Changes in the survival of adult patients with metastasized melanoma with the approval of immune checkpoint inhibitors: A retrospective study from the United States database

BackgroundImmune-checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic melanoma. Ipilimumab and Ipilimumab-Nivolumab combination therapies were approved by the United States Food and Drug Administration in 2011 and 2015, respectively. We aimed to evaluate potential changes in the survival of patients with metastatic melanoma following the approval of these agents.MethodsWe extracted data from the Surveillance, Epidemiology, and End Results (SEER) database (Nov 2021 submission). All patients aged 20 and above who were diagnosed with ‘distant’ melanoma (per ‘combined summary stage’) from 2007 through 2018 were included in the study. This time period was further sub-categorized into 2007–2010 (pre-ICI era), 2011–2014 (single-agent ICI era), and 2015–2018 (combination ICI era) based on the approval timeline of ICI.ResultsThe median overall survival (OS) was 8, 10, and 14 months in the pre-ICI, single-agent ICI, and combination ICI eras respectively (log-rank test, χ² = 189.03, p < 0.001). On Cox-proportional hazard analysis, patients diagnosed in the single-agent and combination ICI eras had a significantly lower risk of dying [HR 0.82 (95% CI 0.78–0.87) and 0.67 (0.64–0.71), respectively] compared to patients diagnosed in the pre-ICI era. Patients who were of the male gender, aged ≥ 65 years, and those receiving chemotherapy and/or radiotherapy were at a significantly higher risk of dying. Married individuals had a significantly lower risk of dying compared to patients who were divorced, separated, or widowed at the time of diagnosis. There was no significant difference in survival demonstrated among non-Hispanic blacks versus non-Hispanic whites.ConclusionSurvival of patients with metastatic melanoma has improved in the era of immune checkpoint inhibitors. It implies that the survival of patients reported in trials can be correlated at a population level as well. Future analysis from the SEER database is needed when new data becomes available to see if there is a further increase in OS.     

Clinical use of aromatase inhibitors (AI) in premenopausal women

Aromatase inhibitors (AI) block the last enzymatic step of estrogen production, the aromatization of the A-cycle of aromatizable androgens and particularly, androstenedione (Δ4) and testosterone (T). Molecules designed for interfering with aromatase activity have existed for many years. Yet the activity of products of the aminogluthetimide era was unspecific and these substances carried too many side effects for being used clinically. Newer third generation AIs, however, are highly specific and essentially devoid of side effects. These molecules have recently been approved for treating breast cancer in postmenopausal women either, in advanced forms or, as part of adjuvant therapy.

In women whose ovaries are active, a temporary inhibition of E2 production will raise gonadotropins and in turn, stimulate follicular growth. In cancer patients, this property precludes the use of AIs in women whose ovaries are still active, unless gonadotropins are blocked. But in infertility patients, this property of AIs has been put to play for inducing ovulation. AIs have been used both in women who do not ovulate but whose hypothalamo-pituitary-gonadal (HPG) axis is active (oligo-anovulators of PCOD type) and those who ovulate regularly but in whom multiple ovulation is sought for treating unexplained infertility or as part of IVF. Like clomiphene citrate (CC), AIs are not usable in women whose gonadotropins are suppressed, as in the case of hypothalamic amenorrhea.

The sum of data available on the use of AI for inducing ovulation remains however meager to this date and is mainly constituted of pilot and non-randomized trials. Yet mounting evidence tends to support AIs’ advantages over CC for induction of ovulation. Hence, we think that the likelihood that these drugs will play a key role in induction of ovulation in the future is high. AIs appear particularly interesting for treating unexplained infertility because AI-FSH/hMG regimens are lighter than FSH-only regimens while retaining the high pregnancy rates of these latter treatments.     

Characteristics of patients with lung cancer in clinical practice and their potential eligibility for clinical trials evaluating tyrosine kinase inhibitors or immune checkpoint inhibitors

IntroductionIn- and exclusion criteria of randomized clinical trials (RCTs) aim to include a homogeneous study-population. This study compared characteristics of lung cancer patients from phase III RCTs evaluating tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) with characteristics of lung cancer patients in a real world setting in the United Kingdom.MethodsA retrospective study was conducted using the Clinical Practice Research Datalink GOLD. Patients (N = 9239) with a first ever lung cancer registration between 2014 and 2018 were identified. Eligibility for inclusion was assessed for twelve RCTs (evaluating TKIs or ICIs). Reasons for potential exclusion and the number of unmet criteria were assessed for each RCT independently. OS was assessed using Kaplan-Meier and Cox proportional hazards analyses.ResultsThe proportion of potentially eligible patients was 74.3% and 51.9% for TKI and ICI RCTs, respectively. History of another malignancy, renal insufficiency or concomitant drug-use were main reasons for exclusion. OS was considerably longer for potentially eligible patients. Hazards ratios varied from 1.17 (95% confidence interval, 1.11–1.24) to 1.35 (1.20–1.42) across the RCTs.ConclusionThis study showed that a considerable proportion of lung cancer patients in a real-world setting would have been ineligible for participation in phase III RCTs and that potentially ineligible patients experienced a shorter OS.     

Aromatase inhibitors for therapy of advanced breast cancer

In postmenopausal women with advanced breast cancer, numerous phase III trials have been performed comparing the third-generation non-steroidal aromatase inhibitors (NS-AIs) anastrozole and letrozole and the steroidal AI (S-AI) exemestane in the “first-line” setting against tamoxifen and in the “second-line” setting against megestrol acetate. In both settings, the AIs were at least as efficacious or superior in some endpoints with a preferable toxicity profile including a lower incidence of thrombotic events. Relatively small differences in potency between the three AIs have been identified and it has not been demonstrated that these differences have clinical implications. The recent establishment of the value of AIs in the adjuvant setting for postmenopausal women will impact on their utilization in advanced disease. In premenopausal women the third-generation AIs have not been studied as monotherapy and there is a paucity of data in combination with ovarian function suppression in the advanced disease setting. The main area of future investigations for the AIs in premenopausal women will be in the adjuvant therapy setting in combination with suppression of ovarian function.     

Fracture Risk and Adjuvant Therapies in Young Breast Cancer Patients: A Population-Based Study

Background

Breast cancer survivors have an increased risk of bone fracture. But the risk among young patients with adjuvant therapies remains unknown. This population-based study is aimed to assess the incidence and risk of fracture among young (age of 20 to 39 years) breast cancer patients who received adjuvant therapies.

Methods

From January 2001 to December 2007, 5,146 newly diagnosed breast cancer patients were enrolled from the National Health Insurance Research Database (NHIRD) in Taiwan. Patients were observed for a maximum of 6 years to determine the incidence of newly onset fracture. Kaplan Meier and Cox regression analyses were used to evaluate the risk of fracture in young breast cancer patients who received adjuvant treatments.

Results

Of the total 5,146 young (age of 20 to 39 years) breast cancer patients, the Cox multivariate proportional hazards analysis showed that AIs, radiotherapy, and monoclonal antibodies were significantly associated with a high risk of fracture. Moreover, patients who received AIs for more than 180 days had a high hazard ratio (HR) of 1.77 (95% CI = 0.68–4.57), and patients who received more than four radiotherapy visits had a high HR of 2.54 (95% CI = 1.07–6.06). Under the site-specific analysis, young breast cancer patients who received AIs had the highest risk of hip fracture (HR = 8.520, 95% CI = 1.711–42.432, p < 0.04), whereas patients who received radiotherapy had the highest risk of vertebral fracture (HR = 5.512, 95% CI = 1.847–16.451, p < 0.01).

Conclusion

Young breast cancer patients who are receiving AIs, radiotherapy or monoclonal antibody need to be more careful for preventing fracture events. Breast cancer treatment plans are suggested to incorporate fracture prevention interventions.     

Use of phosphodiesterase-5 inhibitors and the incidence of melanoma

IntroductionRecent evidence of a causal link between Phosphodiesterase-5-inhibitor (PDE-5i) use and melanoma has caused concern in PDE-5i use and was even addressed in the 2018 American Urological Association guideline on erectile dysfunction (ED). Given that several studies have affirmed this low probability but statistically significant association, one might expect a shift in melanoma diagnoses since PDE-5is were introduced in 1998. We sought to determine if the introduction of PDE-5i drugs for ED treatment increased incidence of melanoma.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to compare the incidence of melanoma diagnosis in American men between 1973 and 2015, providing over a decade of data before and after PDE-5i introduction in 1998. Interrupted time-series and logistic regression were used to assess this relationship.ResultsOver 43 years, the SEER database has reported 292,166 cases of Melanoma, with males accounting for 53.7% of cases (Standard deviation [SD] 3%, Range 47.5–58.3%). After the introduction of PDE-5i, there was no proportional increase in melanoma diagnoses, in fact demonstrating a 2% lower incidence from prediction models (p < 0.05).ConclusionOur analysis of the SEER database demonstrates that the trend in incidence of melanoma has fallen in the era of PDE-5i use for ED. These findings may be of value in counseling patients anxious about the potential association between PDE-5i use and skin cancer; however, continued research analyzing individual-level risk are needed.     

New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

Background  

Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI), which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells.     

Are aromatase inhibitors superior to antiestrogens?

Aromatase inhibitors (AIs) have been in use to treat metastatic breast cancer for over 25 years. Recently potent and specific AIs have been introduced, which, because of their low toxicity profile, are being used in the adjuvant and neoadjuvant situation and also for the prevention of breast cancer. The two non-steroidal AIs, anastrozole and letrozole, and the steroidal AI, exemestane, have all shown superiority to tamoxifen as first-line treatment for advanced breast cancer. Interestingly, the oestrogen receptor downregulator, fulvestrant, was shown to be equivalent to anastrozole when compared as second-line therapy after the failure of tamoxifen. The first adjuvant AI trial began in 1996 and recruited over 9000 patients (ATAC trial). Anastrozole was compared with tamoxifen and a combination of the two drugs. There were no significant differences between tamoxifen and the combination. However, anastrozole showed about a 20% improvement in disease-free survival in ER+ disease compared with the other treatments. An overall survival analysis will be reported later this year. Two trials have compared 5 years of tamoxifen with 2–3 years of tamoxifen, followed by 2–3 years of AI (one trial (ITA) used anastrozole and another (intergroup) exemestane). Both trials show a disease-free advantage for the switch to AI. In another study (MA17) 5 years of tamoxifen was followed by a randomisation to letrozole or placebo and showed a significant disease-free advantage to the AI. Both letrozole and anastrozole show superiority to tamoxifen when used as a neoadjuvant therapy. Anastrozole significantly reduced contralateral breast cancer compared with tamoxifen, and this has led to two prevention trials: one in women at risk comparing anastrozole with placebo and the other after excision of DCIS comparing anastrozole with tamoxifen (IBIS II). The NCI Canada has also just initiated a trial of exemestane for prevention. Nearly all data available indicate that AIs are superior to tamoxifen. The important question is whether survival is improved when they are used as adjuvant therapy?     

Adjuvant trials of aromatase inhibitors: determining the future landscape of adjuvant endocrine therapy

This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant setting, and will summarize major strategies behind individual adjuvant trials using aromatase inhibitors. Studies with the third generation AIs including anastrozole, letrozole and exemestane, have shown better outcome and improved therapeutic ratio over second line hormonal approaches (i.e. progestins or aminoglutethimide) and, more recently, over tamoxifen also. These promising results have led recently to testing of AIs in the adjuvant setting for postmenopausal patients. Most trials now in progress are evaluating the role of new AIs versus tamoxifen (T) given×5 years, which in most institutions is currently the standard hormonal adjuvant therapy for breast cancer. Three adjuvant approaches are being tested. First is the use of AI+T×5 years in combination versus each agent alone, as reflected in the recently completed ATAC trial. Second is a sequential approach T first×2–3 years followed by AIs×2–3 years, or the other way round; and third, T×5 years followed by AIs for additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many patients in the above trials will survive their first cancer. Hence, the non-oncological outcomes known to be affected by hormones are of rising importance. Therefore, the assessment of lipids as surrogates for cardiovascular morbidity, and of bone mineral status, as a marker for osteoporosis/bone fractures, is an important component of these trials. Also discussed in this review are proposals for future studies of AIs with focus on hormone resistance, such as early alteration of multiple hormonal agents or their intermittent use, the impact of the new generation of SERMs or ‘pure’ antiestrogens on activity of AIs, and the rising importance of AIs interacting with biologicals, cytokines or hormone modulators.     

Cardiovascular risk factor reporting in immune checkpoint inhibitor trials: A systematic review

BackgroundImmune checkpoint inhibitors (ICI) have revolutionized the treatment of numerous cancers but are associated with increased risk of myocardial infarction. The prevalence of traditional cardiovascular risk factors (CVRF) in patients treated with ICIs is unknown. This study sought to describe the frequency of reporting of CVRFs among landmark ICI trials.MethodsA systematic review of all phase 2 or 3 cancer trials employing ICIs that led to United States Food and Drug Administration approval was conducted.ResultsOf the 69 identified trials, only one study reported baseline rates of hypertension, diabetes mellitus, and dyslipidemia. Smoking history was reported in 27 studies (39 %) and three (4 %) reported body mass index. No study reported history of previous cardiovascular disease, although 17 (25 %), six (9 %), and 21 (30 %) studies excluded patients with recent myocardial infarction, revascularization and heart failure respectively. Similarly low rates of cardiovascular risk factor reporting were observed in studies employing concurrent vascular endothelial growth factor inhibitors and recruiting (neo)adjuvant cohorts.ConclusionThe prevalence of CVRFs is poorly described in ICI trials despite increasingly reported risks of myocardial infarction. A systematic approach to collecting and reporting CVRFs should be considered in future trials and real world populations.     

Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature

ImportanceThe EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC.ObjectiveTo document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. Data sources: MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts.ResultsEGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81–1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69–0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87–1.09) and PFS HR 0.92 (95% CI 0.83–1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I² = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72–0.94) compared to capecitabine (HR 1.09; 95% CI 0.91–1.30) and bolus 5FU (HR 1.07; 95% CI 0.79–1.45); subgroup interaction was present with I² = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I² = 89.7%, p = 0.002).

Conclusion and Relevance

The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.     

Indications of Clinical and Genetic Predictors for Aromatase Inhibitors Related Musculoskeletal Adverse Events in Chinese Han Women with Breast Cancer

Background

Women with breast cancer treated with aromatase inhibitors (AIs) may experience musculoskeletal symptoms that lead to discontinuation of effective therapy. The purpose of the current study is to evaluate the clinical and genetic predictors for AIs-related musculoskeletal adverse events(MS-AEs).

Methodology and Principal Findings

We recruited 436 postmenopausal Chinese Han women receiving adjuvant AIs therapy for early-stage hormone-sensitive breast cancer. Patients completed a self-administered questionnaire assessing the presence of musculoskeletal symptoms that started or worsened after initiating AIs. 27 single nucleotide polymorphisms (SNP) of ESR1, ESR2 and PGR were analyzed by Sequenom MassARRAY assays and /or PCR-based TaqMan assays.Of the 436 enrolled women, 206 cases experienced musculoskeletal symptoms.Patients who received taxane chemotherapy were more than two times more likely than other patients to have AIs-related MS-AEs. Genetic assay had showed that only two ESR1 SNPs, rs2234693 and rs9340799 were associated with AIs-related MS-AEs.TT genotype and the T allele in rs2234693 was statistically significantly lower in AIs-Related MS-AEs group than controls (P = 0.001; P = 9.49E-7). The frequency of AA genotype and the A allele in rs9340799 was higher (P = 2.20E-5; P = 3.09E-4).

Conclusions and Significance

Our results suggested that prior taxane-based chemotherapy was the clinical predictor, while rs2234693 and rs9340799 were the genetic predictors for AIs-related MS-AEs.     

Heart rate variability as a marker of cardiovascular dysautonomia in post-COVID-19 syndrome using artificial intelligence

IntroductionCardiovascular dysautonomia comprising postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH) is one of the presentations in COVID-19 recovered subjects. We aim to determine the prevalence of cardiovascular dysautonomia in post COVID-19 patients and to evaluate an Artificial Intelligence (AI) model to identify time domain heart rate variability (HRV) measures most suitable for short term ECG in these subjects.MethodsThis observational study enrolled 92 recently COVID-19 recovered subjects who underwent measurement of heart rate and blood pressure response to standing up from supine position and a 12-lead ECG recording for 60 s period during supine paced breathing. Using feature extraction, ECG features including those of HRV (RMSSD and SDNN) were obtained. An AI model was constructed with ShAP AI interpretability to determine time domain HRV features representing post COVID-19 recovered state. In addition, 120 healthy volunteers were enrolled as controls.ResultsCardiovascular dysautonomia was present in 15.21% (OH:13.04%; POTS:2.17%). Patients with OH had significantly lower HRV and higher inflammatory markers. HRV (RMSSD) was significantly lower in post COVID-19 patients compared to healthy controls (13.9 ± 11.8 ms vs 19.9 ± 19.5 ms; P = 0.01) with inverse correlation between HRV and inflammatory markers. Multiple perceptron was best performing AI model with HRV(RMSSD) being the top time domain HRV feature distinguishing between COVID-19 recovered patients and healthy controls.ConclusionPresent study showed that cardiovascular dysautonomia is common in COVID-19 recovered subjects with a significantly lower HRV compared to healthy controls. The AI model was able to distinguish between COVID-19 recovered patients and healthy controls.     

Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update

There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2–3 years followed by exemestane or anastrozole for 2–3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy with an AI for 5 years is superior to sequencing an AI after 2–3 years of tamoxifen.The bone mineral density (BMD) should be measured at baseline and monitored during therapy in women being treated with AIs. Anti-osteoporosis agents should such as bisphosphonates should be considered in patients at high risk of bone fractures.     

Aromatase, aromatase inhibitors, and breast cancer

Estrogens are known to be important in the growth of breast cancers in both pre and postmenopausal women. As the number of breast cancer patients increases with age, the majority of breast cancer patients are postmenopausal women. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. As aromatase catalyzes the final and rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme are effective targeted therapy for breast cancer. Three aromatase inhibitors (AIs) are now FDA approved and have been shown to be more effective than the antiestrogen tamoxifen and are well tolerated. AIs are now a standard treatment for postmenopausal patients. AIs are effective in adjuvant and first-line metastatic setting. This review describes the development of AIs and their current use in breast cancer. Recent research focuses on elucidating mechanisms of acquired resistance that may develop in some patients with long term AI treatment and also in innate resistance. Preclinical data in resistance models demonstrated that the crosstalk between ER and other signaling pathways particularly MAPK and PI3K/Akt is an important resistant mechanism. Blockade of these other signaling pathways is an attractive strategy to circumvent the resistance to AI therapy in breast cancer. Several clinical trials are ongoing to evaluate the role of these novel targeted therapies to reverse resistance to AIs. Article from the special issue on 'Targeted Inhibitors'.     

Current medical treatment of estrogen receptor-positive breast cancer

Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of(1) ovarian function suppression(OFS), usually obtained using gonadotropinreleasing hormone agonists(Gn RHa);(2) selective estrogen receptor modulators or down-regulators(SERMs or SERDs); and(3) aromatase inhibitors(AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs(i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs(i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs(i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors(palbociclib) and mammalian target of rapamycin(m TOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.     

Reproductive consequences of a reciprocal chromosomal translocation in two Duroc boars used to provide semen for artificial insemination

Cytogenetic analysis of 58 boars at an artificial insemination (AI) centre revealed the presence of a reciprocal chromosome translocation, rcp(1;11)(q−;p+), in two Duroc boars. Pedigree analysis of these two boars suggested familial transmission of the chromosome rearrangement. The reproductive consequences of this translocation were determined in a herd of sows that had received semen doses from these and other boars. All sows underwent multiple AI, with different groups established retrospectively depending on the percentage of semen doses provided by the carrier boars ([number of carrier boar doses/total number doses provided] x 100): 0%, 25%, 50%, 75%, 100%. The fertility rates (percentage of successful multiple AIs/total multiple AIs) recorded for multiple AI including semen doses from the carrier boars were not significantly different from those recorded when all semen doses were supplied by normal-karyotype boars. A reduction in litter size of 29.38% was observed, however, in litters sired by one of the carrier boars when its participation in multiple AI was 100%. The number of live-born piglets per litter gradually decreased (P < 0.05) as the percentage participation in multiple AI (25, 50, or 75%) of the carrier boar increased. In addition, both carrier boars sired some piglets with signs of cleft palate and complex malformations of the front legs; these died soon after birth. In conclusion, the boars carrying the translocation rcp(1;11)(q−;p+) showed reduced reproductive performance.     

Risk of Breast Cancer in Females With Hypothyroidism: A Nationwide,Population-Based,Cohort Study

ObjectivesThe results of studies investigating the relationship between breast cancer and hypothyroidism vary greatly from study to study. In this study, we analyzed a large and reliable, population-based database to gain a better understanding of the correlation.MethodsThis retrospective cohort study analyzed patients with hypothyroidism between January 1, 2000 and December 31, 2012 (hypothyroidism cohort) from the Longitudinal Health Insurance Database 2000 in Taiwan. For each woman with hypothyroidism, 1 woman without a history of breast cancer was randomly selected from the Longitudinal Health Insurance Database 2000 and frequency matched (1:4) with women without hypothyroidism by age and index year of hypothyroidism. The study outcome was the diagnosis of breast cancer during a 12-year follow-up period.ResultsIn this study, 6665 women with hypothyroidism and 26 660 women without hypothyroidism were identified. The hypothyroidism cohort had a significantly higher risk of breast cancer than the nonhypothyroidism cohort (adjusted hazard ratio [aHR] 1.69 [95% CI, 1.15-2.49]; P = .01), especially in the group aged 40 to 64 years (aHR 2.07 [95% CI, 1.32-3.23]; P = .01). Women in the hypothyroidism cohort taking levothyroxine for a duration ˃588 days showed a significantly decreased risk of breast cancer (aHR 0.37 [95% CI, 0.19-0.71]; P = .003).ConclusionWomen with hypothyroidism are at a higher risk of breast cancer than those without hypothyroidism. Levothyroxine may reduce the risk of breast cancer in a woman with hypothyroidism.     

Cancer risk and all-cause mortality among Norwegian military United Nations peacekeepers deployed to Kosovo between 1999 and 2011

ObjectiveMedia reports of leukaemia and other cancers among European United Nations (UN) peacekeepers who served in the Balkans, and a scientific finding of excess Hodgkin lymphoma among Italian UN peacekeepers who served in Bosnia, suggested a link between cancer incidence and depleted uranium (DU) exposure. This spurred several studies on cancer risk among UN peacekeepers who served in the Balkans. Although these studies turned out to be negative, the debate about possible cancers and other health risks caused by DU exposure continues. The aim of the present study was to investigate cancer incidence and all-cause mortality in a cohort of 6076 (4.4% women) Norwegian military UN peacekeepers deployed to Kosovo between 1999 and 2011.MethodsThe cohort was followed for cancer incidence and mortality from 1999 to 2011. Standardised incidence ratios for cancer (SIR) and mortality ratios (SMR) were calculated from national rates.ResultsSixty-nine cancer cases and 38 deaths were observed during follow-up. Cancer incidence in the cohort was similar to that in the general Norwegian population. No cancers in the overall cohort significantly exceeded incidence rates in the general Norwegian population, but there was an elevated SIR for melanoma of skin in men of 1.90 (95% confidence interval [CI] 0.95–3.40). A fivefold increased incidence of bladder cancer was observed among men who served in Kosovo for ≥1 year, based on 2 excess cases (SIR = 5.27; 95% CI 1.09–15.4). All-cause mortality was half the expected rate (SMR = 0.49; 95% CI 0.35–0.67).ConclusionOur study did not support the suggestion that UN peacekeeping service in Kosovo is associated with increased cancer risk.     

Detrimental effects of melanocortin‐1 receptor (MC1R) variants on the clinical outcomes of BRAF V600 metastatic melanoma patients treated with BRAF inhibitors

Melanocortin‐1 receptor (MC1R) plays a key role in skin pigmentation, and its variants are linked with a higher melanoma risk. The influence of MC1R variants on the outcomes of patients with metastatic melanoma (MM) treated with BRAF inhibitors (BRAFi) is unknown. We studied the MC1R status in a cohort of 53 consecutive BRAF‐mutated patients with MM treated with BRAFi. We also evaluated the effect of vemurafenib in four ^V600BRAF melanoma cell lines with/without MC1R variants. We found a significant correlation between the presence of MC1R variants and worse outcomes in terms of both overall response rate (ORR; 59% versus 95%, P = 0.011 univariate, P = 0.028 multivariate analysis) and progression‐free survival (PFS) shorter than 6 months (72% versus 33%, P = 0.012 univariate, P = 0.027 multivariate analysis). No difference in overall survival (OS) was reported, probably due to subsequent treatments. Data in vitro showed a significant different phosphorylation of Erk1/2 and p38 MAPK during treatment, associated with a greater increase in vemurafenib IC50 in MC1R variant cell lines.