have emerged as one of the leading causes of malignancies caused by HPV infection. They are also significantly more likely to occur in males and in people with a history of oral sex with multiple partners. Gay and bisexual men are disproportionately affected by HPV-positive oropharyngeal cancers. We studied 1699 gay and bisexual men on 2 major dating sites in the US to assess their knowledge about HPV-related OPCa, attitudes toward screening for it, beliefs about oropharyngeal cancer screening based on the Health Belief Model, and attitudes toward possible screening approaches for OPCa. Knowledge on a 12-item scale was low, with a median of 5 items correct: 72% knew of the benefits of HPV vaccination. Significant predictors of needing OPCa screening included perception of risk for OPCa, seeing it as severe, having lower barriers, fewer reasons to avoid screening, higher knowledge, and being HPV vaccinated were significant predictors, explaining half the total variance. Most participants would accept routine, virtual/online doctor or dental appointments, and over half would accept an in-person screening. Nearly two-thirds stated that they would accept getting checked for OPCa if they could do self-screening at home, and half were prepared to use an online screening tool or app, where they could take an "oral selfie" and send it to a healthcare provider for examination. One-third stated that they would trust the results of a home screening completed by themselves and posted to a website equally as cancer screening completed online by a healthcare provider. Data indicate that despite low OPCA knowledge levels, the risk of HPV-associated OPCa was known. Being at personal risk and having knowledge of disease severity had 70% of the sample thinking about, or preparing to get, screening. Self-screening by a smartphone "oral selfie" transmitted to a screening website was acceptable to many gay and bisexual men, and online screening by a doctor or dentist was acceptable to most. OPCa screening in this population using electronic technology, together with the increasing incidence of HPV-associated OPCa in gay and bisexual men, brings together an opportunity to detect OPCa early.

Predictive factors in the differential diagnosis of benign and malignant causes in patients undergoing endoscopic retrograde cholangiopancreatography for extrahepatic cholestasis.

Diagnosing benign vs. malignant extrahepatic cholestasis is challenging despite the currently available advanced imaging and endoscopic techniques. This study aims to determine the predictive accuracy of initial biochemical data and bile duct dilatation findings in transabdominal ultrasound (US) to differentiate between benign and malignant disease in patients with extrahepatic cholestasis. We reviewed the case records of 814 patients who had undergone endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (in cases of unsuccessful ERCP) for extrahepatic cholestasis. The etiology of biliary obstruction was determined based on ERCP, endoscopic ultrasonography, radiology, cytology, biopsy, and/or clinical follow-up at one year. The patients were divided into benign and malignant groups according to the underlying etiology of biliary obstruction. A complete biochemical profile, transabdominal ultrasonography at presentation, and other demographic data were recorded. Alkaline phosphatase (p = 0.002), aspartate aminotransferase (p = 0.038), and bilirubin levels were significantly higher in malignant patients. The mean age of patients with malignancy was 69.5 years, vs. 60.6 years in benign patients (p < 0.001). The likelihood of malignancy increased with the increased bilirubin levels (> 200 µmol/l: 30.0% sensitivity, 97.6% specificity). The total bilirubin level predicting malignancy as the best cut-off value was 111 mmol/L with optimum sensitivity and specificity (61.8% and 83.8%, respectively) and area under the curve = 0.756, (p < 0.001). Intrahepatic bile duct (IHBD) dilatation was significantly higher in malignant patients (p < 0.001). A serum bilirubin level of 111 µmol/L or higher and the detection of IHBD dilatation on abdominal ultrasonography are important predictors in the differential diagnosis of benign and malignant causes of extrahepatic cholestasis.

Do We Still Need to Perform Bone Marrow Examination in All Subjects Suspected of MDS? Evaluation and Validation of Non-Invasive (Web-Based) Algorithm

Background : The gold standard of diagnosing myelodysplastic syndromes (MDS) still requires a bone marrow examination (BME), an old invasive procedure, with possible associated pain and bleeding, and subjective interpretation with 20-25% inter-observer variability. We first developed a logistic regression formula [Oster HS et al., Leuk Res 2018], and then a non-invasive web-based diagnostic algorithm [Oster HS et al., Bld Adv 2021]. The app requires input of 10 readily available clinical and laboratory parameters (age, gender, Hb, MCV, WBC, ANC, monocytes, PLT, glucose, creatinine), resulting in diagnosing or excluding MDS, perhaps obviating the BME (Figure). Here, we performed external validation of the model, using data of MDS patients and non-MDS controls, who had not been included in the development of the model. Methods: The BM registry of Tel Aviv Sourasky Medical Center (1/2017-12/2021) was reviewed. Inclusion criteria for the MDS group were BME diagnosis, and for the controls, age &amp;gt;50yr, and unexplained anemia requiring BME. We excluded patients with other causes of anemia (renal failure; B12/folic acid or iron deficiency), active malignancy and other hematologic diseases. The relevant parameters were entered into the online model (at https://shiny.york.ac.uk/mds/) and the results of both groups were compared. In a sub-analysis, the model performance was tested in patients with lower risk (LR, IPSS-R&amp;lt;3.5) and higher risk (HR, IPSS-R≥3.5) MDS. Results: In total, 204 patients were included and compared, 103 with MDS, and 101 anemic non-MDS control patients, all with BME. The analysis of model performance (Table, upper portion) showed a sensitivity of 85.6%, specificity of 92.3%, positive predictive value (PPV) of 90.3% and a negative predictive value (NPV) of 88.4%. The algorithm was indeterminate in 26.2% of patients with MDS (BME proven), compared with 9.9% in the control group. In the sub-analysis (Table, lower portion), the model performance in the patients with LR-MDS (n=61) demonstrated sensitivity 85.1%, specificity 92.3%, PPV 90.3% and NPV 88.1%. The performance in HR-MDS (n=32), was 89.3%, 92.3%, 90.6% and 91.1%, respectively. Conclusions : This study validates the potential role of this non-invasive, easy-to-use model to assist in diagnosis, and mainly exclusion of MDS, perhaps allowing to avoid bone marrow examination in some patients. This might be especially relevant for patients suspected to have LR-MDS. Emerging technologies with data generated from peripheral blood (genetics, morphometrics) may be incorporated in the model in the future.

Treatment pattern and outcomes of leptomeningeal carcinomatosis in India – a retrospective study

Leptomeningeal carcinomatosis (LMC), the metastatic spread of cancer to the leptomeninges, is a rare complication and has a dismal prognosis. Due to limited data available on LMC from India, we conducted a country-wise audit of LMC across 15 centres in India. The current study conducted in 2020, was a retrospective, multicentric audit of adult patients (aged ≥18 years) with diagnosis of LMC and who received treatment during 2010-2020. Baseline characteristics, details related to previous treatments, cancer sites, LMC diagnosis, treatment pattern and overall survival (OS) were collected. Descriptive statistics were performed, and Kaplan Meier analysis was performed for the estimation of OS. Among the patients diagnosed with LMC (n=84), diagnosis was confirmed in 52 patients (61.9%) and 'probable' in 32 (38.1%) patients. The three most common cause of malignancy were non-small cell lung cancer (NSCLC), breast cancer and gastrointestinal cancer with 45 (53.6%), 22 (26.1%) and 9 (10.7%) patients respectively. Intrathecal therapy was offered in 33 patients (39.3%). The most common intrathecal agent was methotrexate in 23 patients (27.4%). The median OS was 90 days (95% CI 48-128). Among tested variables, intrathecal therapy administration (hazard ratio [HR]=0.36, 95% CI 0.19-0.68) and primary in lung (HR=0.43, 95% CI 0.23-0.83) had a favourable impact on OS. Prognosis with leptomeningeal carcinomatosis is poor with a significant burden of morbidity and mortality in India. This data aims to highlight the current outcomes and facilitate further research on LMC. None.

ERG Is a New Predisposition Gene for Bone Marrow Failure and Hematological Malignancy

There remain gaps in our knowledge of hereditary and sporadic causes of hematological malignancy (HM) and bone marrow failure (BMF) that prevent optimal diagnosis, disease surveillance and treatment. Here we report the discovery of ERG as a novel predisposition gene for BMF and HM. ERG is a known oncogene, typically via gene-fusions, leading to dysregulated ERG overexpression in blood and solid cancers. We identified a germline ERG ETS domain variant p.Y373C segregating with thrombocytopenia in a mother, who progressed to AML (27 yr) and then therapy-related MDS (35 yr), and in her 2 sons. All three showed copy neutral loss of heterozygosity of all or part of chromosome 21q, including the ERG locus, with the oldest son showing at least 2 somatic genetic rescue (SGR) events. The possibility of causal RUNX1 variants were ruled out, with the smallest somatic cnLOH event beginning within the RUNX1 gene, but not encompassing the RUNT domain where the majority of pathogenic missense variants are located. ERG, a highly constrained gene (LOEUF &amp;lt;0.33), is critical for definitive hematopoiesis, adult hematopoietic stem cell (HSC) function and platelet maintenance. An identical corresponding heterozygous germline variant (p.Y343C) in ERG’s closest gene by homology, FLI1, causes platelet-type bleeding disorder-21 (BDPLT21, OMIM #617443). Through global collaborations, we have identified 15 heterozygous variants in the ERG gene, 13 of which are missense and 2 truncating variants, in 17 individuals with cytopenia and/or HM (mainly myeloid) or lymphedema (Table). Onset of hematological symptoms ranged from birth to 38 years for truncating and constrained ETS domain variants. Of these 15 variants, 12 have been confirmed germline including 2 de novo. Only 4 meiotic transmissions are observed. None of the missense variants in the highly conserved ETS domain of ERG which mediates DNA binding, protein-protein interactions and nuclear localization, are present in gnomAD. We have functionally characterized 19 ERG variants, 12 potentially pathogenic, 1 known mouse pathogenic variant and 3 population controls demonstrating that most ETS domain missense variants display loss-of-function (LOF) characteristics disrupting transcriptional transactivation (Figure), DNA-binding and/or nuclear localization in vitro. Robust preliminary data from ex vivo models of ERG overexpression in mouse fetal liver cells in tissue culture (cytokine-independence), a mouse transplant assay and previous germline mutant Erg mouse models are concordant with ETS domain missense variants being LOF compared to wildtype ERG and benign controls. Together, these data provide clinical, in vitro and ex vivo functional studies implicating LOF variants in hematological disease predisposition. LOF ERG mutations also occur in sporadic cases of HM. Recently, as part of a Genomics England Research Consortium population study, 4 truncating ERG variants were described in 7 individuals across 4 families with 3 meiotic transmissions and a de novo case with primary lymphedema (1) and we add 2 novel missense variants here. One patient showed SGR across the ERG locus in blood. Blood phenotypes were not described. Our results demonstrate that germline ERG variants predispose to diverse cytopenia, BMF and HM in both children and adults. In our family mentioned above, the mother received an unrelated alloHSCT due to t-MDS while her 2 sons with cytopenias continue to be monitored. The natural history of this new syndrome will require careful identification of germline lesions with additional longitudinal studies in more patients and families needed. This ERG syndrome parallels GATA2 deficiency syndrome (HM and lymphedema) and RUNX1 Familial Platelet disorder-myeloid malignancy (thrombocytopenia and HM). Like the well-known disease genes GATA2 and RUNX1, ERG is also a member of the transcription factor heptad involved in HSC maintenance and differentiation. ERG adds to a growing list of genes whose unregulated expression contributes to HM and other cancers. Identification of causal germline ERG variants like those outlined in this study, has direct clinical implications for patient and family management including diagnosis, counselling, surveillance and treatment strategies such as selection of bone marrow transplant donors and potential for targeted therapies including gene and cell therapy. Reference 1. Greene D et al. Nat.Med. 29:679-688 2023