The co-carcinogenic effect of topical vitamin A palmitate on 9, 10-dimethyl-1, 2-benzathracene (DMBA)-induced carcinoma in the buccal pouch of the syrian golden hamster

Salley in 1954, (122) was the first worker to use the hamster cheek pouch as a model for experimental carcinogenesis and to produce squamous cell carcinomas in this organ. For a number of reasons, the pouch is most suitable for sequential studies of carcinogenesis, and these include the fact that it is easily accessible and can be everted simply, facilitating macroscopic examination. Furthermore, its anatomic situation makes it a simple model for topical application of any carcinogen. Each animal has two pouches, thus providing its own control. In addition, the pouch serves as a storehouse and is lined only by stratified squamous epithelium with no glands or hair follicles in its wall, thus rendering it less susceptible to cyclic changes than more complex tissues, in which accessory structures are present

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

Ibrutinib, the first-in-class Bruton’s tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu’s advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden

Phorbol Ester (TPA)-Induced Surface Membrane Alterations in B-Type Hairy Cell and Lymphocytic Leukemia Cells

This report documents phorbol ester (TPA)-induced changes in cell morphology, and in vitro growth patterns in 9 patients with hairy cell leukemia (HCL), 21 with B-type CLL and non-Hodgkin\u27s lymphoma in leukemic phase (NHL), and 10 with acute non lymphoblastic leukemia (ANLL). TPA caused cells from HCL to adhere strongly and produce elongated cytoplasmic extensions. Many of these cells had an appearance resembling fibroblasts, while others showed marked surface ruffling and spreading containing increased dense bodies, and phagolysosomal vacuoles as seen by transmission electron microscopy. This HCL in vitro growth pattern after TPA exposure differed from that seen in B-CLL and NHL cells, which only adhered moderately after 72 hours and readily detached in clumps. CLL and NHL-cells did not show ultrastructural features of macrophages but had either plasmacytic or HCL features. It is suggested that these different growth patterns may aid in distinguishing HCL from other B-cell neoplasias. The expression of surface markers, tartrate resistant acid phosphatase (TRAP) and Ig secretion were studied in some B-CLL, NHL and HCL cells after exposure to different concentrations of TPA for up to 6 days. Results showed that the documented changes were frequently both dose and time dependent and the most striking HCL-features were encountered after 6 days incubation with higher concentrations of TPA. However, individual variation from case to case was noted. Nevertheless, it seems that TPA induces neoplastic B-cells to mature into secreting plasmacytoid lymphocytes, and cells with features of HCL with variable expression of surface markers and TRAP

Topical Modes in the Preparation of Human Spleen Specimens for Routine Scanning Electron Microscopy Studies

Various preparatory techniques were used to improve scanning electron microscopy images of the fine structure of vascular, cellular, and cordal-reticular components of normal human spleens. The progressive method of fixation (GTGO) applied in the present study, allowed air drying of the tissues and rendered the specimens conductive even in newly fractured surfaces. Vascular perfusion proved necessary only in studies of the splenic blood vessels, while a simple immersion of tissue blocks in the washing solution resulted in better images of the white pulps. Interstitial (trans-splenic) perfusion was found to be superior to vascular perfusion for routine preparation of spleen tissues, and freeze-cracking did not necessarily lead to improved images of the specimen\u27s surfaces. Combined with proper washing and shaping protocols, the GTGO procedure is shown to be a superior mode of specimen preparation, abolishing most traditional artifacts and obtaining clear images of the complex splenic tissue

Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: Results of a large multicenter study involving 990 patients

Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non-Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR >6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients

Absolute monocyte count and lymphocyte-monocyte ratio predict outcome in nodular sclerosis Hodgkin lymphoma: Evaluation based on data from 1450 patients

Objective: To verify whether absolute monocyte count (AMC) and lymphocyte-monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL). Patients and Methods: Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007. Results: The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm3, and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm3 was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3). Conclusion: This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice

T-Cell Lymphomas in South America and Europe

Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.424

Salvage Chemotherapy Using a Combination of Fludarabine and Cyclophosphamide for Refractory or Relapsing Indolent and Aggressive Non-Hodgkin's Lymphomas

The prognosis of patients with refractory or relapsing non-Hodgkin's lymphoma (NHL) after primary therapy is poor and multi-drug salvage treatments are associated with less than 60% response rates, usually of short duration. Here we report the results of a phase II study using a fludarabine-cyclophosphamide (FAMP-Cy) combination as a salvage failure regimen in refractory and relapsing low-grade (6) and intermediate-grade (9) NHL patients. Fifteen patients, who had received up to 4 regimens prior to therapy with FAMP-Cy were treated with fludarabine (25 mg/ml2) and cyclophosphamide (300 mg/m2) for 3 consecutive days followed by G-CSF (5 μg/kg). The overall response was 74%, 4 achieving complete responses (CR) and 7 partial responses (PR). All patients with low-grade NHL responded (4 CR, 2 PR); 5 patients with intermediate-grade NHL achieved PR lasting for a median of 5 months. The main toxicity encountered was moderate myelosuppression. Three patients had febrile neutropenia, one had drug-induced fever and a single patient developed severe neurotoxicity. Opportunistic infections due to lymphopenia were not seen. The combination of fludarabine and cyclophosphamide used as a salvage regimen showed an impressive response in a small group of heavily pretreated low-grade NHL patients who had previously received a large number of prior regimens. FAMP-Cy had limited effect in a similar group of intermediate-grade NHL patients. Results with this "failure" regimen are encouraging, however further studies are needed in order to confirm these observations in a larger series of patients