Clonal heterogeneity in chronic lymphocytic leukemia cells: superior response to surface IgM cross-linking in CD38, ZAP-70-positive cells.

Background Patients with chronic lymphocytic leukemia whose cells express CD38 and ZAP-70 and utilize unmutated Ig VH region genes have a very poor prognosis. We studied whether cells expressing CD38 and ZAP-70 are more susceptible to stimulation through B-cell receptors than are cells that do not express CD38 and ZAP-70.Design and Methods CD38-positive and CD38-negative leukemic cells were separated from single cases and compared for their response to B-cell receptor cross-linking and ZAP-70 expression. Cohort studies were also carried out by measuring the apoptotic response to surface immunoglobulin M (IgM) cross-linking in 82 patients with chronic lymphocytic leukemia and the protein tyrosine phosphorylation induced by surface IgM in 21 patients.Results CD38-positive cells, isolated from cases of chronic lymphocytic leukemia classified as CD38-positive or CD38-negative, expressed more ZAP-70 than the corresponding CD38-negative cells, exhibited more robust protein tyrosine phosphorylation and had a greater tendency to apoptosis upon B-cell receptor cross-linking. In the cohort studies, surface IgM-induced protein tyrosine phosphorylation correlated significantly with CD38 and ZAP-70 expression and with the absence of Ig VH gene mutations. Apoptosis induced by surface IgM cross-linking correlated significantly only with the proportion of CD38-positive cells. Difficulties in finding more definitive correlations were probably related to imprecision in the in vitro test system and in the definition of cases as positive or negative.Conclusions Collectively, these data indicate that CD38-positive, ZAP-70-positive cells have a greater capacity for signaling through the B-cell receptor and suggest a function for B-cell receptor signaling in promoting chronic lymphocytic leukemia cell expansion, especially within the CD38-positive fraction of the leukemic clone

Case report: lenvatinib in neoadjuvant setting in a patient affected by invasive poorly differentiated thyroid carcinoma

We report a case of an elderly woman presenting with a huge cervical mass invading the tracheal lumen. Diagnosed as invasive poorly differentiated thyroid cancer, after an endotracheal biopsy, stenting and radiotherapy, it was judged eligible for total thyroidectomy, but surgery was delayed due to pulmonary thromboembolism. The patient was therefore treated with lenvatinib with a neoadjuvant intent until hemodynamic stability was obtained. Thyroidectomy and radioiodine therapy were then performed and the postdose scan revealed an area of modest uptake in the anterior part of the neck. The patient is now in a good clinical status and she continues her follow-up program without any adjuvant therapy

Do benthic and planktonic diatoms produce equivalent effects in crustaceans?

13 páginas, 4 figuras, 2 tablas.Hippolyte inermis Leach 1814 is a benthic shrimp characterized by a peculiar mechanism of sex reversal influenced by diatom foods. In fact, the appearance of primary females in spring is due to an apoptotic early disruption of the androgenic gland and of the male gonad, triggered by still unknown compounds present in diatoms of the genus Cocconeis. The influence of diatoms on the reproductive ecology and life cycle of planktonic crustaceans has been demonstrated previously: some planktonic diatoms produce aldehydes inducing apoptosis in the embryos and in the larvae of marine copepods, reducing their viability. Both benthic and planktonic diatoms therefore produce compounds having an apoptotic effect on some tissues of target crustaceans, although the ecological significance of the two processes is different: deleterious for copepod populations, regulative for shrimps associated with Posidonia oceanica. In the present article we experimentally administered specific planktonic diatoms, their fractions and compounds known to induce apoptosis in planktonic copepods, to H. inermis postlarvae, to check whether the apoptotic effect is due to an identical family of diatom compounds, and to establish whether the processes observed in the plankton and in the benthos, respectively, are analogous or homologous, from an ecological point of view. Our results indicated that diatom compounds acting in the two systems are different, since both planktonic diatoms and their aldehydes had negligible effects on the sex ratios of cultured shrimps.This research was conducted within the research project ‘Pharmapox’, funded by the European Community (EU 4800) and aimed at investigating the chemistry, pharmacology, and bioactivity of the diatom factor acting as a sex regulator in decapod crustaceans. The research activities of Patrizia Messina and Michela Nappo were fully covered by the EU grant.Peer reviewe

Papillary thyroid cancer in a struma ovarii: a report of a rare case

After removal of an ovarian mass in a 43-year-old woman, a struma ovarii was diagnosed. Within this teratoma, a papillary thyroid cancer was found. The tumor was negative for BRAF, NRAS, KRAS, PIK3CA and c-KIT mutations on molecular analysis. Thyroid function and morphology were normal. Thyroidectomy, L-T4 TSH-suppressive therapy and rhTSH-induced radioiodine ablation were performed. So far, the follow-up has been favorable. This is the first case of thyroid cancer in a struma ovarii in which mutations of PIK3CA exons 9 and 20, and c-KIT exons 9, 11 and 13 have been evaluated and the third in which ablation has been performed under rhTSH. The prognosis of patients with thyroid cancer in a struma ovarii is generally poor. In our patient, as in those who undergo ablative radioactive iodine therapy, this was not the case

Multiorgan infiltration by CD8+ T cells and 1p;16p translocation in a patient with hypogammaglobulinemia and a reduced number of B cells

Common variable immunodeficiency (CVID) disorders are the most common form of clinically significant primary immunodeficiencies found in adults. There is now clear evidence that CVID includes a group of clinically and genetically heterogenous conditions. In addition to recurrent infections, some patients are highly prone to granulomatous lesions. Rarely, CVID may be characterized by an increased number of circulating CD8+ T cells with tissue infiltration. We report a unique case of CVID associated with a sarcoidosis-like disease and polyclonal CD8+ T cell expansion with multiple tissue infiltration occurring in a subject with the chromosome translocation t(1;16). No sequence variant in TACI, APRIL, BAFF, ICOS or BTK genes was discovered. Cytometric analysis showed that the chemokine receptors expressed on peripheral and tissue CD8+ T cells are responsible for the tissue homing of the cells. Moreover, CD8+ T cells produced high amounts of IFN-gamma, but not IL-4 and IL-17, with regular expression of the transcription factor Vav1. Genes coding for IL-32 and FRAP1, both involved in the regulation of memory T cell differentiation, are located in the translocation breakpoint. This suggests that a chromosomal abnormality plays a role in the clinical features of this phenotypic variant of CVID. Copyright (C) 2012 S. Karger AG, Base

Small cell lung cancer transformation and the T790M mutation: A case report of two acquired mechanisms of TKI resistance detected in a tumor rebiopsy and plasma sample of EGFR-mutant lung adenocarcinoma

The present study describes the case of a 45-year-old man diagnosed with metastatic lung adenocarcinoma, which harbored a deletion within exon 19 of the epidermal growth factor receptor (EGFR) gene. The patient was subsequently treated with gefitinib (250 mg/day orally from May 2013 to March 2014), but developed acquired resistance to the drug following 11 months of treatment. Tumor burden molecular analysis was performed on a tumor rebiopsy and plasma sample, and histological analysis was also performed on the tumor rebiopsy. A small cell transformation retaining the original EGFR mutation was detected in the tumor rebiopsy, while the T790M mutation together with the activating ex19del mutation were identified only in the plasma sample. The patient was treated with cytotoxic chemotherapy (off-label schedule with epirubicin 80 mg/mq and paclitaxel 160 mg/mq every 21 days for 6 cycles) and radiation (50.4 Gy administered in 28 fractions of 1.8 Gy once daily for 5.5 weeks) specific for small cell lung cancer, and may also have benefitted from treatment with a third generation T790M-specific EGFR-TKI. To better describe the mechanisms of resistance to TKI inhibitors and to optimize therapeutic regimens, the simultaneous analysis of tumor biopsies and circulating tumor DNA should be considered

Eating Disorders in the Time of the Covid-19 Pandemic: A Perspective

Background: Current epidemiological conditions due to the COVID-19 pandemic may exacerbate the risk of new onset, recurrence and relapse of eating disorders. The aim of this perspective is to better analyse the phenomenon. Results: Some data suggest that new onset and recurrence/relapse of eating disorders are increasing due to the ongoing pandemic. Government restrictions, self-confinement, social isolation, restriction to healthcare facilities access, delayed access to diagnosis and cure, fear of contagion, distress and difficulties related to telemedicine approach are believed to contribute to this burden. Immune system dysfunction usually observed in undernourishment (e.g., anorexia nervosa) could play a role in delaying the diagnosis of respiratory infections, including COVID-19, and predisposing to possible bacterial superinfection. Conversely, patients with binge eating, obesity or metabolic syndrome are susceptible to high-grade systemic inflammation and poor prognosis once the infection has occurred. Discussion: Despite some evidence, more detailed data combining research in the field of eating disorders and COVID-19 are required. Many data show that telemedicine has some beneficial aspects, but its impact on long-term mental health is still poorly understood. Short- and long-term consequences of COVID-19 in patients with eating disorders are unknown, but it is likely that they will become more apparent over time. Conclusion: Working on emotion regulating strategies in a post-pandemic world, when people have inadequate control over the background of negative emotions, could be a strategy for treatment in the future. Long-term studies with a larger sample size are essential to assess long-term consequences of blockade on patients and their healthcare providers and identify useful strategies to improve clinical management

Retrospective cytological evaluation of indeterminate thyroid nodules according to the British Thyroid Association 2014 classification and comparison of clinical evaluation and outcomes

reserved10The cytology of 130 indeterminate nodules (Thy 3) was retrospectively reviewed according to the British Thyroid Association 2014 classification. Nodules were divided into Thy 3a (atypical features) and Thy 3f (follicular lesion) categories. Histology was available as a reference for 97 nodules. Pre-surgical evaluations comprised biochemical tests, color-Doppler ultrasonography (US), semi-quantitative elastography-US (USE), contrast-enhanced US (CEUS), and mutation analysis from cytological slides. Thyroid malignancy was the final diagnosis for 19% of surgically-treated nodules. No statistically significant difference in the risk of malignancy was found between Thy 3a (26%) and Thy 3f (14%) nodules. Histology of the Thy 3a and Thy 3f nodules showed a higher incidence of Hurtle cell adenomas in Thy 3f (29%) than in Thy 3a (3%) nodules (P=0.01). The only pre-surgical difference concerned the BRAF V600E mutation, which was positive in some Thy 3a but not in any Thy 3f nodules (P=0.04). Receiver-operating characteristic (ROC) analysis was used to obtain cut-off values from US (score), USE (ELX 2/1 strain index), and CEUS (time-to-peak index and peak index) data. The cut-off values were similar for Thy 3a and Thy 3f nodules. Data showed that malignancy can be suspected if the US score is >2, ELX 1/2 strain index >1, time-to-peak index >1, and peak index <1. In a sub-group of 24 revised nodules (12 Thy 3a and 12 Thy 3f) with histology as a reference, the diagnostic power of cumulative pre-surgical analysis by means of US, USE, and CEUS showed high positive and negative predictive values (83% and 100%, respectively) for the presence of malignancy in Thy 3a and Thy 3f nodules. In conclusion, in our series of revised Thy 3 nodules, malignancy was low and displayed no significant differences between Thy 3a and Thy 3f categories. The use of cut-offs based on histology as a reference could reduce surgery. Our data support the conviction that, in mutation-negative Thy 3a and Thy 3f nodules, observation should be the first choice when not all instrumental results are suspect.mixedGiusti, Massimo; Massa, Barbara; Balestra, Margherita; Calamaro, Paola; Gay, Stefano; Schiaffino, Simone; Turtulici, Giovanni; Zupo, Simonetta; Monti, Eleonora; Ansaldo, GianlucaGiusti, Massimo; Massa, Barbara; Balestra, Margherita; Calamaro, Paola; Gay, Stefano; Schiaffino, Simone; Turtulici, Giovanni; Zupo, Simonetta; Monti, Eleonora; Ansaldo, Gianluc

Nutraceuticals and Oral Supplements in Cancer Prevention: A Narrative Review

Epidemiological studies have shown that food is a compelling means of maintaining a state of well-being and preventing health. Many malignant diseases are related to nutrition, and the nutrient-organism interaction could define the balance between health and disease. Nutrients and dietary components influence epigenetic phenomena and modify drug response so that food-organism interactions may influence individual predisposition to disease and its potential therapeutic response

BRAF Mutations in an Italian Regional Population: Implications for the Therapy of Thyroid Cancer

Background. Molecular diagnostics has offered new techniques for searching for mutations in thyroid indeterminate lesions. The study’s aim was to evaluate the BRAF mutations’ incidence in an Italian regional population. Subjects and Methods. 70 Caucasian patients born in Liguria with indeterminate or suspicious cytological diagnoses. Results. A BRAF gene mutation was successfully analyzed in 56/70 patients. The mutation was BRAF V600E in 12/56 cases (21%) and BRAF K601E in 2/56 (4%). Of the BRAF mutated samples on cytological diagnosis (14/56 cases), 2/14 cases (14%) were benign on final histology and 12/14 (86%) were malignant. All BRAF-mutated cases on cytology that were found to be benign on histological examination carried the K601E mutation. Of the nonmutated BRAF cases (42/56, 75%) which were later found to be malignant on definitive histology, 5 cases were follicular carcinomas (36%), 3 cases were incidentally found to be papillary microcarcinomas (22%), 2 were cases papillary carcinomas (14%), 1 was case follicular variant of papillary carcinoma (7%), 1 was case medullary carcinoma (7%), 1 case was Hurtle cell tumor (7%), and 1 case was combined cell carcinoma and papillary oncocytic carcinoma (7%). Conclusions. The presence of the BRAF V600E mutation may suggest a more aggressive surgical approach. BRAF K601E mutation did not correlate with malignancy indexes