In view of advances in early detection and treatment, the 5-year relative survival rate for all cancer patients combined is now approximately 66%. As a result, there are more than 13.7 million cancer ...survivors in the United States, with this number increasing by 2% annually. For many patients, improvements in survival have been countered by therapy-associated adverse effects that may seriously impair long-term functional status, workplace productivity, and quality of life. Approximately 20% to 40% of cancer patients given neurotoxic chemotherapy develop chemotherapy-induced peripheral neurotoxicity (CIPN), which represents one of the most common and potentially permanent nonhematologic side effects of chemotherapy. Permanent bilateral hearing loss and/or tinnitus can result from several ototoxic therapies, including cisplatin- or carboplatin-based chemotherapy. CIPN and ototoxicity represent important challenges because of the lack of means for effective prevention, mitigation, or a priori identification of high-risk patients, and few studies have applied modern genomic approaches to understand underlying mechanisms/pathways. Translational genomics, including cell-based models, now offer opportunities to make inroads for the first time to develop preventive and interventional strategies for CIPN, ototoxicity, and other treatment-related complications. This commentary provides current perspective on a successful research strategy, with a focus on cisplatin, developed by an experienced, transdisciplinary group of researchers and clinicians, representing pharmacogenomics, statistical genetics, neurology, hearing science, medical oncology, epidemiology, and cancer survivorship. Principles outlined herein are applicable to the construction of research programs in translational genomics with strong clinical relevance and highlight unprecedented opportunities to understand, prevent, and treat long-term treatment-related morbidities.
Abstract
Background
There are close ties between injecting drug use and incarceration as a result of imprisonment for drug-related crimes and therefore Hepatitis C virus (HCV) transmission in prisons ...is high. The most effective strategies to prevent HCV transmission, including needle-syringe exchange (NSP) and opiate substitution therapies (OST) are commonly unavailable in the prisons. Understanding trends in incidence and associated factors in prisons is crucial for developing and improving HCV prevention and treatment programs in the prison setting.
Aims
This study investigated trends in HCV incidence and associated factors among a cohort of prisoners in New South Wales (NSW), Australia.
Methods
Data were available from the Hepatitis C Incidence and Transmission Study in prisons (HITS-p) from 2005–2014. Temporal trends in HCV incidence were evaluated. Factors associated with time to HCV seroconversion were assessed using Cox proportional hazards regression.
Results
Among 590 participants enrolled, 320 were eligible for inclusion (≥1 follow-up visit, lifetime history of injecting drugs, and HCV antibody/RNA negative at enrolment). The mean age was 26 years, 72% (n=229) were male, 33% (n=104) reported recent injecting drug use, 11% (n=35) reported greater than or equal to weekly injecting since entering prison, and 25% (n=81) reported syringe sharing during follow-up. 93 seroconversions were observed in the overall sample 815 person-years (py) of follow-up while 32 seroconversions were seen in the continuously imprisoned population (507 py of follow-up). HCV incidence was 11.4/100 p-yrs (95% CI: 9.3–14.0/100 p-yrs) in the overall sample and 6.3/100 p-yrs (95% CI: 4.5–8.9/100 p-yrs) among the continually imprisoned sample. A stable trend in incidence was observed over the study period (Figure 1). In adjusted analyses among the overall sample, greater than or equal to weekly injecting was independently associated with time to HCV seroconversion. In adjusted analyses among the continuously imprisoned population, syringe sharing was independently associated with time to HCV seroconversion.
Conclusions
This study demonstrates that current prevention strategies have failed to reduce the incidence of HCV in the Australian prison setting between 2005 and 2014. This study also highlights the need for clean injecting equipment in prison given that needle and syringe sharing was associated with HCV infection among continually imprisoned participants, irrespective of frequency of injecting or the type of drug injected. Prison remains a high risk environment for acquisition of HCV infection and highlights the need for improved harm reduction strategies including NSP and evaluation of interferon-free HCV treatment as prevention strategies in prisons.
Figure 2: Incidence density of HCV infection among participants in the HITS-p cohort by year of study enrolment in: A) the overall population; and B) those participants continually in prison during follow-up.
Funding Agencies
NHMRC
To determine the effectiveness and outcomes of minimally invasive parathyroidectomy.
Prospective, non-randomised, non-blinded trial.
Affiliated university teaching hospitals of the Northern Clinical ...School, University of Sydney, New South Wales, May 1998 to October 1999.
50 consecutive patients who underwent minimally invasive parathyroidectomy for primary hyperparathyroidism, and 150 consecutive patients undergoing open parathyroidectomy over the same period.
Minimally invasive parathyroidectomy was successfully completed and resulted in cure (normocalcaemia) in 42 of 50 patients (84%). Seven patients (14%) required conversion to an open procedure, all of which also resulted in normocalcaemia, giving an overall cure rate of 98%. One patient had persistent hyperparathyroidism after minimally invasive parathyroidectomy which was cured at subsequent open reoperation. Three patients had a temporary recurrent laryngeal nerve palsy. Open parathyroidectomy was successful in 147 of 150 patients (98%) at initial operation; one patient had a temporary recurrent laryngeal nerve palsy. Intraoperative measurement of parathyroid hormone levels by a quick technique in 23 of the patients (13 having minimally invasive and 10 open procedures) correctly identified the presence of multiple-gland disease.
Minimally invasive parathyroidectomy is a feasible procedure, although there are concerns about the complication rate.
Distant metastases are unusual occurrences at presentation and during the progression of epithelial ovarian cancer. There are no good clinical predictors of this phenomenon. Because p53 dysfunction ...is common in ovarian cancer, we chose to investigate whether specific types of mutations predicted a predisposition to distant metastasis. We hypothesized that the complete absence of intact p53 protein as seen with p53 null mutations may be associated with an enhanced tendency to develop distant metastatic disease. The complete coding sequence of 130 tumor DNA samples was screened for p53 mutations by single-strand conformational polymorphism analysis. Abnormal single-strand conformational polymorphism findings were correlated with the specific DNA sequence abnormalities and outcome. Ninety-four (72%) tumors carried p53 mutations. Sixty-two were missense mutations, and 32 were null mutations (6 nonsense mutations, 23 frameshift mutations, and 3 splice-site mutations). Twenty-eight patients were found to have distant metastases (pericardium, brain, parenchymal liver, spleen, or lung) either at presentation or during the course of their treatment. Distant metastases were nearly 8-fold more common in patients whose tumors carried a null mutation (66%) than in those with either missense mutations (8%) or wild-type p53 (8%; P<0.001). When a null mutation was present, 25% of the tumors were associated with distant metastases at initial diagnosis. No individual with wild-type p53 or a missense mutation in the tumor presented with distant metastasis. Tumors with null mutations were more likely to be associated with lymph node metastasis (P = 0.003), advanced stage (stage III/IV; P<0.001) and high grade (grade II/III; P<0.001), at presentation. These tumors progressed with distant metastases more swiftly than did tumors with either missense mutations (mean, 1.18 versus 2.71 years; P = 0.04) or wild-type p53 (3.57 years; P = 0.015). In contrast to the popular dogma, distant metastases in ovarian cancer do not necessarily result from prolonged treatment of disease. They may be predicted to occur early in the disease course due to a specific molecular genetic abnormality: null mutation of the p53 tumor suppressor gene. These findings need to be carefully considered when choosing between regional versus systemic treatment modalities.
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