Among 157 patients treated with ICIs, 65 (41.4%) experienced at least one irAE. Median time to the first irAE onset was 28 days (IQR:15-56). Baseline clinicopathologic characteristics were well balanced between patients who developed irAEs and those who did not. Median tumor mutational burden (TMB) was significantly higher among patients with irAEs compared to those without (14.4 vs 8.4 mutations/megabase [mut/Mb], P <0.01). Patients who developed at least one irAE had a significantly higher objective response rate (26.3% versus 3.3%, P <0.001), and significantly longer median progressionfree survival (mPFS, 4.1 vs 1.3 months, HR: 0.30 [0.20-0.43, P <0.001]) and median overall survival (mOS, 14.1 vs 2.9 months, HR: 0.32 [0.21-0.48], P <0.001). The proportion of patients who were progression-free at 6, 9, and 12 weeks was significantly higher in patients who developed early irAEs compared to those who did not develop early irAEs (6 weeks: 89.5% vs 69.5%, P ¼0.01; 9 weeks: 71.1% vs 40%, P ¼0.001; 12 weeks: 65.8% vs. 31.6%, P <0.001). The median TMB was also significantly higher in patients who developed early irAEs (14.5 vs 8.7 mut/Mb, P <0.01). Conclusion: Patients with SCLC treated with ICIs who developed early irAEs had a higher TMB and enhanced antitumor responses compared to those who did not develop irAEs. Whether a higher TMB is associated with the development of irAEs remains to be determined mechanistically.

Background and Objectives: Current recommendations and treatment regimens in breast cancer are a reflection of its heterogeneity on multiple levels including histological subtypes, grading, molecular profiling, and numerous prognostic indices. Although based on extensive research, current guidelines are not explicit in the case of surgical specimens showing various degrees of mismatch between different parts of the same tumor and even more so between multicentric lesions. Synchronous breast cancer is the ideal prototype for studying inter- and intra-tumoral heterogeneity, therefore we envisaged that a study on patients with multicentric and multifocal lesions could contribute to the reshaping of the staging, prognosis, and treatment of breast malignancies. Material and Methods: A prospective observational study was conducted between January 2013 and May 2017 on 235 patients diagnosed with breast cancer (BC) and surgically treated at Emergency University Hospital, Bucharest. Thirty-seven patients had multiple breast tumors and were eligible for assessment of the heterogeneity of their lesions. Results: 6 were multicentric and 31 multifocal. The number of foci varied from 2 to 11. We encountered numerous mismatches between the index and the secondary tumors, as follows: 3 cases (8.1%) with histopathological mismatch, 13 (35.1%) with different grades of differentiation, 11 (29.8%) with ER (Estrogen Receptors) status mismatch, 12 (32.4%) with PR (Progesterone Receptors) status mismatch, 8 (21.6%) with molecular phenotype mismatch, and 17 (45.9%) cases with variable Ki-67. After careful analysis of index and secondary tumors, apart from the mismatches reported above, we discovered that the secondary tumors were actually dominant in 5 cases (13.5%), and therefore at least those cases had to be reclassified/restaged, as the supplementary data commanded changes in the therapeutic decision. Conclusions: For synchronous breast tumors, the current Tumor-Node-Metastasis (TNM) staging system ignores not only the histopathological and immunohistochemical characteristics of the secondary foci, but also their size. When secondary lesions are more aggressive or their cumulative mass is significantly bigger than that of the index tumor, the treatment plan should be adapted accordingly. We believe that information obtained from examining secondary foci in synchronous breast cancer and assessment of the cumulative tumoral mass should be reflected in the final staging and definitive treatment. The clinical benefit of staging the patients based on the most aggressive tumor and the cumulative tumoral burden rather than according to the biggest single tumor, will avoid under-treatment in cases with multifocal/multicentric BC displaying intertumoral mismatch.

Introduction Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm triggered by HTLV1 infection. According to the Japanese studies, the median onset of disease is around age 60 (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). The aggressive forms exhibit a poor prognosis, due to intrinsic or acquired chemotherapy resistance and severe immunosuppression. Combination chemotherapy can improve the response rates, and consolidation with allogenic hematopoietic stem cell transplantation (allo-HSCT) prolongs complete remission (CR) (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). The overall survival (OS) rates at 1 and 2 years after transplantation were reported to be 34% and respectively 27% (Kamiunten A et al. Hematol Oncol 2018). Romania is one of the regions with the highest prevalence of HTLV1 infection (5.33 at 10.000 donors in 2003-2008, Leperche S et al. Vox Sang 2009), therefore the prevalence of ATL is also higher. Methods A prospective observational study was performed on all patients with aggressive forms of ATL, diagnosed in Bucharest between April 2010 and January 2019, respectively 56 patients. Patients under 18 years of age and with chronic or smoldering type were excluded. The goal of this study was to better describe the disease characteristics and to discover novel factors that influence response and survival. All patients were assessed in collaboration with Necker Hospital, Paris, France, as reference center. Clinical and lab data were collected, the treatment was administered at investigator choice using CHOP/CHOP-like, Hyper-CVAD and LSG15 regimens, and allo-HSCT was offered to all eligible patients as soon as CR was obtained. Statistical analyses were performed using IBM SPSS Statistics 25. For survival analysis we used Kaplan-Meier estimate. The ROC curve was used to set cutoff values. The statistical significance was calculated using Chi-squared test and Fisher's exact test. Results In this study we analyzed a total of 56 ATL patients (M:F=1:1.3), with a median age of 42.5 years, all having aggressive types. Within this group, 33.9% had hypercalcemia and 73.2% elevated LDH (64.3% >2xN). Most used chemotherapy regimens were: CHOP/CHOP-like (60.7%), followed by LSG15 (23.2%) and Hyper-CVAD (7.1%); antiretroviral therapy (51.8%) and allo-HSCT (12.5%) were also used. LSG15 regimen is not fully applicable in our country due to unavailability of Ranimustine and Vindesine, therefore a small proportion of patients received this treatment. In multivariate analysis, factors showing significant association with lower rate of CR were: age >40.5 years, leukocytosis with a cut-off of 8950/μl, hypercalcemia >9.5 mg/dl, high LDH >512 U/L. LSG15 was associated with a higher CR rate (50%) compared to CHOP/CHOP-like (22.7%) and Hyper-CVAD (33.3%), although not statistically significant. Median OS was 6.5 months (5.1 - acute type, 8.0 - lymphomatous type), versus 3.5 months in acute type and 9.5 months in lymphomatous type in previous data in our center. Early death rate (< 1 month) was found in 8.9% (n=5) of patients. Factors associated with early death were: acute type (n=4), leukocytosis (n=5), hypercalcemia (n=4), high LDH (n=5), extranodal involvement (n=4). Patients who obtained CR (n=9) had a better survival that those who did not (median OS 40.7 vs 5.1 months, p=0.000) (Fig a); undergoing allo-HSCT also significantly increased OS (median OS not reached vs 6.1 months, p=0.003) (Fig b). Among patients who underwent allo-HSCT, OS at 1 year and 2 years after the allo-HSCT were 57.1% and 42.9%, respectively. Three patients died, all less than 1 year after transplantation. Conclusions Median age at diagnosis in our group was lower (42.5 years) versus the Japanese studies (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). This might reflect an origin of infection in the 1980s in Romania, where other outbreaks occurred by horizontal transmission in that period, including an outbreak of HIV-1 (Patrascu I V et al, Lancet 1990). Future in-depth studies of this cohort might better correlate age of infection, HTLV1 subtype and latency to ATL. The best predictors of better survival were obtaining CR and receiving allo-HSCT. Among the treatments we used, LSG15 regimen had higher rate of CR. Survival after transplantation was higher in our group compared to the Japanese studies (Kamiunten A et al. Hematol Oncol 2018). Disclosures Constantinescu: AgenDix GmbH: Other: Co-Founder, MyeloPro Research and Diagnostics; AlsaTech: Other: Co-Founde; Wiley & Sons: Other: Editor in Chief, Journal of Cellular and Molecular Medicine; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hermine:Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding; Novartis: Research Funding.

Primary immune thrombocytopenia (ITP) is characterized by isolated low platelet count and it is a diagnosis of exclusion, contrasting to secondary ITP. Therefore, a positive diagnosis is difficult and requires extensive investigation. Some of the underlying conditions that are associated with ITP are lymphoproliferative disorders and infections, especially viral ones. In the present study, the case of a patient diagnosed with diffuse large B-cell lymphoma, who received chemotherapy and autologous hematopoietic stem cell transplantation is presented. After a complete remission of four years, the patient presented with sudden intense hemorrhagic syndrome and severely decreased platelet count. The most frequent causes of secondary ITP were excluded, including lymphoma relapse, and intravenous corticosteroids were started. However, shortly after hospital admission, the patient developed neuro-psychiatric anomalies, fever and pancytopenia, and West-Nile encephalitis was diagnosed. Although the initial development was favorable, he started to complain of progressive severe muscle weakness and eventually succumbed to infectious complications in the setting of prolonged hospitalization, corticotherapy, and immobilization.

Background and Objectives: Hematological malignancies are usually systemic diseases of life-threatening impact, and frequently require prompt and energetic therapeutic intervention. Due to systemic involvement, the role of surgery is generally limited to diagnostic approaches, and it is very rarely employed as a therapeutic modality. Splenectomy represents an exception to this paradigm, being used both as a diagnostic and tumor debulking procedure, notably in splenic lymphomas. Materials and Methods: We investigated the role of splenectomy in a single center prospective study of splenectomy outcome in patients with splenic involvement in the course of lymphoproliferative disorders. In the present study, we included all patients treated in our department for lymphoid malignancies over a period of six years, who underwent splenectomy as a diagnostic or debulking procedure after referral and workup, or had been referred to our department after first being splenectomized and diagnosed with splenic lymphoma. Patient characteristics and treatment outcome were investigated. Results: We enrolled 54 patients, with 34 (63%) splenectomized patients: 12 splenectomies (22.2%) for diagnostic purposes and 22 (40.7%) for treatment. Special attention was given to the 28 (51.85%) patients diagnosed with splenic marginal zone lymphoma (SMZL), a subtype with a clear therapeutic indication for splenectomy. Average age of patients was 57.5 (±13.1) years with a higher prevalence of feminine gender (66.67%). Age above 60 years old (p = 0.0295), ECOG (Eastern Cooperative Oncology Group) > 2 (p = 0.0402) and B-signs (p nonsignificant (NS)) were most frequently found in SMZL patients. Anemia, and notably autoimmune anemia, was more frequent in SMZL versus other small-cell lymphomas and also in splenectomized patients, as was leukocytosis and lymphocytosis. Treatment of patients with lymphoproliferative disorders consisted of chemotherapy and/or splenectomy. Most SMZL patients received chemotherapy as first line treatment (61.5%) and had only partial response (57.7%). Second treatment line was splenectomy in 80% of patients who required treatment, followed by a 60% rate of complete response (CR). Splenectomy offered a higher complete response rate (twice as high than in non-splenectomized, regardless of histology type, p = NS), followed by a survival advantage (Overall Survival (OS)~64 versus 59 months, p = NS). Particularly, SMZL patients had a 4.8 times higher rate of CR than other non-Hodgkin lymphoma (NHL) patients (p = 0.04), a longer progression free survival (73 months vs. 31 months for other small-cell NHLs p = NS) and a 1.5fold lower death rate (p = NS). The procedure was rather safe, with a 38.5% frequency of adverse reactions, mostly minor and manageable. Conclusions: Our data suggest that splenectomy is an effective and safe therapeutic option in patients with lymphoid malignancies and splenic involvement, particularly splenic marginal zone lymphoma.

Taurine is a semi-essential, the most abundant free amino acid in the human body, with a six times higher concentration in platelets than any other amino acid. It is highly beneficial for the organism, has many therapeutic actions, and is currently approved for heart failure treatment in Japan. Taurine has been repeatedly reported to elicit an inhibitory action on platelet activation and aggregation, sustained by in vivo, ex vivo, and in vitro animal and human studies. Taurine showed effectiveness in several pathologies involving thrombotic diathesis, such as diabetes, traumatic brain injury, acute ischemic stroke, and others. As human prospective studies on thrombosis outcome are very difficult to carry out, there is an obvious need to validate existing findings, and bring new compelling data about the mechanisms underlying taurine and derivatives antiplatelet action and their antithrombotic potential. Chloramine derivatives of taurine proved a higher stability and pronounced selectivity for platelet receptors, raising the assumption that they could represent future potential antithrombotic agents. Considering that taurine and its analogues display permissible side effects, along with the need of finding new, alternative antithrombotic drugs with minimal side effects and long-term action, the potential clinical relevance of this fascinating nutrient and its derivatives requires further consideration.

ATL is a rare but a highly aggressive T-cell neoplasm associated with human T-cell leukemia virus-1 (HTLV-1) infection. Human T-cell lymphotropic virus type-1 (HTLV-1) is a oncogenic retrovirus responsible for the development of adult T-cell leukemia (ATL), but also for other non-malignant diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 has a higher prevalence in Japan, the Caribbean, South America, intertropical Africa, Romania, and northern Iran. ATL patients can have an extensive spectrum of neurological manifestations. Numerous factors can be implicated, such as central nervous system infiltrates, neurolymphomatosis, complications to medication or allogeneic stem cell transplantation, HAM/TSP, infections, metabolic disturbances. The neurological complications are not always easy to recognize and treat. Thus, this review underlines the necessity of a multidisciplinary approach in ATL patients with neurological symptomatology.

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