Swiss cost-effectiveness analysis of universal screening for Lynch syndrome of patients with colorectal cancer followed by cascade genetic testing of relatives.

BACKGROUND: We estimated the cost-effectiveness of universal DNA screening for Lynch syndrome (LS) among newly diagnosed patients with colorectal cancer (CRC) followed by cascade screening of relatives from the Swiss healthcare system perspective. METHODS: We integrated decision trees with Markov models to calculate incremental cost per quality-adjusted life-year saved by screening all patients with CRC (alternative strategy) compared with CRC tumour-based testing followed by DNA sequencing (current strategy). RESULTS: The alternative strategy has an incremental cost-effectiveness ratio of CHF65 058 compared with the current strategy, which is cost-effective according to Swiss standards. Based on annual incidence of CRC in Switzerland, universal DNA screening correctly identifies all 123 patients with CRC with LS, prevents 17 LS deaths and avoids 19 CRC cases, while the current strategy leads to 32 false negative results and 253 LS cases lost to follow-up. One way and probabilistic sensitivity analyses showed that universal DNA testing is cost-effective in around 80% of scenarios, and that the cost of DNA testing and the number of invited relatives per LS case determine the cost-effectiveness ratio. CONCLUSION: Results can inform policymakers, healthcare providers and insurance companies about the costs and benefits associated with universal screening for LS and cascade genetic testing of relatives.

The novel CD19-targeting antibody-drug conjugate huB4-DGN462 shows improved anti-tumor activity compared to SAR3419 in CD19-positive lymphoma and leukemia models.

Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked via sulfo-SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved in vitro anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines. In vivo experiments using lymphoma xenografts models confirmed the in vitro data. The response of B-cell lymphoma lines to huB4-DGN462 was not correlated with CD19 expression, the presence of BCL2 or MYC translocations, TP53 inactivation or lymphoma histology. In conclusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.

A Dietary Intervention to Lower Serum Levels of IGF-I in BRCA Mutation Carriers.

BACKGROUND: Insulin-like growth factor I (IGF-I) and other markers of insulin resistance (IRm) might influence the penetrance of BRCA gene mutation. In a demonstration project on BRCA mutation carriers we tested the effect of the 'Mediterranean diet', with moderate protein restriction, on serum levels of IGF-I and IRm. METHODS: BRCA mutation carriers, with or without breast cancer, aged 18⁻70 years and without metastases were eligible. After the baseline examinations, women were randomized to an active dietary intervention or to a control group. The intervention group attended six full days of life-style intervention activities (cookery classes followed by lunch, sessions of walking for 45 min and nutritional conferences) over the next six months. RESULTS: 213 BRCA mutation carriers completed the six-month study. Women in the intervention group (110) showed major changes in all the parameters under study. They significantly lost weight (p < 0.001), fat mass (p = 0.002), with reduced hip circumference (p = 0.01), triglycerides (p = 0.02) and IGF-I (p = 0.02) compared with controls. They also had a significantly higher levels of insulin-like growth factor-binding protein 3 (IGFI-BP3) (p = 0.03) and a lower IGF-I/IGFI-BP3 ratio (p = 0.04). The reduction of serum levels of IGF-I was significantly associated with the reduction in the consumption of animal products (p = 0.04). CONCLUSIONS: Women in the intervention group showed significant improvements in IGF-I and in other IRm that might influence the penetrance of BRCA mutations.

Procalcitonin measurement to screen medullary thyroid carcinoma: A prospective evaluation in a series of 2705 patients with thyroid nodules.

BACKGROUND: To prospectively evaluate the role of procalcitonin (PCT) in screening of patients with thyroid nodules for medullary thyroid carcinoma (MTC). MATERIALS AND METHODS: We measured PCT in 2705 patients with thyroid nodules referred to our centre between January 2011 and December 2017. Those with a positive PCT were operated after positive confirmatory tests such as fine-needle aspiration, measurement of calcitonin (CT) in serum and fine-needle aspiration washouts or CT stimulation testing. Patients with a negative PCT were operated based on the results of further diagnostics. The diagnostic performance of PCT was evaluated, and the best cut-off level was selected by ROC curve analysis. RESULTS: Among 2705 patients, 9 with positive serum PCT (ie, above 0.1 µg/L) and 370 with negative PCT underwent thyroid surgery. MTC was histologically confirmed in all patients with positive PCT but not found in patients with negative PCT. Serum PCT levels were significantly higher in patients with MTC (median 0.64 µg/L, range 0.16-12.9 µg/L) than in those without (median 0.075 µg/L, range 0.075-0.16 µg/L; P < .0001). ROC curves were plotted to calculate the optimal PCT value separating patients with MTC from those without. The best cut-off was 0.155 µg/L with sensitivity, specificity, positive and negative predictive values as well as accuracy of 100%, 99.7%, 91.7%, 100% and 99.7%, respectively. Positive and negative likelihood ratios were 329 and zero, respectively. CONCLUSIONS: Measurement of PCT is a sensitive and accurate method for detecting MTC in patients with thyroid nodules and can thus be a reliable alternative to CT measurement.

PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy.

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120-9. ©2017 AACR.

Challenges in managing genetic cancer risk: a long-term qualitative study of unaffected women carrying BRCA1/BRCA2 mutations.

PURPOSE: Women carrying BRCA1/BRCA2 germ-line mutations have an increased risk of developing breast/ovarian cancer. To minimize this risk, international guidelines recommend lifelong surveillance and preventive measures. This study explores the challenges that unaffected women genetically predisposed to breast/ovarian cancer face in managing their risk over time and the psychosocial processes behind these challenges. METHODS: Between 2011 and 2013, biographical qualitative interviews were conducted in Switzerland with 32 unaffected French- and Italian-speaking women carrying BRCA1/BRCA2 mutations. Their mutation status had been known for at least 3 years (mean, 6 years). Data were analyzed through constant comparative analysis using software for qualitative analysis. RESULTS: From the time these women received their positive genetic test results, they were encouraged to follow medical guidelines. Meanwhile, their adherence to these guidelines was constantly questioned by their social and medical environments. As a result of these contradictory pressures, BRCA1/BRCA2 mutation carriers experienced a sense of disorientation about the most appropriate way of dealing with genetic risk. CONCLUSION: Given the contradictory attitudes of health-care professionals in caring for unaffected BRCA1/BRCA2 mutation carriers, there is an urgent need to educate physicians in dealing with genetically at-risk women and to promote a shared representation of this condition among them.Genet Med 17 9, 726-732.

99mTc-sestamibi imaging and bone marrow karyotyping in the assessment of multiple myeloma and MGUS.

AIM: The first pathogenetic step in multiple myeloma is the emergence of a limited number of clonal plasma cells, clinically known as monoclonal gammopathy of undetermined significance (MGUS). Patients with MGUS do not have symptoms or end-organ damage but they do have a 1% annual risk of progression to multiple myeloma or related malignant disorders. With progression of MGUS to multiple myeloma, complex genetic events occur in the neoplastic plasma cell. Karyotyping and fluorescence in-situ hybridization (FISH) were shown to be of prognostic value in patients with multiple myeloma. Tc-sestamibi imaging reflects myeloma disease activity in bone marrow with very high sensitivity and specificity predicting disease evolution. This study was undertaken to evaluate the role of Tc-sestamibi imaging and cytogenetic analysis in prognosis prediction of MGUS and multiple myeloma. METHODS: We enrolled 30 consecutive patients with a confirmed diagnosis of multiple myeloma or MGUS. Bone marrow biopsy and biochemical staging according to the International Staging System (ISS) were performed in all cases. Karyotype analysis and FISH were performed in 11 of 12 patients with MGUS and in 17 of 18 patients with multiple myeloma having adequate metaphases. RESULTS: The karyotype was abnormal in four of 11 MGUS and in six of 17 multiple myeloma. Abnormalities of chromosome 13 were present in one case of MGUS and in six cases of multiple myeloma whereas the involvement of immunoglobulin was observed in one case of multiple myeloma. An abnormal FISH panel was found in four MGUS and nine multiple myeloma patients. All patients with MGUS showed a normal MIBI scan (score 0). Among patients with multiple myeloma only three, all with ISS stage I, showed a normal scan while a positive scan was obtained in others (score range, 1-7). The MIBI uptake was strongly related to the bone marrow plasma cell infiltration and to cytogenetic abnormalities. Particularly, a MIBI uptake score above 5 identified patients with poor prognosis encompassing all stage III multiple myeloma and three of seven stage II multiple myeloma. On the other hand all stage I and II patients having a MIBI score less than 5 showed a good prognosis. CONCLUSION: Both cytogenetic analysis and a MIBI scan add no relevant prognostic information to the ISS in patients with stage I and III multiple myeloma. The MIBI scan was of prognostic value in stage II multiple myeloma patients. Additionally, MIBI imaging may be useful to guide bone marrow biopsy in order to obtain adequate samples for cytogenetic analysis.

Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma.

Among B-cell lymphomas mantle cell lymphoma (MCL) has the worst prognosis. By using a combination of genomic and expression profiling (Affymetrix GeneChip Mapping 10k Xba131 and U133 set), we analysed 26 MCL samples to identify genes relevant to MCL pathogenesis and that could represent new therapeutic targets. Recurrent genomic deletions and gains were detected. Genes were identified as overexpressed in regions of DNA gain on 3q, 6p, 8q, 9q, 16p and 18q, including the cancer genes BCL2 and MYC. Among the transcripts with high correlation between DNA and RNA, we identified SYK, a tyrosine kinase involved in B-cell receptor signalling. SYK was amplified at DNA level, as validated by fluorescence in situ hybridisation (FISH) analysis, and overexpressed at both RNA and protein levels in the JeKo-1 cell line. Low-level amplification, with protein overexpression of Syk was demonstrated by FISH in a small subset of clinical samples. After treatment with low doses of the Syk inhibitor piceatannol, cell proliferation arrest and apoptosis were induced in the cell line overexpressing Syk, while cells expressing low levels of Syk were much less sensitive. A combination of genomic and expression profiling suggested Syk inhibition as a new therapeutic strategy to be explored in lymphomas.

Genetic and cytogenetic observations among different types of ovarian tumors are compatible with a progression model underlying ovarian tumorigenesis.

In this report we present the characterization of ovarian neoplasms including benign tumors, borderline tumors, and invasive carcinomas in order to assess whether a sharing of cytogenetic abnormalities is present in all three types of tumors. A cohort of 114 newly diagnosed and untreated ovarian epithelial tumors were analyzed by cytogenetic and molecular cytogenetic approaches with probes specific for chromosome 6. Three groups of chromosome abnormalities were identified: the first group included abnormalities common to all tumor classes (losses of chromosomes 6, 8, 10, 11, 15, 16, 17, 18, 19, 20, 21, 22, and X; gains of chromosomes 1, 3, 5, and 12; 6q24 approximately qter deletions); the second group presented specific abnormalities present in malignant but not in benign tumors (losses of chromosomes 2, 7, 13, and 14; gains of chromosome 4 and chromosome markers); and the last group included abnormalities unique to invasive carcinomas (loss of chromosome 4; gains of chromosomes 2, 7, 8, 9, 10, 16, 17, 18, 19, 20, and 21; 6q16 approximately q24 deletions; rearrangements of 3p, 3q, 13q, and 21q regions). The presence of shared chromosomal alterations in all three types of ovarian neoplasms investigated in this report seems therefore to suggest a progression model for these types of tumors.

Idiopathic fetal intrauterine growth restriction: a possible inheritance pattern.

OBJECTIVE: This study was conducted to assess if the delivery of a previous growth-retarded (IUGR) fetus increases the risk of having an IUGR fetus in subsequent pregnancies and to explore if a familial pattern of transmission is involved. METHODS: Seventy consecutive multiparous women whose fetus was IUGR (group 1) and 70 controls (group 2) were enrolled in this study. RESULTS: The proportion of women who developed preeclampsia (9 versus 2, p = 0.05) and who had delivered an IUGR fetus in a previous pregnancy (20 versus 4, p < 0.05) were higher in group 1 than in group 2. There was no difference in the incidence of chronic hypertension, diabetes, smoking, substance or alcohol abuse, and HIV infection between the groups. After adjustment for preeclampsia, the delivery of a previous IUGR fetus remained a risk factor for having a subsequent IUGR fetus [Odds ratio = 6.7 (CI 2.15-21.22), p < 0.01]. Pedigree analysis conducted in 15 families revealed a familial cluster of IUGR infants in all families that were investigated. In 9 out of 15 families, a dominant pattern of inheritance of IUGR was observed while the remaining families were more heterogeneous. In one family, a balanced carrier of chromosome 7 inversion generated a malformed fetus and two IUGR infants. CONCLUSIONS: This study clarifies that IUGR may be an inherited genetic condition and emphasizes that a knowledge of the family history and of the parental karyotype may be helpful in the prevention of both fetal malformations and adverse neonatal morbidity in subsequent low birth weight infants.