Efficacy and safety of nilotinib as frontline treatment in elderly (> 65 years) chronic myeloid leukemia patients outside clinical trials.

Here, we report real-world evidence on the safety and efficacy of nilotinib as a first-line treatment in elderly patients with chronic phase CML, treated in 18 Italian centers. Sixty patients aged > 65 years (median age 72 years (65-84)) were reported: 13 patients were older than 75 years. Comorbidities were recorded at baseline in 56/60 patients. At 3 months of treatment, all patients obtained complete hematological response (CHR), 43 (71.6%) an early molecular response (EMR), while 47 (78%) reached a complete cytogenetic response (CCyR). At last follow-up, 63.4% of patients still had a deep molecular response (MR4 or better), 21.6% reached MR3 as best response and 11.6% persisted without MR. Most patients (85%) started the treatment at the standard dose (300 mg BID), maintained at 3 months in 80% of patients and at 6 months in 89% of them. At the last median follow-up of 46.3 months, 15 patients discontinued definitively the treatment (8 due to side effects, 4 died for unrelated CML causes, 1 for failure, 2 were lost to follow-up). One patient entered in treatment-free remission. As to safety, 6 patients (10%) experienced cardiovascular events after a median time of 20.9 months from the start. Our data showed that nilotinib could be, as first-line treatment, effective and relatively safe even in elderly CML patients. In this setting, more data in the long term are needed about possible dose reduction to improve the tolerability, while maintaining the optimal molecular response.

Primary Cutaneous B-Cell Lymphomas with Large Cell Morphology: A Practical Review.

Most primary cutaneous lymphomas consist of T-cell lymphomas or small cell lymphomas; however, the skin may also be affected by lymphomas with large cell morphology, as a primary or secondary localization. A minority of cases consist of primary cutaneous B-cell lymphomas (PCBCLs). PCBCLs are a heterogeneous group of rare neoplasms with an overlapping morphological and immunohistochemical picture of the different subtypes. Nevertheless, differential diagnosis in the setting of this group of neoplasms is mandatory to identify the correct therapy and prognosis, but it may be challenging since, due to the rarity of these neoplasms, they may not always be familiar to pathologists. Indeed, immunohistochemistry may not be enough to distinguish the different histotypes, which overlap in immunohistochemical features. Furthermore, the ever-increasing knowledge of the molecular features of systemic B-cell lymphomas, such as gene rearrangements with clinical significance, has led in recent years to further investigation into the molecular landscape of PCBCLs with large cell morphology. This work aimed to provide a practical diagnostic guide for pathologists dealing with primary cutaneous large B-cell lymphomas.

Sorafenib in Metastatic Papillary Thyroid Carcinoma with BRAF K601E Mutation on Liquid Biopsy: A Case Report and Literature Review.

Differentiated thyroid cancer (DTC) includes papillary and follicular carcinomas and is the most common type of thyroid cancer. The incidence of this cancer has increased in the last few years, and even if its prognosis is generally good for a subset of patients that does not respond to radioactive iodine (RAI) therapy, the prognosis is much worse: the median overall survival (OS) from discovery of metastasis is 3-5 years and the 10-year survival rate is only 10%. Several mutations, including RAS or RET, as well as BRAF signaling, are associated with thyroid cancer. Liquid biopsy may be useful in selected patient to identify genomic alterations and thus allowing for a precision medicine approach with target therapy. Sorafenib, an oral multi-kinase inhibitor, can be used in the treatment of DTC. Case presentation: A 77 years old. man with diagnosis of metastatic DTC and evidence of presence of mutation of BRAF K601E on liquid biopsy was treated with sorafenib, showing a good response to the treatment and an improvement in the quality of life (QoL). Currently, this patient is still on treatment with sorafenib, gaining control of a multi-metastatic disease, generally characterized by a very poor prognosis. In conclusion, sorafenib has an active role in the treatment of DTC. It also has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). In our case we observe the efficacy of using sorafenib in Papillary thyroid carcinoma (PTC) such as confirming both stable disease (SD) in the CT scan as clinical benefit with an increase in QoL. Therefore, use of sorafenib remains an important treatment option, even in case of BRAF mutation, despite a rapidly evolving treatment landscape. It also seems important to perform liquid biopsies, especially in patients in whom it is not possible to repeat a new tissue biopsy. Ongoing clinical trials continue to evaluate sorafenib in different settings, and in combination with other therapies in DTC and HCC.

The impact of the SARS-CoV-2 infection, with special reference to the hematological setting.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a disease known from a few months, caused by a recently arisen virus and, consequently, it is little known. The disease has a benign course in most infected subjects (children and young adults), is often symptomatic in adults over the age of 50 and often serious and life threatening in people with comorbidities and the elderly. The few data published on coronavirus disease-2019 (COVID-19) in the blood-oncology field report a serious clinical presentation, a serious course of the disease, and a high mortality rate, as has also been reported for other cancer contexts. The current strategy for treating patients with SARS-CoV-2 includes antivirals that are effective against other viral infections and drugs that can moderate the cytokine storm. There is no specific vaccine and consequently all possible precautions must be taken to prevent SARS-CoV-2 infection in the areas of oncology, oncohematology, and bone marrow transplantation. In this reviewer's article, we report the information currently available on SARS-CoV-2 infection to help young doctors and hematologists to successfully manage patients with COVID-19.

SARS-CoV-2 infection affects the lower urinary tract and male genital system: A systematic review.

PubMed, Scopus, and ISI Web of Knowledge databases were searched to identify studies published up to December 2020 on the involvement of urinary and male genital systems in COVID-19. Sixteen studies involving a total of 575 patients (538 males and 37 females) were included in this systematic review. The COVID-19 phase was available for 479 patients: 426 in the acute and 53 in the recovery phase. De novo lower urinary tract symptoms (LUTS) were observed in 43 patients and deterioration of pre-existing LUTS in 7. Bladder hemorrhage was observed in three patients and acute urinary retention in one. Regarding the male genital system, scrotal discomfort was observed in 8 patients, swelling in 14, pain in 16, and erythema in 1; low flow priapism was observed in 2 patients. Ultrasound examination identified acute orchitis in 10 patients, acute epididymitis in 7, and acute epididymo-orchitis in 16. A case-control study reported that patients with moderate COVID-19 show a significant reduction in sperm concertation, the total number of sperms per ejaculate, progressive motility, and complete motility. In contrast to what is known from the first studies on the subject, this review also includes subsequent studies that give evidence of the involvement of the lower urinary tract and male genital system in COVID-19.

Renal involvement in COVID-19: focus on kidney transplant sector.

INTRODUCTION: Kidney transplant recipients and patients on the waiting list for kidney transplant who acquire SARS-CoV-2 infection are at serious risk of developing severe COVID-19, with an increased risk of mortality for the their immunosuppressive state; other risk factors for mortality have been identified in some comorbidities such as obesity, diabetes, asthma and chronic lung disease. MATERIALS AND METHODS: The COVID-19 pandemic has led to a sharp reduction in kidney transplants in most countries, mainly due to the concern of patients on the waiting list for their potential increased susceptibility to acquire SARS-CoV-2 infection in healthcare facilities and for the difficulties of transplant centers to ensure full activity as hospitals have had to focus most of their attention on COVID-19 patients. Indeed, while the infection curve continued its exponential rise, there was a vertical decline in kidney donation/transplant activity. CONCLUSION: This review article focuses on the damage induced by SARS-CoV-2 infection on kidney and on the adverse effect of this pandemic on the entire kidney transplant sector.

A case of primary cutaneous B-cell lymphoma with immature features in an old man. Diffuse large B-cell lymphoma with immature features or B-cell lymphoblastic lymphoma?

Primary cutaneous B-cell lymphomas are a heterogeneous group of lymphoid neoplasms primarily occurring in the skin. Although most cases are represented by primary cutaneous follicle center cell lymphoma, primary cutaneous marginal zone lymphoma and leg-type diffuse large B-cell lymphoma, other diffuse large B-cell lymphomas and B-cell lymphoblastic lymphoma may rarely present primarily in the skin. In this setting, the presence of histopathologic and immunohistochemical features of cellular immaturity is exceedingly rare and may represent a diagnostic challenge. We present the first case of a primary cutaneous diffuse large B-cell lymphoma characterized by diminished expression of CD45, expression of TdT and rearrangement of MYC gene. The differential diagnosis mainly included B-cell lymphoblastic lymphoma, and required the genetic analysis of heavy chain (IGH) gene rearrangements.

HIV-1 recombinant forms in immigrants regularly residing in Milan, northern Italy.

To assess the HIV -1subtypes distribution in HIV-1 positive migrants living in Milan we studied 77 HIV-1 patients followed at the San Raffaele Hospital of Milan. Twenty subjects were born in Europe, 43 in the Americas, 10 in Africa and 4 in Asia. Unsafe heterosexual activity prevailed in migrants born in Africa and male homosexuality in those born in European, American and Asian countries (p = 0.05). The phylogeny showed that 38/77 (49.3%) subjects carried HIV-B subtype while the remaining strains were classified as not pure HIV-1 B subtypes 13/77 (16.9%) or recombinant forms 26/77 (33.8%). Female gender more frequently showed HIV-1 non-B strains and rarely HIV-1 B subtypes (12/39, 30.8% vs. 3/38, 7.9%, p = 0.02). Transmitted drug resistance was identified in 10/77 (13%) patients predominately with B subtype. Our data underscore a large heterogeneity in HIV-1 subtypes and a large proportion of recombinant forms.

Rescue Therapy of Refractory Diffuse Large B-Cell Lymphomas BCL2 with Venetoclax: Case Report.

Eleven years ago, a 64-year-old Caucasian man had LNH Follicular 3a, IV A stage, FLIPI 2 as a prognostic index of follicular lymphoma. He received 8 cycles of RCHOP followed by rituximab maintenance, with complete remission. Due to a systemic recurrence, a new treatment schedule (RCOMP, 6 cycles) was introduced with partial remission persisting during a long-term maintenance treatment with rituximab. Three years ago, LNH Follicular 3a progressed into GC type diffuse large B-cell lymphomas (DLBCL); 6 cycles of rituximab and bendamustine were followed by R-ICE and R OXALI DHAP treatments without beneficial effect. Due to the worse general condition (ECOG 3-4), the patient was treated with pixantrone (6 cycles) until July 10, 2019, with a partial response. On Jan 13, 2020, an extreme compassioned treatment with venetoclax alone was started; this drug was well tolerated and provided a satisfactory clinical and laboratory improvement. In June 2020, however, he developed bone marrow toxicity and septic fever. Nasal and pharyngeal secretions were SARS-CoV-2 RNA negative. Blood cultures for mycotic agents and Gram-positive, Gram-negative, and anaerobic bacteria were negative, but few days later, the patients died of sepsis due to unidentified agents. The use of venetoclax as a single drug to treat DLBCL BCL2 patients deserves further investigation.

Direct-Acting Antivirals in Hepatitis C Virus-Associated Diffuse Large B-cell Lymphomas.

BACKGROUND: International guidelines suggest hepatitis C virus (HCV) eradication by direct-acting antivirals (DAAs) after first-line immunochemotherapy (I-CT) in patients with HCV-positive diffuse large B-cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I-CT have been reported. SUBJECTS, MATERIALS, AND METHODS: We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV-positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort [ConC]: n = 9) or subsequently (sequential cohort [SeqC]: n = 38) to first-line I-CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]-like). RESULTS: Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I-CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir-based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1-2 adverse events. Twenty-three patients experienced hepatic toxicity (grade 3-4 in seven) following I-CT in SeqC, compared to only one patient in ConC. At a median follow-up of 2.8 years, two patients died (2-year overall survival, 97.4%) and three progressed (2-year progression-free survival, 93.1%). CONCLUSION: Excellent outcome of this cohort of HCV-positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I-CT. Moreover, concurrent DAAs and R-CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity. IMPLICATIONS FOR PRACTICE: Hepatitis C virus (HCV)-associated diffuse large B-cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune-chemotherapy (I-CT) and long-term hepatic complications. The advent of highly effective and toxicity-free direct-acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first-line immunochemotherapy (usually R-CHOP). This retrospective international study reports the real-life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I-CT) in 47 patients. The favorable reported results on long-term outcome seem to support the eradication of HCV with DAAs in all patients with HCV-positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I-CT.

Development of an Artificial-Intelligence-Based Tool for Automated Assessment of Cellularity in Bone Marrow Biopsies in Ph-Negative Myeloproliferative Neoplasms.

The cellularity assessment in bone marrow biopsies (BMBs) for the diagnosis of Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is a key diagnostic feature and is usually performed by the human eyes through an optical microscope with consequent inter-observer and intra-observer variability. Thus, the use of an automated tool may reduce variability, improving the uniformity of the evaluation. The aim of this work is to develop an accurate AI-based tool for the automated quantification of cellularity in BMB histology. A total of 55 BMB histological slides, diagnosed as Ph- MPN between January 2018 and June 2023 from the archives of the Pathology Unit of University "Luigi Vanvitelli" in Naples (Italy), were scanned on Ventana DP200 or Epredia P1000 and exported as whole-slide images (WSIs). Fifteen BMBs were randomly selected to obtain a training set of AI-based tools. An expert pathologist and a trained resident performed annotations of hematopoietic tissue and adipose tissue, and annotations were exported as .tiff images and .png labels with two colors (black for hematopoietic tissue and yellow for adipose tissue). Subsequently, we developed a semantic segmentation model for hematopoietic tissue and adipose tissue. The remaining 40 BMBs were used for model verification. The performance of our model was compared with an evaluation of the cellularity of five expert hematopathologists and three trainees; we obtained an optimal concordance between our model and the expert pathologists' evaluation, with poorer concordance for trainees. There were no significant differences in cellularity assessments between two different scanners.

Multidisciplinary Management of Descending Necrotizing Mediastinitis: Is Thoracoscopic Treatment Feasible?

Background: Descending necrotizing mediastinitis (DNM) is a life-threatening condition, generally caused by downward dissemination of oropharyngeal infections through cervical fascial planes. Mediastinal drainage is conventionally achieved by thoracotomy, but a Video-Assisted Thoracoscopic Surgery (VATS) approach is gaining interest due to the reduced invasiveness of procedure. We aimed to evaluate the effectiveness of VATS treatment in patients with DNM. Methods: We conducted a retrospective multicenter study including patients with descending mediastinitis that underwent mediastinal drainage through VATS (VATS group) or thoracotomy (thoracotomy group), both in association with cervical drainage. Patients with mediastinitis secondary to cardiac, pulmonary, or esophageal surgery were excluded. The intergroup differences regarding surgical outcome and postoperative morbidity and mortality were compared. Results: A total of 21 patients were treated for descending mediastinitis during the study period. Cervicotomy and thoracotomy were performed in 15 patients (71%), while cervicotomy and VATS were performed in 6 patients (29%). There were no significant differences in surgical outcome, postoperative morbidity, and mortality between groups. VATS treatment was not associated with a higher complication rate. Patients in the VATS group had a shorter operative time (p = 0.016) and shorter ICU stay (p = 0.026). Conclusions: VATS treatment of DNM is safe and effective. The comparison with thoracotomy showed no significant differences in postoperative morbidity and mortality. The VATS approach is associated with a shorter operative time and ICU stay than thoracotomy.

Transient reactivation of occult hepatitis B virus infection despite lamivudine prophylaxis in a patient treated for non-Hodgkin lymphoma.

A female patient with non-Hodgkin lymphoma who tested positive for surface antigen of the hepatitis B virus and negative for hepatitis B core antibody experienced a reactivation of occult HBV infection 20 months after rituximab discontinuation despite lamivudine prophylaxis covering the 4 months of rituximab administration and the subsequent 12 months.

How to Diagnose Anaplastic Large Cell Lymphoma on Cytological Samples? A Series with Emphasis on Diagnostic Clue and Pitfalls.

INTRODUCTION: Anaplastic large cell lymphoma (ALCL) is a rare mature T-cell non-Hodgkin's lymphoma characterized by large and pleomorphic neoplastic CD30-positive T cells. ALCL includes different subtypes with different clinical and biological features: systemic ALCL, primary cutaneous ALCL, breast implant-associated ALCL (BIA-ALCL). Anaplastic lymphoma kinase (ALK) is overexpressed and rearranged in some systemic cases. Diagnosis of ALCL may be challenging on cytological samples, but the correct diagnosis is mandatory for the management of the patient. METHODS: A retrospective series of 12 ALCLs diagnosed by cytology is reported. Cytological samples included lymph nodes and skin lesions fine needle aspiration cytology, peritoneal effusion, and periprosthetic fluid. Microscopic evaluation was performed on direct smears, cell-block sections, and cytocentrifugated slides. Immunocytochemistry was performed on cell-block sections, direct smears, and cytocentrifugated slides. Molecular evaluation by fluorescent in-situ hybridization (FISH) was performed on cell-block sections. RESULTS: The series included 4 ALK+ ALCLs, 5 ALK- ALCLs, and 3 BIA-ALCLs. FNAC was performed on lymph nodes in 8 cases and on skin lesion in 1 case. In this last case, a peritoneal effusion was also evaluated. Breast periprosthetic fluids were evaluated in 3 cases. A large immunocytochemical panel was performed in each case, and FISH in 3 cases, demonstrating ALK rearrangement in a case of ALK+ ALCL. A final diagnosis was rendered in all cases. In the case of skin lesion, the differential diagnosis between systemic ALCL and primary cutaneous ALCL was possible. CONCLUSION: The cytological diagnosis of ALCL may be challenging, and the proper management of the collected sample is mandatory. The rapid on-site evaluation and the realization of a cell block are strongly recommended. Immunocytochemistry is mandatory for the diagnosis and a large antibodies panel is needed as differential diagnosis includes many different neoplasms. FISH may be useful to evaluate ALK rearrangements. When properly managed, cytology can lead to a reliable final diagnosis of ALCL.

Management of Non-Melanoma Skin Cancer: Radiologists Challenging and Risk Assessment.

Basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma are the three main types of nonmelanoma skin cancers and their rates of occurrence and mortality have been steadily rising over the past few decades. For radiologists, it is still difficult to treat patients with advanced nonmelanoma skin cancer. Nonmelanoma skin cancer patients would benefit greatly from an improved diagnostic imaging-based risk stratification and staging method that takes into account patient characteristics. The risk is especially elevated among those who previously received systemic treatment or phototherapy. Systemic treatments, including biologic therapies and methotrexate (MTX), are effective in managing immune-mediated diseases; however, they may increase susceptibility to NMSC due to immunosuppression or other factors. Risk stratification and staging tools are crucial in treatment planning and prognostic evaluation. PET/CT appears more sensitive and superior to CT and MRI for nodal and distant metastasis as well as in surveillance after surgery. The patient treatment response improved with advent and utilization of immunotherapy and different immune-specific criteria are established to standardized evaluation criteria of clinical trials but none of them have been utilized routinely with immunotherapy. The advent of immunotherapy has also arisen new critical issues for radiologists, such as atypical response pattern, pseudo-progression, as well as immune-related adverse events that require early identification to optimize and improve patient prognosis and management. It is important for radiologists to have knowledge of the radiologic features site of the tumor, clinical stage, histological subtype, and any high-risk features to assess immunotherapy treatment response and immune-related adverse events.

Multidisciplinary Approach to the Diagnosis and Therapy of Mycosis Fungoides.

Mycosis fungoides is the most common primary cutaneous T-cell lymphoma, characterized by skin-homing CD4+ T cells derivation, indolent course, and low-grade of malignancy. Mycosis fungoides's classic type typically onsets with cutaneous erythematous patches, plaque, and tumor. In WHO-EORTC classification, folliculotropic mycosis fungoides, pagetoid reticulosis, and granulomatous slack skin are recognized as distinct variants of mycosis fungoides, because of their clinical and histological features, behavior, and /or prognosis. Mycosis fungoides often shows diagnostic difficulties, due to its absence of specific features and lesional polymorphism. A patient's treatment requires staging. In about 10% of cases, mycosis fungoides can progress to lymph nodes and internal organs. Prognosis is poor at advanced stage and management needs a multidisciplinary team approach. Advanced stage disease including tumors, erythroderma, and nodal, visceral, or blood involvement needs skin directed therapy associated with systemic drugs. Skin directed therapy includes steroids, nitrogen mustard, bexarotene gel, phototherapy UVB, and photochemiotherapy, i.e., total skin electron radiotherapy. Systemic therapies include retinoids, bexarotene, interferon, histone deacetylase inhibitors, photopheresis, targeted immunotherapy, and cytotoxic chemotherapy. Complexity of mycosis fungoides associated with long-term chronic evolution and multiple therapy based on disease stage need a multidisciplinary team approach to be treated.

Outcomes of Thoracoscopic Lobectomy after Recent COVID-19 Infection.

BACKGROUND: The COVID-19 outbreak had a massive impact on lung cancer patients with the rise in the incidence and mortality of lung cancer. METHODS: We evaluated whether a recent COVID-19 infection affected the outcome of patients undergoing thoracoscopic lobectomy for lung cancer using a retrospective observational mono-centric study conducted between January 2020 and August 2022. Postoperative complications and 90-day mortality were reported. We compared lung cancer patients with a recent history of COVID-19 infection prior to thoracoscopic lobectomy to those without recent COVID-19 infection. Univariable and multivariable analyses were performed. RESULTS: One hundred and fifty-three consecutive lung cancer patients were enrolled. Of these 30 (19%), had a history of recent COVID-19 infection prior to surgery. COVID-19 was not associated with a higher complication rate or 90-day mortality. Patients with recent COVID-19 infection had more frequent pleural adhesions (p = 0.006). There were no differences between groups regarding postoperative complications, conversion, drain removal time, total drainage output, and length of hospital stay. CONCLUSIONS: COVID-19 infection did not affect the outcomes of thoracoscopic lobectomy for lung cancer. The treatment of these patients should not be delayed in case of recent COVID-19 infection and should not differ from that of the general population.

Prevention of HBV Reactivation in Hemato-Oncologic Setting during COVID-19.

Onco-hematologic patients are highly susceptible to SARS-CoV-2 infection and, once infected, frequently develop COVID-19 due to the immunosuppression caused by tumor growth, chemotherapy and immunosuppressive therapy. In addition, COVID-19 has also been recognized as a further cause of HBV reactivation, since its treatment includes the administration of corticosteroids and some immunosuppressive drugs. Consequently, onco-hematologic patients should undergo SARS-CoV-2 vaccination and comply with the rules imposed by lockdowns or other forms of social distancing. Furthermore, onco-hematologic facilities should be adapted to new needs and provided with numerically adequate health personnel vaccinated against SARS-CoV-2 infection. Onco-hematologic patients, both HBsAg-positive and HBsAg-negative/HBcAb-positive, may develop HBV reactivation, made possible by the support of the covalently closed circular DNA (cccDNA) persisting in the hepatocytic nuclei of patients with an ongoing or past HBV infection. This occurrence must be prevented by administering high genetic barrier HBV nucleo(t)side analogues before and throughout the antineoplastic treatment, and then during a long-term post-treatment follow up. The prevention of HBV reactivation during the SARS-CoV-2 pandemic is the topic of this narrative review.