The Role of Pre-treatment Inflammatory Biomarkers in the Prediction of an Early Response to Panitumumab in Metastatic Colorectal Cancer.

Background Systemic inflammation is a critical component of the development and progression of several types of cancer. Neutrophil-lymphocyte ratio (NLR) and lymphocyte-monocyte ratio (LMR) are simple, inexpensive, and reliable predictors of the systemic inflammatory response to the therapy in different malignant tumors, including colorectal cancer. Methods Metastatic colorectal cancer (mCRC) patients treated with panitumumab plus chemotherapy at first-line at the medical oncology unit of Fondazione Institute for Research, Hospitalization and Health Care (IRCCS) Policlinico San Matteo di Pavia between January 1st 2016 and February 1st 2021 were retrospectively analyzed. NLR and LMR were divided into two groups (high and low) based on the cut-off points, with the estimation of the prognostic accuracy of NLR for the early treatment response as the primary end-point of this study. Results The receiver operating characteristic (ROC) analysis showed a fair prognostic accuracy of NLR for early treatment response (area under the curve (AUC)=0.76, 95% CI: 0.62-0.89). A slightly lower prognostic accuracy was found for LMR (AUC=0.71, 95% CI: 0.57-0.85). In the univariable proportional hazard Cox model, no effect of NLR on PFS was found (NLRHigh vs. NLRLow HR=1.3; 95% CI: 0.7-2.4, p=0.414). Patients with higher levels of LMR showed a trend towards higher PFS (LMRHigh vs. LMRLow HR=0.4; 95% CI: 0.2-1.1, p=0.066). No association was found between NLR (or LMR) and skin toxicity. Conclusions NLR and LMR may be used as biomarkers of prognostic accuracy for the early treatment response in mCRC patients treated with panitumumab.

Men with COVID-19 die. Women survive.

The severity and mortality rate of COVID-19 differ between the sexes. Several biopsychosocial determinants may account for the better outcomes in women. The notion that sex steroid hormones account for the gender disparity is reasonable but not proven; the same is true of the role of menopause as a risk factor. A retrospective analysis of patients (=1764) hospitalized in Italy showed a higher mortality (HR 1.58, 95%CI 1.30-1.91, adjusted for age and multi-comorbidities) in males only after the age of 65 (the rate is twice as high in the 65-79-year age group and 1.5-fold higher in those aged over 80). The higher mortality of men is mostly evident among those aged over 65 years, long after the average age of menopause.

Clinical, virological and immunological evolution of the olfactory and gustatory dysfunction in COVID-19.

PURPOSE: New-onset olfactory and gustatory dysfunction (OGD) represents a well-acknowledged COVID-19 red flag. Nevertheless, its clinical, virological and serological features are still a matter of debate. MATERIALS AND METHODS: For this cohort study, 170 consecutive subjects with new-onset OGD were consecutively recruited. Otolaryngological examination, OGD subjective grading, nasopharyngeal swabs (NS) for SARS-CoV-2 RNA detection and serum samples (SS) collection for SARS-CoV-2 IgG quantification were conducted at baseline and after one (T1), two (T2) and four weeks (T3). RESULTS: SARS-CoV-2 infection was confirmed in 79% of patients. Specifically, 43% of positive patients were detected only by SS analysis. The OGD was the only clinical complaint in 10% of cases. Concurrent sinonasal symptoms were reported by 45% of patients. Subjective improvement at T3 was reported by 97% of patients, with 40% recovering completely. Hormonal disorders and RNA detectability in NS were the only variables associated with OGD severity. Recovery rate was higher in case of seasonal influenza vaccination, lower in patients with systemic involvement and severe OGD. Not RNA levels nor IgG titers were correlated with recovery. CONCLUSION: Clinical, virological and serological features of COVID-19 related OGD were monitored longitudinally, offering valuable hints for future research on the relationship between host characteristics and chemosensory dysfunctions.

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies.

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous stem cell transplantation. Overall, 19% of patients received ibrutinib during the course of the disease. According to IPSSWM, 63% were classified as low risk, 27% as intermediate risk and 10% as high risk. Five-year OS was shorter in high-risk as compared with low or intermediate risk patients (92.9% vs 100% P = .002). According to revised IPSSWM, 92% were classified as very low or low risk and 8% as intermediate risk, with a shorter 5-year OS in the latter group (87.5% vs 100%, P = .028). The OS of young WM patients was not significantly reduced as compared with age-matched, sex-matched and calendar year-matched general population. Early diagnosis, absence of high-risk features in symptomatic patients and high efficacy of modern treatments are the main determinants of the excellent outcome of young WM patients.

A risk-stratification model based on the initial concentration of the serum monoclonal protein and MYD88 mutation status identifies a subset of patients with IgM monoclonal gammopathy of undetermined significance at high risk of progression to Waldenström macroglobulinaemia or other lymphoproliferative disorders.

IgM monoclonal gammopathies of undetermined significance (IgM MGUS) are associated with a risk of progression to Waldenström macroglobulinaemia (WM) or other lymphoproliferative disorders (LPD) of 1-2% per year. We analysed 176 consecutive patients with IgM MGUS to evaluate risk factors for progression. With a median follow-up of 83 months (1214 person-years), 15 patients (8·5%) progressed to WM (n = 14) or marginal zone lymphoma (n = 1). The rate of progression was 1·32% per year (95% confidence interval [CI] 0·80-2·20). The serum monoclonal protein concentration and the MYD88 mutation were independent risk factors for progression (Hazard ratio [HR] 23·3, 95% CI 2·0-273·3, P = 0·012 and HR 24·4, 95% CI 2·2-275·3, P = 0·010, respectively). The cumulative incidence of progression, while considering death as a competing event, was 11·6% at 5 years and 38·0% at 10 years in MYD88-mutated patients with a serum monoclonal protein of 10 g/l or higher, as compared with 0% at 5 years and 1·1% at 10 years for patients with none or one risk factor. This risk-stratification model is able to identify a subset of patients with IgM MGUS at high risk of progression to WM or LPD who deserve a lifelong follow-up.

The Italian Mastocytosis Registry: 6-year experience from a hospital-based registry.

AIM: We collected 'real-life' data on the management of patients with mastocytosis in the Italian Mastocytosis Registry. METHODS: Six hundred patients diagnosed with mastocytosis between 1974 and 2014 were included from 19 centers. RESULTS: Among adults (n = 401); 156 (38.9%) patients were diagnosed with systemic mastocytosis. In 212 adults, no bone marrow studies were performed resulting in a provisional diagnosis of mastocytosis of the skin. This diagnosis was most frequently established in nonhematologic centers. In total, 182/184 pediatric patients had cutaneous mastocytosis. We confirmed that in the most patients with systemic mastocytosis, serum tryptase levels were >20 ng/ml and KIT D816V was detectable. CONCLUSION: The Italian Mastocytosis Registry revealed some center-specific approaches for diagnosis and therapy. Epidemiological evidence on this condition is provided.

High-dose therapy and autologous stem cell transplantation in marginal zone lymphomas: a retrospective study by the EBMT Lymphoma Working Party and FIL-GITMO.

The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL. Eligible patients had non-transformed nodal, extra-nodal (MALT) or splenic MZL (SMZL), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1-8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy-based high-dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub-group and more transplants performed in recent years in the other sub-groups. After a median follow-up of 5 years, 5-year cumulative incidence of relapse/progression and non-relapse mortality were 38% and 9%, respectively. Five-year event-free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five-year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy.

Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria.

The recently revised World Health Organization (WHO) classification of myeloid neoplasms recognizes prefibrotic myelofibrosis (prePMF) as a distinct entity, characterized by well-defined histopathologic features together with minor clinical criteria (leukocytes, anemia, increased LDH, splenomegaly). The aim of the study was to examine the clinical relevance of distinguishing prePMF from essential thrombocythemia (ET). We identified in our database all patients affected with ET, prePMF and primary myelofibrosis (PMF) diagnosed according to 2008 WHO criteria with a bone marrow fibrosis grade 0-1 at diagnosis and one DNA sample to define the mutational status. The bone marrow morphology of all 404 identified patients was reviewed by an expert pathologist and patients were reclassified according to the 2016 WHO criteria. After reclassification, our cohort included 269 ET, 109 prePMF, and 26 myeloproliferative neoplasm unclassificable. In comparison with ET, patients with prePMF had higher leukocyte count, lower hemoglobin level, higher platelet count, higher LDH values, and higher number of circulating CD34-positive cells; they showed more frequently splenomegaly (all P values < ·001). CALR mutations were more frequent in prePMF than in ET (35·8% vs 17·8%, P < ·001). PrePMF patients had shorter overall survival (P < ·001) and a trend to a higher incidence of leukemic evolution (P ·067) compared to ET patients, while they did not differ in terms of thrombotic and bleeding complications. In conclusion, ET and prePMF diagnosed according to 2016 WHO criteria are two entities with a different clinical phenotype at diagnosis and a different clinical outcome.

Sequential evaluation of CALR mutant burden in patients with myeloproliferative neoplasms.

We investigated the variation of CALR-mutant burden during follow-up in 105 CALR-mutant MPN and compared it to the variation of JAK2-mutant burden in 226 JAK2-mutant MPN.The median allele burden at last evaluation was significantly higher than at first evaluation in essential thrombocythemia (ET) (49.5% vs 45%, P < .001) but not in primary myelofibrosis (PMF) (52% vs 51%, P 0.398). Median values of slope were positive both in ET (0.071) and in PMF (0.032). In CALR-mutant ET there was a difference between natural and therapy-related slope (P 0.006).In the JAK2-mutated cohort, the median allele burden at last evaluation was not different respect to that at first evaluation, neither in ET (22.9% vs 23.2%, P = 0.216) nor in PMF (50.5% vs 45.0%, P = 0.809), despite a positive slope. Multivariate analysis to evaluate the effect of mutation (CALR vs JAK2) on the slope of mutant burden in not treated pts with a positive slope adjusting for diagnosis (ET vs PMF) showed a trend toward a higher increase of mutant burden in CALR vs JAK2 (ß = 0.19, P = 0.061) with no difference between diagnosis (P = 0.419). The findings of this study suggest that clonal expansion in CALR-mutant MPN is faster than that observed in JAK2-mutant MPN.

Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation.

PURPOSE: The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. PATIENTS AND METHODS: We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT. RESULTS: Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%. CONCLUSION: Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection.

Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lymphoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%-56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%-77%) for those without these genetic lesions. By univariate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome.

CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis.

Somatic mutations in the calreticulin (CALR) gene were recently discovered in patients with sporadic essential thrombocythemia (ET) and primary myelofibrosis (PMF) lacking JAK2 and MPL mutations. We studied CALR mutation status in familial cases of myeloproliferative neoplasm. In a cohort of 127 patients, CALR indels were identified in 6 of 55 (11%) subjects with ET and in 6 of 20 (30%) with PMF, whereas 52 cases of polycythemia vera had nonmutated CALR. All CALR mutations were somatic, found in granulocytes but not in T lymphocytes. Patients with CALR-mutated ET showed a higher platelet count (P = .017) and a lower cumulative incidence of thrombosis (P = .036) and of disease progression (P = .047) compared with those with JAK2 (V617F). In conclusion, a significant proportion of familial ET and PMF nonmutated for JAK2 carry a somatic mutation of CALR.

Psychological care of caregivers, nurses and physicians: a study of a new approach.

There is much evidence demonstrating that psychosocial interventions in caregivers and oncological staff produce an improvement in their patients' quality of life. The aim of this explorative study was to evaluate the effect of a new approach in promoting more functional ways to face stressful situations in the constellation of people around patients: caregivers, physicians and nurses. Thirty-four subjects were divided into three groups: 10 caregivers, 11 physicians, and 13 nurses. A "Balint Group" method modified according to a mindfulness technique was used as the intervention. Three assessment tools were administered to the participants at baseline, during, and after completion of the study: the Response Evaluation Measure (REM-71), the Satisfaction Profile (SAT-P), and the Group Climate Questionnaire (GCQ). Mean values of defense mechanisms determined by the REM-71 were compared with those of the standard population. At baseline, we observed a prevalence of immature defenses in the three groups, with mean values above those in the standard population. After the psychological intervention, a tendency to normalization of the mean values was observed, indicating the development of more adaptive ways of using defense mechanisms and the effectiveness of the intervention. Group climate, assessed through the GCQ, showed an increase in the "Engagement" factor and a decline in the "Conflict" factor in all groups. This study suggests that group treatment focused on changing personal responses to stressful situations can induce more adaptive strategies enabling caregivers, hematologists, and nurses to help patients better and thereby improve their quality of life.

Epidemiology and geographical variation of myasthenia gravis in the province of Pavia, Italy.

BACKGROUND AND AIMS: Previous studies have reported a prevalence estimate of myasthenia gravis (MG) from 7.7 to 11.1 per 100,000 inhabitants in Europe. Moreover, the study of the geographical distribution of MG should be useful to generate specific hypotheses. The aims are to estimate MG prevalence and to investigate its geographical variation in a delimited area in Northern Italy. METHODS: The primary source of data was the MG database of the Neurological Institute of Pavia and all other sources of case collection in and outside the province. We adopted a Bayesian approach to analyze MG geographical variation within the finest geographical grid. RESULTS: We identified 119 live MG prevalent cases resident in the province of Pavia on December 31, 2008. The overall crude prevalence was 24 per 100,000 inhabitants. The Bayesian analysis identified a small cluster of higher MG prevalence in the northern area of the province. CONCLUSIONS: The estimated MG prevalence sets the province of Pavia among the high-risk areas. The identification of high/low MG risk areas deserves further investigation of genetic and environmental factors possibly related to a major risk of the disease in that area.