Germline BRCA testing in pancreatic cancer: improving awareness, timing, turnaround, and uptake

Prognosis is generally poor for patients with pancreatic ductal adenocarcinoma. However, patients with germline BRCA1 or BRCA2 mutations (gBRCAm) may benefit from first-line platinum-based chemotherapy and maintenance therapy with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib following at least 16 weeks of first-line platinum-based chemotherapy without disease progression. Germline breast cancer gene (BRCA) testing is therefore important to ensure that patients receive the most effective treatment. In addition, testing for other DNA damage response gene mutations beyond gBRCAm may also guide treatment decisions. However, clinical pathways for genetic testing are often suboptimal, leading to delays in treatment initiation or missed opportunities for personalized therapy. Barriers to testing include low rates of referral and uptake, delays to referral and slow result turnaround times, cost, and biopsy and assay limitations if somatic testing is performed, leading to the requirement for subsequent dedicated germline testing. Low rates of referral may result from lack of awareness among physicians of the clinical value of testing, coupled with low confidence in interpreting test results and poor availability of genetic counseling services. Among patients, barriers to uptake may include similar lack of awareness of the clinical value of testing, anxiety regarding the implications of test results, lack of insurance coverage, fear of negative insurance implications, and socioeconomic factors. Potential solutions include innovative approaches to testing pathways, including ‘mainstreaming’ of testing in which BRCA tests are routinely arranged by the treating oncologist, with the involvement of genetic counselors if a patient is found to have a gBRCAm. More recently, the utility of multigene panel analyses has also been explored. Access to genetic counseling may also be improved through initiatives such as having a genetic counseling appointment for all new patient visits and telemedicine approaches, including the use of telephone consultations or DVD-assisted counseling. Educational programs will also be beneficial, and cost effectiveness is likely to improve as the number of targeted treatments increases and when the earlier detection of tumors in family members following cascade testing is considered

Effectiveness of an Ultrasound Training Module for Internal Medicine Residents

<p>Abstract</p> <p>Background</p> <p>Few internal medicine residency programs provide formal ultrasound training. This study sought to assess the feasibility of simulation based ultrasound training among first year internal medicine residents and measure their comfort at effectively using ultrasound to perform invasive procedures before and after this innovative model of ultrasound training.</p> <p>Methods</p> <p>A simulation based ultrasound training module was implemented during intern orientation that incorporated didactic and practical experiences in a simulation and cadaver laboratory. Participants completed anonymous pre and post surveys in which they reported their level of confidence in the use of ultrasound technology and their comfort in identifying anatomic structures including: lung, pleural effusion, bowel, peritoneal cavity, ascites, thyroid, and internal jugular vein. Survey items were structured on a 5-point Likert scales (1 = extremely unconfident, 5 = extremely confident).</p> <p>Results</p> <p>Seventy-five out of seventy-six interns completed the pre-intervention survey and 55 completed the post-survey. The mean confidence score (SD) increased to 4.00 (0.47) (p < 0.0001). The mean (SD) comfort ranged from 3.61 (0.84) for peritoneal cavity to 4.48 (0.62) for internal jugular vein. Confidence in identifying all anatomic structures showed an increase over the pre-intervention means (p < 0.002).</p> <p>Conclusion</p> <p>A simulation based ultrasound learning module can improve the self-reported confidence with which residents identify structures important in performing invasive ultrasound guided procedures. Incorporating an ultrasound module into residents' education may address perceived need for ultrasound training, improve procedural skills, and enhance patient safety.</p

Challenges in the management of a patient with Cowden syndrome: case report and literature review

We would like to present a patient with a classical phenotype of a rare disorder - Cowden syndrome, its diagnostics and management challenges. A breast surgeon has to be aware of this rare condition when treating a patient with breast manifestations of Cowden syndrome and has to refer the patient to a clinical geneticist for further evaluation. Sequencing of the PTEN gene showed the Asp24Gly mutation. According to the latest literature data, the lifetime risk of breast cancer for Cowden syndrome patients is 81% and surgery is a justified option to reduce the risk of breast cancer. Bilateral risk-reducing mastectomy with immediate reconstruction was performed to eliminate further risk of breast cancer. 3 years after the risk-reducing breast surgery the patient is satisfied with the outcome. This is to our best knowledge the first reported Cowden syndrome case with follow-up data after risk-reducing measures have been taken

The Association of Telomere Length with Colorectal Cancer Differs by the Age of Cancer Onset

OBJECTIVES: Telomeres are nucleoprotein structures that cap the end of chromosomes and shorten with sequential cell divisions in normal aging. Short telomeres are also implicated in the incidence of many cancers, but the evidence is not conclusive for colorectal cancer (CRC). Therefore, the aim of this study was to assess the association of CRC and telomere length. METHODS: In this case-control study, we measured relative telomere length from peripheral blood leukocytes (PBLs) DNA with quantitative PCR in 598 CRC patients and 2,212 healthy controls. RESULTS: Multivariate analysis indicated that telomere length was associated with risk for CRC, and this association varied in an age-related manner; younger individuals (≤50 years of age) with longer telomeres (80-99 percentiles) had a 2-6 times higher risk of CRC, while older individuals (>50 years of age) with shortened telomeres (1-10 percentiles) had 2-12 times the risk for CRC. The risk for CRC varies with extremes in telomere length in an age-associated manner. CONCLUSIONS: Younger individuals with longer telomeres or older individuals with shorter telomeres are at higher risk for CRC. These findings indicate that the association of PBL telomere length varies according to the age of cancer onset and that CRC is likely associated with at minimum two different mechanisms of telomere dynamics

Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome.

The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance

FISH Diagnosis of Acute Graft-Versus-Host Disease Following Living-Related Liver Transplant

Acute graft-versus-host disease (GVHD) is an uncommon but often fatal complication following liver transplant. We describe a GVHD case in which a female patient with primary biliary cirrhosis underwent a living-related liver transplant from her son. The human leukocyte antigen typing of the donor was homozygous at all loci. The recipient's human leukocyte antigen type was haplo-identical to that of the donor. A bone marrow aspirate performed for pancytopenia revealed a severely hypoplastic marrow. Fluorescent in situ hybridization (FISH) using X- and Y-chromosome probes demonstrated that 80% of marrow cells were of donor origin. Comparison of Giemsa-stained cell morphology and FISH showed that the erythroid precursor cells were predominantly of male pattern (XY). This report is one of only a few studies that prove the migration of a donor's hematopoietic stem cells to a recipient's bone marrow. We demonstrated that FISH analysis using sex chromosome probes is useful to confirm a diagnosis of GVHD following organ transplantation from a donor of the opposite sex. We also showed that donor hematopoietic stem cells in a liver graft can migrate to the recipient's bone marrow. We suggest that FISH is a rapid and reliable test for confirming the diagnosis of GVHD in a peripheral blood or skin biopsy sample