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In the modern era of Chronic Lymphocytic Leukemia (CLL) targeted therapy, the loss of p53 function due to genetic abnormalities remains a significant challenge. This is because even targeted agents, which are currently the mainstay of treatment for CLL, do not directly target p53 or restore its disrupted pathway. Consequently, resistance to therapy and unfavorable clinical outcomes often accompany these p53‐related abnormalities. An essential goal of future clinical research should be to address the ostensibly "undruggable" p53 pathway. Currently, multiple therapeutic approaches are being explored to tackle TP53 dysfunction and improve outcomes in high‐risk CLL. These approaches include the use of oncoprotein murine double minute 2 inhibitors, small‐molecule p53 reactivators, exportin 1 (XPO1) inhibitors, and ataxia‐telangiectasia mutated and Rad3‐related (ATR) inhibitors. Combinations of these p53‐targeting strategies, along with established novel therapies such as B‐cell receptor or B‐cell lymphoma‐2 (BCL‐2) inhibitors, may shape the future of therapeutic trials in this challenging‐to‐treat disease. [ABSTRACT FROM AUTHOR]

Note: the green color indicates higer sucra values with a greater probability ofbeing the more effective (c) or the safer (d) treatment and the red color indicates lower sucra values with a lower probability of being the best (c) or the safest treatment. gl When we analyzed safety outcomes, reduced toxicity was associated with increased SUCRA values. 7 Molica S, Giannarelli D, Montserrat E. Comparison between Venetoclax-based and Bruton tyrosine kinase inhibitor-based therapy as upfront treatment of chronic lymphocytic leukemia (CLL): a systematic review and network meta-analysis. To the Editor, The current shift in the treatment paradigm from chemoimmunotherapy to targeted agent (TA) therapy has rapidly changed the therapeutic landscape of chronic lymphocytic leukemia (CLL).[1] Current European and US guidelines recommend continuous first-generation or second-generation Bruton tyrosine kinase inhibitors (BTKis) and time-limited venetoclax-based therapy in the setting of previously untreated or relapsed-refractory CLL.[[2]] However, the lack of head-to-head randomized clinical trials, especially in the upfront setting, limits the potential of guidelines to address questions related to the choice of TA. Of note, adverse events lead to lower adherence to therapy, compromising the chosen treatment's clinical efficacy and need to be considered in treatment selection.[19] This study has some limitations. [Extracted from the article]

In immunocompetent people, the mRNA vaccines BNT162b2 and mRNA‐1273 have been shown to be safe and effective against coronavirus disease of 2019 (COVID‐19). However, results of cohort studies and meta‐analyses have indicated that the degree of humoral response to SARS‐CoV‐2 vaccines in patients with chronic lymphocytic leukemia (CLL) appears to be lower than that observed in the general population. These inadequate responses are mainly related to the disease itself and to the immunosuppressive effect of therapies administered. In the specific context of CLL, enrolling patients with sub‐optimal vaccine‐response in pivotal vaccine trials could be considered as an appropriate approach to improve response to the COVID‐19 vaccine. These clinical trials should also address the issues of regularity and timing of vaccine booster doses or re‐vaccinations, especially in patients undergoing therapy with pathway‐targeting agents and anti‐CD20 monoclonal antibodies. However, since hypogammaglobulinemia is a serious consequence of CLL, patients who do not have a detectable antibody response should be natural candidates for preventive antibody therapy. [ABSTRACT FROM AUTHOR]

Despite the increase in the number of prognostic models currently available for evaluating patients with chronic lymphocytic leukemia (CLL), their current application and utilization in clinical practice in the era of targeted agents is unclear. A critical reappraisal of recently developed prognostic models is presented in this review. The underlying CLL's genetic instability and changes in the host's health and comorbidities can all contribute to the acquisition of additional risk factors for adverse outcomes during the course of the disease. Therefore, available risk models solely based on pretreatment variables only partially predict patients' clinical outcome. A dynamic prognostic model that takes into account changes in the risk profile over time could indeed be useful in routine clinical practice. The next generation of risk assessment models should incorporate post‐treatment and response biomarkers such as minimal residual disease. Finally, recent advances in the field of machine learning present novel opportunities to generate models capable of providing an individualized estimation of clinical outcomes in CLL. However, in the era of improved prognostic models, it is important to remember that these indices should supplement but not replace clinical expertise and medical decision‐making. [ABSTRACT FROM AUTHOR]

Autoimmune manifestations are known to occur in patients with chronic lymphocytic leukemia (CLL) and of these hemolytic anemia and immune thrombocytopenia are the most well recognized. Autoimmunity may also be triggered by some of the therapeutic agents used like purine analoges and these events may sometimes be severe and even fatal. Non‐hematological autoimmune stigmata occur far less frequently and are rarely encountered. Here we report a 59 year‐old‐woman, with CLL, who complained of recurrent headache starting 1 month after completing 6 cycles of fludarabine, cyclophosphamide, and rituximab combination therapy. Computed tomography scan of the brain showed a contrast enhancing lesion of 1 cm in diameter, with surrounding edema in the right frontal lobe. Brain MRI revealed ring enhancing lesions in the right frontal lobe and some additional small lesions in the left parietal lobe. Brain biopsy showed an inflammatory demyelinating lesion, not associated with JC virus. The patient subsequently improved after steroid therapy. Currently, after 2 years of follow‐up, she remains in complete hematologic remission, has no neurological deficits, and is carefully followed by a team of neurologists and hematologists. Treating physicians should be aware of this rare autoimmune inflammatory demyelinating lesion which can occur in patients with CLL during the course of treatment and that may be linked to treatment with purine analogues like fludarabine. [ABSTRACT FROM AUTHOR]

Skeletal involvement is a rare complication of hairy cell leukemia (HCL) with an incidence of approximately 3%. Bone lesions are commonly lytic, and the most common sites of involvement are the femoral head and neck. Skeletal involvement is typically associated with high tumor burden and bone marrow infiltration. However, isolated cases of skeletal disease without splenomegaly or bone marrow involvement are occasionally reported. This review focuses on skeletal lesions in HCL, particularly the pathogenesis, clinical symptoms, diagnostic methods, and treatment approach. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skeletal symptoms, bone involvement was conducted via PubMed. Publications from January 1970 to May 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles. [ABSTRACT FROM AUTHOR]

The main purpose of this study was to assess whether it is possible to improve the prognostic impact of international prognostic index (IPI) score by combining it with peripheral blood counts. Thus, we evaluated the prognostic power of lymphocyte, neutrophil, and monocyte counts in 520 patients with diffuse large B cell lymphoma treated with R‐CHOP, confirming that these parameters have a strong impact on overall survival (OS). Using revised IPI (R‐IPI), 44% of patients were categorized as poor‐risk and showed an OS at 5 years of 46%. As OS at 5 years of the 520 patients is 67%, it is clearly evident that R‐IPI tends to overestimate the proportion of patients with poor prognosis. Accordingly, in an attempt to improve the discriminating power of R‐IPI, we evaluated and compared three different scores by combining the neutrophil lymphocyte ratio (NLR) and absolute monocyte count (AMC) with the following values: (a) IPI score 3‐5, (b) age > 60 years and performance status, (c) age ≥ 65 years and LDH > ULN. The three indexes studied, had a similar 5 years OS for the high‐risk group (46%‐52%), but the proportion of patients classified as poor‐risk were 37%, 20%, and 32%, respectively, which are lower than 44% identified with R‐IPI. Thus, while R‐IPI overestimates the number of high‐risk patients, after applying our models, it is possible to recognize patients who are truly at high‐risk. Of the three scores, the most accurate appears to be that based on NLR, AMC, LDH > ULN and age ≥ 65 years, which identifies 32% of high‐risk patients, correlating well with what is seen in clinical practice. [ABSTRACT FROM AUTHOR]

A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib-resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. In the meantime second-generation BTK inhibitors have already aroused considerable interest and gathered momentum. A possible strategy to overcome some of these obstacles is to combine ibrutinib with other targeted agents especially in high-risk disease, such as previously treated refractory patients or those with TP53 aberrations or complex karyotypes, in whom rapid eradication of disease is most desirable. Therapy with single agent ibrutinib should be part of a sequential approach for patients with low risk disease, especially in older patients (aged >70 years) with a higher burden of comorbidities. Long-term results of ongoing studies combining Ibrutinib with (chemo)-immunotherapy or other targeted agents are eagerly awaited. Future clinical trials are indeed still needed to provide answers to these open questions. [ABSTRACT FROM AUTHOR]

Background: Chronic lymphocytic leukemia (CLL) is frequently accompanied by immune dysregulation. Aims: In this multicenter prospective study, we investigated whether heavy + light chains (HLC: IgGκ, IgGλ, IgAκ, IgAκ, IgMκ, IgMλ) and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) could be used as novel prognostic markers of immunoparesis in 105 treatment‐naïve patients with CLL. Results: Heavy + light chains immunoparesis of ≥1, ≥2, and ≥3 isotypes was evident in 74 (70%), 58 (55%), and 36 (34%) patients, respectively. Severe HLC immunoparesis was identified in 40 (38%) patients. Of the IgG subclasses, IgG1 and IgG2 were most frequently suppressed, affecting 46 (44%) and 36 (34%) patients, respectively; 63 (60%) patients had low levels of at least one IgG subclass. In multivariate analysis, severe HLC immunoparesis (hazard ratio [HR]: 36.5; P = .010) and ΣFLC ≥ 70 mg/L (HR: 13.2; P = .004) were the only factors independently associated with time to first treatment (TTFT). A risk model including these variables identified patients with 0, 1, and 2 risk factors and significantly different TTFT (P < .001). Patients with two factors represented an ultra‐high‐risk group with a median TTFT of only 1.3 months. Conclusion: The above findings demonstrate the potential for the use of HLC immunoparesis, together with sFLC measurements, as future prognostic biomarkers in CLL. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. The fludarabine, cyclophosphamide, and rituximab (FCR) regimen is considered the treatment of choice for young fit patients with CLL; however, this combination is toxic for older patients. At the time this study was first planned and initiated, there was no standard chemo-immunotherapy regimen regarded as standard therapy for the less fit elderly patient with CLL. Here, we conducted a single-arm, phase II trial to examine the efficacy and safety of lower-dose fludarabine and cyclophosphamide combined with a standard dose of rituximab (LD-FCR) in elderly patients with previously untreated CLL. Forty patients received LD-FCR and were included in the efficacy analysis. Two patients treated with FC alone were only included in the safety analysis. The median age was 72.7 years (range, 65.0 to 85.0). The overall response and complete response rates were 67.5% and 42.5%, respectively. Median progression-free survival (PFS) was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Hematological toxicities and infections were the most common complications encountered; grade 3 to 4 treatment-related neutropenia occurred in 20 (47.6%) patients. During the entire study follow-up, 26 patients (61.9%) had all grades of infection including six (14.3%) with neutropenic fever and eight (19%) with grade 3 to 4 non-neutropenic infections. In conclusion, LD-FCR is an effective and relatively safe regimen for previously untreated patients with CLL. It has the advantage of being both "time and cost limited" and, even in the era of novel agents, can still be considered when planning treatment for elderly patients without high-risk biomarkers. However, recent results in fit elderly patients using the combination of bendamustine and rituximab which have achieved longer PFS with good safety profile must be taken into consideration in this regard. [ABSTRACT FROM AUTHOR]

Patients with rheumatoid arthritis (RA) have a greater risk of developing both Hodgkin lymphoma (HL) and non-HL than the general population. Non-Hodgkin lymphoma is more common than HL in these patients, and diffuse large B cell lymphoma is the most frequent subtype observed. Although the clinical course of lymphoma in RA is often aggressive, the prognosis in these cases is similar to that of lymphoma in the general population. In this review, we summarize data derived from both retrospective and prospective studies, regarding incidence, pathogenesis, and outcome of lymphomas in RA patients and outline the possible mechanisms and hypotheses linking these 2 disorders. Over the years, 3 main theories have been suggested to explain this association. These hypotheses relate to genetic predisposition, persistence of long standing disease activity with continued immune stimulation, and the role of anti-RA therapy given. A common genetic predisposition linking RA and lymphoma has not been established. As for treatment of RA, this includes immunosuppressive antitumor necrosis factor drugs or conventional disease modifying antirheumatic drugs like methotrexate. Neither of these drug categories appears to be associated with a higher risk of lymphoma in RA. The impact of continuing disease activity and immune stimulation appears to be the most significant in lymphomagenesis in these patients. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate disease characteristics and long‐term outcomes in patients requiring second‐line treatment following fludarabine, cyclophosphamide, and rituximab (FCR), for relapsed/refractory disease (R/R), or following discontinuation due to toxicities. Method: A retrospective analysis of 126 chronic lymphocytic leukemia patients treated with frontline FCR: 63 received second‐line treatment (41 relapsed, nine refractory [SD/PD], 13 prior toxicity). Time to next treatment (TTNT) was calculated from beginning FCR to initiation of second‐line therapy. Overall and event‐free survival was calculated from initiation of salvage treatment (OS2/EFS2). Results: Median follow‐up for the entire cohort was 67 and 37 months from second‐line therapy. TTNT < 24 months was associated with shorter OS2 and EFS2 similar to those observed with primary refractory disease (OS2 19 and 23 months; EFS2 12 and 9 months for TTNT < 24 months and SD/PD, respectively). TTNT ≥ 24 months (71% chemotherapy‐based second‐line), had longer OS2 and EFS2 (48 and 20 months). Among the 13 patients receiving second‐line therapy after discontinuing FCR due to toxicity EFS2 was 41 months (59 months from initiation of FCR). Conclusion: With limitations of sample size and treatment heterogeneity, patients progressing <24 months following FCR have poor outcomes, similar to refractory patients, while longer remissions are indicative of a chemoimmunotherapy sensitive disease. Patients who discontinue FCR for toxicities may achieve excellent outcomes with subsequent treatment. [ABSTRACT FROM AUTHOR]

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis (<4.0 × 103 cells/μL) or better after FCR. Absolute lymphocyte counts were recorded at 3-, 6-, 9-, and 12-month posttreatment and correlated with overall survival (OS) and event-free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC < 1.0 × 103 cells/μL) at 3 m after FCR (69% of patients n = 68), was associated with a longer OS (5y OS 91% vs 64%, P = .001), as were ALC ≤ 2 × 103 cells/μL at 6 m (5y OS 85% vs 48%, P = .004) and ALC ≤ 1.8 × 103 cells/μL at 9 m (5y OS 93% vs 54%, P = .009). A normal-range ALC (≤4 × 103 cells/μL) at 12 m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27 months for ALC > 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P < .0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted Treg depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored. [ABSTRACT FROM AUTHOR]

In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly "biological drugs." One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib. The first case was a 70-year-old woman with relapsed CLL who developed bilateral pneumonia with hypoxia 1 week after starting ibrutinib. She did not respond to broad-spectrum antibiotics and was treated empirically with trimethoprim-sulphamethoxazole and improved. In the second case, we describe a 76-year-old woman with relapsed CLL who developed recurrent pneumonia after 3 years of treatment with ibrutinib. Presuming that ibrutinib was the cause of pneumonitis with secondary infection, it was stopped with subsequent improvement. The third patient a 67 year-old man died because of severe bilateral necrotizing pneumonia due to invasive aspergillosis and mucormycosis with pulmonary hemorrhage. The fourth patient with relapsed mantle cell lymphoma died because of severe bilateral pneumonia, caused by pseudomonas and candida, despite receiving appropriate antibiotics. From this experience, we hypothesize that the etiology of severe pneumonia associated with ibrutinib treatment is probably multifactorial, involving factors like preexisting immune-suppression, drug induced pneumonitis and infections. We suggest that patients with CLL or other lymphoproliferative disorders with suspected pneumonia during monotherapy with ibrutinib should be very carefully evaluated and need to undergo complete diagnostic workup to establish an exact diagnosis. Understanding which patients with CLL or lymphoma treated with kinase inhibitors are at a higher risk for developing pulmonary complications could be one of the important future challenges, when selecting the best available therapy for these patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Previous studies have shown an increase risk of second malignancies after non-Hodgkin's lymphoma (NHL), which is probably related to a combination of factors including genetic predisposition, molecular background, host immunological status and therapy administered. Here, we determined the incidence of NHL and risk of second solid tumours and haematological malignancies among survivors of NHL diagnosed in Israel during 1980-2011. Data were collected from the records of the Israeli National Cancer Registry. The total cohort of 24 666 NHL-patients included 22 601 Jews and 2065 Arabs. Median age of diagnosis for Jews was 61.3 years and 48.2 for Arab patients. Of the Jews with NHL, 11 265 (50%) were of European-American origin, 5005 (22%) Asian or African and 6114 (27%) were born in Israel. Second cancers were recorded in 2010 NHL survivors, 1918 Jews and 92 Arabs, representing a rate of 8.5%, and 4.5% o, respectively. Second malignancies in all recorded sites were more frequent than in the general population, with a standardized incidence ratio (SIR) of 1.28 for Jewish men, 1.25 for Jewish women, 1.73 for Arab men and 1.98 for Arab women. This higher risk was even more pronounced for the 309 cases with secondary haematological malignancies (secondary haematological malignancies of 1.97, 1.81, 4.48 and 4.15, respectively). Our findings show that there is an increased risk of second malignancies occurring after diagnosis of NHL in Israel, particularly for haematological malignancies such as leukaemia and NHL. The differences we report in the incidence of NHL and the types of second malignancies occurring among Jews and Arabs suggest that ethnicity and genetic susceptibility may be important relevant risk factors. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Daniel Catovsky was trained in Argentina and graduated in Medicine in 1961. Daniel joined the Hammersmith Hospital and Royal Postgraduate Medical School as a Research fellow in 1967 and in 1976, he became Honorary Consultant Physician/Senior Staff Member in the Medical Research Council Leukaemia Unit under Professor David Galton. Besides his scientific and medical skills, Daniel was a remarkable and unforgettable man with unique attributes and amazing appeal, full of humanity, well reflected in his empathy towards patients, fellows and colleagues. [Extracted from the article]

The article discusses the therapy, prognosis and survival in malignant lymphoma and the treatment of diffuse large B cell lymphoma patients by immuno-chemotherapy. Topics discussed include of the lymphocyte count of the patients, and evaluation of the Hodgkin lymphoma and prognostic test of the patients to evaluate the prognosis of lymphoma.

Objectives Hypogammaglobulinemia, commonly encountered in chronic lymphocytic leukemia ( CLL), is one of the main causes of morbidity and mortality; however, its prognostic significance in patients diagnosed in early stages of disease remains uncertain. The aim of this study was to evaluate the predictive power of hypogammaglobulinemia at Bonet stage A. Methods Using the database of the Israeli CLL Study Group, we analyzed the relationship between low serum levels of IgG, IgA, and IgM; the presence of paraproteinemia, as well as other well-recognized prognostic markers in CLL; and time to first treatment ( TTT) and overall survival. A total of 1113 patients consecutively diagnosed during the last 25 yrs with Binet stage A CLL were evaluated, and baseline information on serum immunoglobulin levels was found in 857 of the cases. Results Overall survival times correlated with age >65 yr, male gender, the presence of lymphadenopathy, high serum beta 2-microglobulin (b2m), CD38 and ZAP-70 expression, but not with low levels of immunoglobulin or the presence of paraproteinemia. By univariate analysis, patients with low IgA levels had a shorter TTT; however, on multivariate analysis, the presence of lymphadenopathy ( P 0.02), b2m ( P 0.04), CD38 ( P < 0.001), and ZAP-70 ( P < 0.001) was the only laboratory parameters with prognostic significance. Conclusions In our cohort of patients with early-stage CLL, baseline hypogammaglobulinemia and the presence of paraproteinemia were not found to correlate with prognosis. [ABSTRACT FROM AUTHOR]

Some patients with lymphoma have monocytosis at diagnosis, but its significance is unclear. The recently recognized subpopulation, monocytic myeloid-derived suppressor cells (M-MDSCs), has immunoregulatory function, suppresses host anti-tumour immunity and plays a role in cancer tolerance. Data from 91 untreated patients with diffuse large B-cell lymphoma (DLBCL) were evaluated for monocytosis >1000/mm3 at diagnosis and its significance compared with a number of well-established prognostic factors for DLBCL including age, stage, gender, B symptoms, extranodal sites, LDH and CRP levels, bone marrow involvement and International Prognostic Index (IPI) score. In 23 of these patients with DLBCL and 15 healthy controls, the proportion of M-MDSCs in the peripheral blood was determined by flow cytometry. Monocytosis was found in 17.6% of the patient cohort examined. In the multivariate analysis, bone marrow involvement, IPI score and monocytosis were the only independent prognostic factors seen to be associated with decreased progression free and overall survival. Patients with DLBCL had on average increased M-MDSCs counts at diagnosis compared with controls, which returned to normal after achieving remission. In conclusion, monocytosis was identified as an independent prognostic factor in DLBCL and correlated with worse overall survival. The significant increases in the M-MDSCs pool observed in some of the cases examined may possibly help to explain why monocytosis is associated with poor outcome in these patients. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

An insect-bite-like reaction is known to occur in patients with chronic lymphocytic leukemia ( CLL). Most of the literature, however, consists of isolated case reports or small case series. The aim of this retrospective study was to review the national experience with insect-bite-like reaction in a large group of patients with CLL. The study cohort of patients with these skin reactions consisted of 48 patients (25 males, 23 females) of mean age 64.8 yr (range 33-89) at skin eruption. Data on clinical, histologic, immunophenotypic, and cytogenetic characteristics, treatment, and outcome were collected from the medical files. Mean time between diagnosis of CLL and appearance of the skin lesions was 3.1 yr (range −4 to 14 yr). The eruption was not related to disease activity or the course of the hematological disease. The eruption preceded the diagnosis of CLL in 10 patients (by 0-4 yr); and followed the diagnosis in 36; in 11 patients, it occurred during therapy for CLL and in nine after therapy. Mean duration of the skin findings was 21.5 months (range 0.3-132). The eruption usually presented in summer, although it occurred also at other times of the year, and predominantly affected the upper and lower limbs, although it also appeared on unexposed areas. Treatment included local ointments, antihistaminics, oral steroids, antibiotics, phototherapy, and dapsone with varying responses. Insect-bite-like reactions is a relatively common and disturbing skin reaction in CLL patients, it may be related to the immune dysregulation accompanying CLL and further exacerbated by external factors, including actual insect bites, chemoimmunotherapy, and pyogenic infection. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma ( MCC) is a rare aggressive skin tumour that appears to be associated with a large number of other tumours. We collected all reported cases in Israel and estimated its association with other tumours, including haematological malignancies. The population based Israel Cancer Registry identified 335 patients with MCC diagnosed between1989 and 2010. Ninety-seven percent were in the Jewish population; median age at diagnosis for Jewish patients was 73·4 and 55·6 years for the Arab population. Other associated malignancies were encountered in 92 patients (27·4%) with MCC (90 Jews, two Arabs). Of the Jewish cases, 66 presented with an associated malignancy before, and 24 after, the diagnosis of MCC. Solid tumours were not significantly increased among patients with MCC. Thirty-one of these associated cancers (34·4%) were haemato-oncological malignancies, 24 were detected before and seven after the diagnosis of MCC. The standardized incidence ratio ( SIR) for haematological malignancy was 3·67 for males and 3·62 for females, and the most frequent haemato-oncological neoplasias recorded were chronic lymphocytic leukaemia (45%) and lymphomas (29%). Although MCC is rare, clinicians should be aware of the possible association with B-cell lymphoproliferative disorders when evaluating patients with neuroendocrine skin tumours. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells at different stages of maturation that play a role in cancer tolerance and function as an immune-suppressive cell subpopulation. They utilize different mechanisms to block both innate and adaptive arms of anti-tumour immunity, mostly through inhibition of T cell activation and expansion. Further advances in our understanding of this cell population in both murine models and humans has enabled more accurate characterization of their phenotype and the recognition of two major classes of MDSCs: granulocytic and monocytic. Recently, the mechanism of action and clinical importance of MDSCs has been more clearly defined and their interactions with cancer cells have been shown to be among the factors influencing tumour development and induction of tolerance. Most of the earlier studies were performed using murine models, but recent clinical investigations have shown their potential role in human cancers. Here, we review the origin of MDSCs, their mechanisms of action, the factors influencing their production and related signalling pathways. We focus on their role in human solid tumours and haemato-oncological malignancies, and relate to possible novel therapeutic approaches targeting MDSCs which could be considered together with other anticancer strategies in the not too distant future. [ABSTRACT FROM AUTHOR]

Background: 18Fluoro-2-deoxyglucose (18FDG) positron emission tomography (PET) is widely used for initial staging and follow-up in patients with malignant lymphoma. While earlier studies suggested a limited role for PET in extranodal marginal zone mucosa-associated lymphoid tissue (MALT) lymphoma patients due to their non-FDG avidity, more recent reports have suggested that the issue is controversial. In the present study, we evaluated the diagnostic accuracy of PET integrated with CT (PETCT) in patients with MALT lymphoma and assessed its reliability in clinical staging and monitoring response. Methods: Thirty-three patients with biopsy proven MALT lymphoma in 37 sites, who underwent PET/CT at diagnosis, were enrolled. Medical records, PET/CT findings and data obtained by other diagnostic procedures were reviewed. Results: Common sites of MALT lymphoma were the stomach (18), lung (5), orbit (4), and parotid gland (3). PET/CT detected active disease in 18 of 33 patients (54.5%) at diagnosis. Sensitivity in gastric MALT (38.9%) was lower when compared with non-gastric MALT (75%). PET/CT detected active disease in 100% patients with advanced disease (stage III–IV) but only in 42.3% with early stage disease (I–II). The incidence of gastric FDG uptake was higher in patients showing gastric ulcer on gastroscopy than in subjects with minimal or no macroscopic findings. Of the 33 patients in the study cohort, 12 had a follow-up PET/CT which detected relapse in three patients. Conclusions: These data suggest that PET/CT is a useful tool for both, initial staging and follow-up after therapy in patients with MALT lymphoma. Its sensitivity depends on disease location and stage at initial diagnosis. [ABSTRACT FROM AUTHOR]

Background: In the light of an emerging role for early-mid treatment 18 F-deoxyfluoroglucose positron emission tomography (FDG-PET) as an important prognostic indicator in aggressive non-Hodgkin’s lymphoma (NHL) , we attempted to determine whether a simple parameter, such as the early-mid treatment CRP (C-reactive protein) level, could also be utilized as a significant prognostic factor in aggressive NHL. Patients and methods: Serum CRP levels were monitored in 55 patients with aggressive NHL. The lowest value of the early mid-term CRP levels recorded was compared with the interim PET-CT results, as well as with the clinical course and eventual outcome. Results: During chemotherapy, the lowest value of early-mid treatment CRP levels significantly predicted the results of the interim FDG-PET ( P = 0.04 with an odds ratio of 1.13). Patients who did not achieve an early-mid treatment CRP level of <5 mg/L, had a shorter time to disease progression or relapse ( P = 0.001) as well as a reduced overall survival (OS) ( P = 0.016). Conclusions: The early-mid treatment serum CRP level is a prognostic factor in aggressive NHL. Patients who do not achieve an early-mid treatment level of <5 mg/L have quicker disease progression or earlier relapse and also appear to have an inferior OS. [ABSTRACT FROM AUTHOR]

Background: Recently, it was shown that fat tissue produces and releases inflammatory cytokines, and that obesity may be regarded as a state of low-grade inflammation. In this regard, we aimed to establish an association between obesity and persistent leukocytosis. Patients and methods: We present clinical observations of obese subjects primarily referred for further evaluation of leukocytosis without a cause and validated the link between leukocytosis and elevated body mass index (BMI) in a cross-sectional study. Results: During 1999–2005, 327 patients were referred for further investigation because of persistent leukocytosis. Of these, 15.3% were asymptomatic obese, mostly females, with mild persistent neutrophilia accompanied by elevated acute-phase reactants. After careful evaluation, no recognized cause for leukocytosis was found other than the fact that the patients were obese. During a mean follow-up of 45.6 months, the leukocytosis and the elevated acute-phase reactants persisted and no new causes for leukocytosis were evident. Furthermore, in a cross-sectional analysis of 3716 non-smoker subjects, 62 were found to have leukocytosis. Compared with the population with a normal white blood count range, these subjects with leukocytosis had higher BMI, serum C-reactive protein (CRP) levels, waist circumference, and neutrophil and platelet count (all P < 0.0005). After logistic regression analysis, only BMI was shown to be associated with leukocytosis ( P < 0.0005). Conclusions: Obesity is recognized as a possible cause for reactive leukocytosis. Awareness of this ‘obesity-associated leukocytosis’ may help the clinician to avoid more extensive and unnecessary diagnostic work-up, particularly in similar obese subjects. [ABSTRACT FROM AUTHOR]

We present the findings from a qualitative study examining the marital perceptions of 9 wives of veterans with posttraumatic stress disorder (PTSD). Data were from a semistructured in-depth focus group interview. Findings reveal how the lives of these women largely revolved around their husbands’ illness. The wives faced constant tension between being drawn into a fusion with their husbands and the struggle to maintain their independence. In addition, the wives identified positive aspects of the marital relationship that granted them strength for current and future coping. Implications for practice are included. [ABSTRACT FROM AUTHOR]

Abstract: Novel therapeutic regimens containing purine analogs and monoclonal antibodies have led to significant improvement in the course of indolent lymphoproliferative diseases (LPD). Complete clinical and even molecular remissions have been achieved in an increasing proportion of patients. In parallel to their tumor cytotoxic effect, these agents are inevitably associated with prolonged immunosuppression inherent to their mechanism of antilymphocytic activity. Until now, attention has been paid mainly to opportunistic infection occuring as a result of the above drug-induced immunosuppression and less to other possible complications, such as malignancy or tumor progression in the immunocompromised host. Here we briefly report nine patients with previously treated indolent LPD in whom the onset of large-cell transformation occured during or shortly after the initiation of regimens containing these agents before transformation occured. One patient had received rituximab alone, three fludarabine-containing regimens and five received sequential regimens containing both agents. This ‘switch’ in the histopathology could merely reflect the natural course of progressive lymphoma and be unrelated to the therapy given. The onset of this complication during, or so soon after, administration of these regimens seems to us more than just a chance relationship in these cases; however, we have no conclusive evidence to prove this hypothesis definitively. We draw attention to this phenomenon. [ABSTRACT FROM AUTHOR]

Abstract: Alternate splicing of exons of the CD45 molecule generates multiple isoforms differing in their molecular weights (MWs). In B-lymphocytes the CD45RA isoform was previously shown to be expressed on glycoproteins with MWs of 220 and 205 kDa, while the CD45RO isoform was expressed on glycoproteins with MW of 180 kDa. The present study demonstrated that B cell lymphomas and activated B-cells contain CD45 molecules with a MW of 185 kDa that express the CD45RA and CD45RC specificities but neither the CD45RB nor the CD45RO specificities. 185 kDa CD45RA+ molecules were detected in B cell lymphoma B lines, in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines, and in tonsillar B cells, but not in normal, unstimulated peripheral blood B cells. These molecules were not detected in neoplastic and normal T cells. CD45RA+ 185 kDa molecules were present in B cells from three non-Hodgkin's patients in leukemic phase were not detected in B lymphocytes of seven of nine CLL patients tested. Trypsin treatment eliminated only 220 kDa CD45RA+ molecules but not 185 kDa CD45RA+ molecules, indicating that the 185 kDa CD45RA+ molecules are not expressed on the cell surface. Pulse-chase experiments, and studies on the effects of tunicamycin, neuraminidase and O -glycosidase, indicated that the 185 kDa molecules are partially glycosylated CD45RABC molecules that constitute precursors of the 220 kDa molecules. The high concentration of 185 kDa CD45RA+ molecules in B lymphoma cells and in activated B cells seems to reflect a high turnover of CD45RA+ molecules characteristic for these cells. [ABSTRACT FROM AUTHOR]

Abstract: Renal involvement as part of systemic lymphoma (LY) is quite frequent, however, primary extranodal renal non-Hodgkin's lymphoma (NHL) is extremely rare, and only about 65 cases have been reported in the world literature. In a retrospective study of renal manifestations in 700 patients with documented LY and chronic lymphocytic leukemia (CLL) seen at our hospital during 1986–95, 83 patients had signs of acute renal failure. Only five of these had proven renal infiltration, but none of them satisfied the criteria for primary renal LY. Glomerulonephritis (GN) has also rarely been reported in association with LY and CLL, and only 37 glomerular lesions in NHL and 42 in CLL have been documented, respectively. GN may precede, coexist, or follow the diagnosis of LY by several years. Of the 42 cases of CLL reported worldwide, 36 had nephrotic syndrome. Renal failure was seen in about one third. The most common glomerular lesion reported is membranoproliferative GN, followed by membranous GN. In our study, we found only five biopsy-proven cases with GN amongst the 700 patients seen. In this report we also briefly describe some rare interesting associated renal syndromes in CLL and NHL. [ABSTRACT FROM AUTHOR]

Examines the prevalence, presentation and clinical characteristics of late-onset multiple sclerosis (MS) in Israel. Mean age at onset; Duration of disease; Disease course; Occurrence of motor symptoms at onset; Diagnosis of depressive episodes in patients prior to the diagnosis of MS; Increase in sphincteric and cerebellar involvement; Number of patients who suffered a major depressive episode after diagnosis.

Examines the role of 2-chlorodeoxyadenosine (2-CDA) therapy in hypoplastic/aplastic foci in bone marrow biopsies incidence increase. Use of 2-CDA in treating hairy cell leukemia (HCL); Clinical manifestations of HCL.

Abstract: In the present study the cell surface expression of CD45 isoforms on normal and neoplastic human B cells was correlated with splice products of the CD45 mRNA, using RT-PCR technology. In non-Hodgkin's lymphoma cells in the leukemic phase (NHL) the majority of the cells expressed a high level of CD45RA, while in CLL most of the cells expressed a low level. In the Raji and Daudi Burkitt B-cell lymphoma lines the main CD45 mRNA product was the largest, unspliced, full-length isoform (456) and the 56 splice product. Similar results were obtained with B-cell lymphoma cells isolated from the peripheral blood of patients with NHL in the leukemic phase. In EBV-transformed B-cell lines, the 456 and the 56 isoform of CD45 mRNA were predominant, but in addition a low level of the 5- and 0-exon splice products was detected. A strikingly different pattern was obtained with B-CLL cells. In CLL the level of the 456 and the 56 isoforms was low, while that of the 5- and 0-exon splice products was increased. Thus, in contrast to the heterogeneity in the expression of CD45RO in B-CLL, the majority of the cells contained the CD45 mRNA splice product coding for CD45RO. Analysis of splice products of the CD45 mRNA may serve as an additional tool to differentiate CLL from the leukemic phase of NHL. [ABSTRACT FROM AUTHOR]

ObjectivesThis study was designed to describe the variation in marking tendencies among different examiners in an oral examination. DesignMarks awarded in a family practice board examination between 1984 and 1996 were analysed, relating to 5328 examination sessions graded by 94 examiners. Examiners were ranked by the rates at which they awarded ‘fail’, ‘pass’ or ‘distinction’ grades. The effects of examiners’ gender, experience, academic rank, regional affiliation and country of qualification on examiner behaviour were studied. SettingNational Family Medicine Examination Board, Scientific Council, Israel Medical Association. SubjectsOral examiners. ResultsEighteen per cent of examiners were classified as ‘tough’, being in the lowest tertile for ‘distinction’ rates and the highest tertile for ‘failure’ rates; 19% were classified as ‘mild’; 52% were ‘regular’, falling in the middle tertile for both distinction and failure rates. Four per cent of examiners were in the top tertile for both distinctions and failures, labelled ‘extremists’, and 6% were in the bottom tertile for both, and were labelled ‘noncommittal’. Higher failure rates were associated with examiners’ academic rank, experience and graduation from an English-speaking medical school. ConclusionsExaminers differ significantly in their degree of severity. Those who demonstrate clearly deviant patterns of grading should be withdrawn. Candidates should be presented with a balanced panel of examiners, and a degree of standardization of content should be introduced into oral examinations. [ABSTRACT FROM AUTHOR]