Treatment of patients with multiple myeloma progressing on frontline-therapy with lenalidomide

Over the last years, there has been great progress in the treatment of multiple myeloma with many new agents and combinations having been approved and being now routinely incorporated into treatment strategies. As a result, patients are experiencing benefits in terms of survival and better tolerance. However, the multitude of treatment options also presents a challenge to select the best options tailored to the specific patient situation. Lenalidomide is increasingly being used as part of frontline therapy in newly diagnosed multiple myeloma. This agent is typically administered until disease progression. It is currently unclear, how to best manage patients, who relapse while receiving lenalidomide as part of their frontline treatment. We conducted a review to summarize the available evidence in this setting. Our summary shows that there are very few data from current trials testing new combinations based on carfilzomib, pomalidomide, or daratumumab that address this specific patient population. Our review is aimed to summarize the available evidence to assist treatment decision making and to raise awareness of this lack of data to encourage further analyses and the incorporation of sequencing questions in future trial designs

A simple immunohistochemical bio-profile incorporating Bcl2 curbs those cases of invasive breast carcinoma for which an Oncotype Dx characterization is needed

Aim Our goal has been to evaluate the importance that the incorporation of Bcl2 in the ER/PGR/ Her2/Ki67 bio-profile can have as predictor of the Oncotype Dx categories. Material and methods 156 consecutive cases of HR+/Her2- pN0/1 primary breast carcinoma were sent to the Oncotype Dx test. Immunohistochemical determination of Bcl2/ER/PGR/Ki67/Her2 expression was evaluated for each case. After the selection of the appropriate cut-off values for PGR and Ki67, explorative as well as confirmative statistical analyses were performed to build and validate predictive risk-of-recurrence immunohistochemical only bio-profiles. Results The predictive capacity of these immunohistochemical profiles was compared with both traditional and TAILORx Oncotype Dx risk class classification. This comparison showed that immunohistochemical bio-profiles select those cases not associated with high risk-of-recurrence of disease (luminal-A/B and luminal A/B Bcl2) and those that are instead at high risk and therefore worthy of chemotherapy (luminal-B ki67 and luminal-B Bcl2/Ki67), strongly suggesting to only submit PGR-positive/Bcl2-Ki67 altered cases to Oncotype Dx, thus reducing the number of cases to be tested. Conclusions Our results indicate that the addition of Bcl2 to an immunohistochemical bio-profile definitely improves its predictive capacity to correctly select which cases to send to the Oncotype Dx test. We have also suggested that institutions with a significant number of breast carcinomas sent to the Oncotype Dx test can use these latter to derive their own PGR and Ki67 cutoff values, overcoming the drawbacks of sharing common inter-laboratory values. Validation of these bio-profiles as predictors of the Oncotype Dx categories is ongoing in a prospective series of new cases

The Neoadjuvant Net: A patient- and surgeon-friendly device to facilitate safe breast-conserving surgery in patients who underwent neoadjuvant treatment

The primary goal of the study was to describe an innovative and helpful tool in defining the minimal surgical margins necessary during breast-conserving surgery (BCS) after neoadjuvant treatment: the Neoadjuvant Net (NN). The secondary endpoint was to assess its usefulness in achieving postoperative disease-free margins and reducing Ipsilateral Breast Tumor Recurrences (IBRTs). The breast-conserving surgical technique together with the use of the Neoadjuvant Net is herein reported. Age, stage at diagnosis, clinical and pathological response, lymph node status, type of surgery, margin status, and incidence of local and distant recurrence were retrospectively analyzed. Seventy-five patients underwent BCS following medical treatment from 2000 to 2011. The majority of the patients had significant size reduction (63/75, 84%). Twenty-two had a complete clinical response but only 11 (11/75, 14.7%) showed a complete pathological response. Two patients (2/75, 2.67%) had infiltrated surgical margins. After a mean follow-up of seventy months, 3 patients (3/75, 4%) had IBRTs and 4 women had distant metastases (4/75, 5.34%). The NN is an easy-to-use, non-invasive instrument designed with the purpose of facilitating the surgeon's task of reducing infiltrated margins and IBTRs

Calcium and phosphate homeostasis in dogs with newly diagnosed naturally occurring hypercortisolism

Background: Hypercortisolism affects calcium and phosphate metabolism in dogs; however, the exact mechanisms are not completely understood. Objectives: To evaluate circulating concentrations of whole parathormone (wPTH), 25-hydroxyvitamin D (25-(OH)D), calcitriol, and fibroblast growth factor-23 (FGF-23) in dogs with naturally occurring hypercortisolism (NOHC) and healthy dogs, and their association with calcium and phosphate homeostasis. Animals: Twenty-three client-owned dogs with NOHC, and 12 client or staff-owned healthy dogs. Methods: Prospective cross-sectional study. The circulating concentrations of total calcium, ionized calcium (iCa), phosphate, wPTH, 25-(OH)D, calcitriol and FGF-23, and the urinary fractional excretion of phosphate (FEP) and calcium (FECa) were compared between dogs with NOHC before treatment and healthy dogs. Results: Dogs with NOHC had higher mean serum phosphate concentrations (4.81 mg/dL, SD ± 0.71 vs 3.86 mg/dL, SD ± 0.60; P <.001), median FECa (0.43%, range, 0.03-2.44 vs 0.15%, range, 0.06-0.35; P =.005), and median serum wPTH concentrations (54.6 pg/mL, range, 23.7-490 vs 24.6 pg/mL, range, 5.5-56.4; P =.003) as compared to the controls. Circulating concentrations of total calcium, iCa, and calcitriol and the FEP did not differ between groups, whereas the serum 25-(OH)D concentrations were lower in dogs with NOHC as compared to the controls (70.2 pg/mL, SD ± 42.3 vs 106.3 pg/mL, SD ± 35.3; P =.02). The dogs with NOHC had lower plasma FGF-23 concentrations than controls (316.6 pg/mL, range, 120.8-575.6 vs 448.7 pg/mL, range, 244.8-753; P =.03). Conclusions and Clinical Importance: Urine loss of calcium and hyperphosphatemia could contribute to the adrenal secondary hyperparathyroidism

Per una storia della retribuzione : lavoro, valore e metodi di remunerazione dall’antichità ad oggi

Il volume ripercorre a grandi tappe la storia della valorizzazione e della remunerazione del lavoro umano, nel lungo periodo che va dall\u2019antichit\ue0 ai giorni nostri e alla luce delle culture che hanno maggiormente valorizzato lo sviluppo economico globale. A partire dal passaggio da un\u2019economia naturale a un\u2019economia monetaria, remunerazione in denaro e remunerazione in natura si sono fino a oggi variamente combinate, anche a seconda del grado di libert\ue0 di erogazione del lavoro. Dall\u2019affascinante riepilogo qui proposto emerge come la tensione tra mero compenso dello sforzo erogato e necessit\ue0 di sopravvivenza del lavoratore e della sua famiglia \ue8 stata fin da subito presente nella pratica e discussa a livello teorico-morale, con importanti implicazioni sulla struttura delle remunerazioni

"3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained"

The potential of a spheroid tumor model composed of cells in different proliferative and metabolic states for the development of new anticancer strategies has been amply demonstrated. However, there is little or no information in the literature on the problems of reproducibility of data originating from experiments using 3D models. Our analyses, carried out using a novel open source software capable of performing an automatic image analysis of 3D tumor colonies, showed that a number of morphology parameters affect the response of large spheroids to treatment. In particular, we found that both spheroid volume and shape may be a source of variability. We also compared some commercially available viability assays specifically designed for 3D models. In conclusion, our data indicate the need for a pre-selection of tumor spheroids of homogeneous volume and shape to reduce data variability to a minimum before use in a cytotoxicity test. In addition, we identified and validated a cytotoxicity test capable of providing meaningful data on the damage induced in large tumor spheroids of up to diameter in 650 micron by different kinds of treatments

Natural cases of polyarthritis associated with feline calicivirus infection in cats

The limping syndrome is occasionally reported during acute feline calicivirus (FCV) infections or as consequence of vaccination. In this retrospective study, three clinical cases of lameness in household cats naturally infected by FCV were described and phylogeny of the virus were investigated by analysing the hypervariable E region of the ORF2 viral gene. Cats were diagnosed with polyarthritis and FCV RNA or antigens were detected in symptomatic joints. One cat, euthanized for ethical reasons, underwent a complete post-mortem examination and was subjected to histopathological and immunohistochemical investigations. No phylogenetic subgrouping were evident for the sequenced FCV. Histopathology of the euthanized cat revealed diffuse fibrinous synovitis and osteoarthritis eight months after the onset of lameness and the first detection of FCV RNA, supporting the hypothesis of a persistent infection. FCV was demonstrated by immunohistochemistry in synoviocytes and fibroblasts of the synovial membranes. This study provides new data on the occurrence of polyarthritis in FCV-infected cats, demonstrates by immunohistochemistry the presence of FCV in the synovial membranes of a cat with persistent polyarthritis and supports the absence of correlation between limping syndrome and phylogenetic subgrouping of viruses

HLA-J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer

The human leukocyte antigen (HLA) genes are cell-surface proteins, essential for immune cell interaction. HLA-G is known for their high immunosuppressive effect and its potential as predictive marker in breast cancer. However, nothing is known about the HLA-J and its immunosuppressive, prognostic and predictive features, as it is assumed to be a pseudogene by in silico sequence interpretation. HLA-J, ESR1, ERBB2, KRT5 and KRT20 mRNA expression were analysed in 29 fresh frozen breast cancer biopsies and their corresponding resectates obtained from patients treated with neoadjuvant chemotherapy (NACT). mRNA was analysed with gene specific TaqMan-based Primer/Probe sets and normalized to Calmodulin 2. All breast cancer samples did express HLA-J and frequently increased HLA-J mRNA levels after NACT. HLA-J mRNA was significantly associated with overexpression of the ESR1 mRNA status (Spearman ρ 0,5679; p = 0.0090) and KRT5 mRNA (Spearman ρ 0,6121; p = 0.0041) in breast cancer core biopsies and dominated in luminal B subtype. Kaplan Meier analysis revealed that an increase of HLA-J mRNA expression after NACT had worse progression free survival (p = 0,0096), indicating a counterreaction of tumor tissues presumably to prevent elimination by enhanced immune infiltration induced by NACT. This counterreaction is associated with worse prognosis. To our knowledge this is the first study identifying HLA-J as a new predictive marker in breast cancer being involved in immune evasion mechanisms.Humane Leukozyten-Antigene (HLA) sind Proteine auf der Zelloberfläche, die essenziell für die Immunzellinteraktion sind. HLA-G ist für seine hohe immunosuppressive Wirkung sowie als potenzieller prädikativer Marker für Brustkrebs bekannt. Dagegen ist kaum etwas über HLA-J und seine immunosuppressiven, prognostischen und prädiktiven Eigenschaften bekannt, da es basierend auf In-silico-Sequenzanalysen als „Pseudogen“ interpretiert wurde. Die Expression von HLA-J, ESR1, ERBB2, KRT5 und KRT20 mRNA wurde in 29 frisch gefrorenen Brustkrebsbiopsien analysiert und mit den klinisch-pathologischen Daten von Patientinnen, welche mit neoadjuvanter Chemotherapie behandelt wurden, verglichen. Die mRNA-Expression wurde mit genspezifischen TaqMan-basierten Primer/Probe-Sets analysiert und auf Calmodulin 2 normalisiert. Alle Gewebeproben von Patientinnen mit Brustkrebs exprimierten HLA-J, und der HLA-J-mRNA-Spiegel war nach NACT oft erhöht. In den Brustkrebsstanzbiopsien war die HLA-J-mRNA-Expression signifikant mit der Überexpression von ESR1-mRNA (Spearmans ρ 0,5679; p = 0,0090) und KRT5-mRNA (Spearmans ρ 0,6121; p = 0,0041) assoziiert und dominierte im Luminal-B-Subtyp. Die Kaplan-Meier-Analyse zeigte, dass ein Anstieg der HLA-J-mRNA-Expression nach NACT mit einem schlechteren progressionsfreien Überleben einhergeht (p = 0,0096), womöglich als Gegenreaktion des Tumorgewebes, um eine Eliminierung durch tumorinfiltrierende Lymphozyten, welche durch eine NACT induziert wurden, zu verhindern. Diese Gegenreaktion ist mit einer schlechteren Prognose assoziiert. Soweit uns bekannt, handelt es sich hierbei um die erste Studie, die HLA-J als neuen prädiktiven Marker im Brustkrebs identifiziert hat und möglicherweise zur Immunevasion beiträgt