Use of the Drospirenone-Only Contraceptive Pill in Adolescents with Endometriosis.

STUDY OBJECTIVE: To evaluate the efficacy and tolerability of a progestin-only pill containing 4 mg drospirenone (DRSP) as a hormonal therapy for the management of endometriosis-associated symptoms in adolescents and young adults. DESIGN: Retrospective cohort study. METHODS: A retrospective chart review was performed of all adolescents who were prescribed DRSP continuously (without placebo) for treatment of endometriosis at a single pediatric tertiary care center between 2019 and 2022. Electronic medical records were reviewed to obtain demographics and clinical characteristics of the patients. Measured outcomes included symptom resolution and medication discontinuation. The study was deemed IRB exempt. RESULTS: A total of 61 patients with endometriosis were prescribed DRSP during the study period, with a median age of 18.9 years (SD 2.3). The majority (97%) were laparoscopically confirmed to have endometriosis, and 85% had stage I disease. Before DRSP use, the most common medications trialed were norethindrone (57%) and norethindrone acetate (68%), and 56% had at least one medical contraindication to receiving estrogen-containing therapy. Of those with follow-up, 52% established an absence of bleeding/spotting, and 67% reported less pain at follow-up. One in 4 patients discontinued DRSP during the study period, most commonly due to breakthrough bleeding. CONCLUSION: DRSP is a well-tolerated and effective option for the treatment of endometriosis-associated symptoms in adolescents and young adults.

Association of Pubertal Blockade at Tanner 2/3 With Psychosocial Benefits in Transgender and Gender Diverse Youth at Hormone Readiness Assessment.

PURPOSE: Compare psychosocial function at the time of hormone readiness assessment for transgender and gender diverse (TGD) youth who received pubertal blockade to prevent a nonaffirming puberty with those who did not. METHODS: Retrospective cohort study of psychological assessment data from hormone readiness evaluations conducted at a multispecialty gender clinic. Participants include all TGD youth between the ages of 13 and 17 assessed for hormone readiness between 2017 and 2021. RESULTS: Our cohort consisted of 438 TGD youth, 40 who were prescribed pubertal blockade at Tanner stage 2 or 3, and 398 who had not. The blocker population was younger, more likely to be assigned male and affirming a female identity, and had a different racial/ethnic identity distribution. Having puberty blocked was associated with significantly lower T-scores on the Youth Self Report for internalizing problems (ß = -7.4, p < .001), anxiety problems (ß = -4.6, p = .003), depressive problems (ß = -6.5, p < .001), stress problems (ß = -4.0, p = .01), and total problems (ß = -4.9, p = .003). The blocker population was also significantly less likely to report any suicidal thoughts (odds ratio = 0.38, p = .05). With the exception of increased risk of suicidal thoughts, these associations remained significant when adjusted for gender. DISCUSSION: At the time of hormone readiness evaluation, TGD youth who received pubertal blockade at Tanner 2 or 3 were found to have less anxiety, depression, stress, total problems, internalizing difficulties, and suicidal ideation than TGD peers who had been through more of a nonaffirming puberty.

Race-shifting in the United States: Latinxs, Skin Tone, and Ethnoracial Alignments.

In the study, we engage the question of racial "fluidity" by examining patterns of ethnoracial identification in adolescence and, importantly, shifts in ethnoracial identification between adolescence and adulthood using two waves of data from a nationally representative, longitudinal study of adolescents who were in Grades 7 to 12 during the 1994 to 1995 school year. Our theoretical framework draws from social identity theory and brings together bodies of research in race and immigration to make a case for the importance of phenotype, ancestry, and sociocultural elements as potential mechanisms for patterns among Latinx youth, as shifts in ethnoracial identification are predominantly a Latinx phenomenon. The bulk of the findings suggest that both phenotype and immigration are important factors for ethnoracial self-identification among Latinx youth, as well as shifts in their ethnoracial identification in young adulthood. Given what we know about ethnoracial categorization and ascription, findings suggest that, overall, shifts in ethnoracial identification among Latinx youth are primarily about bringing their self-identification into alignment with how they think they tend to be (and most likely are) perceived by others, which we suggest represents a Sedimentation of the Color Line. We close by discussing the myriad implications of our findings for the U.S. racial order and the ongoing debate about how to "measure" the Latinx population.

Establishment and range expansion of Dermacentor variabilis in the northern Maritimes of Canada: Community participatory science documents establishment of an invasive tick species.

Tick populations are dependent on a complex interplay of abiotic and biotic influences, many of which are influenced by anthropic factors including climate change. Dermacentor variabilis, the wood tick or American dog tick, is a hardy tick species that feeds from a wide range of mammals and birds that can transmit pathogens of medical and agricultural importance. Significant range expansion across North America has been occurring over the past decades;this study documents northwards range expansion in the Canadian Maritime provinces. Tick recoveries from passive surveillance between 2012 and 2021 were examined to assess northward population expansion through Atlantic Canada. At the beginning of this period, D. variabilis was abundant in the most southerly province, Nova Scotia, but was not considered established in the province to the north, New Brunswick. During the 10-year span covered by this study, an increasing number of locally acquired ticks were recovered in discrete foci, suggesting small established or establishing populations in southern and coastal New Brunswick. The pattern of population establishment follows the climate-driven establishment pattern of Ixodes scapularis to some extent but there is also evidence of successful seeding of disjunct populations in areas identified as sub-optimal for tick populations. Dogs were the most common host from which these ticks were recovered, which raises the possibility of human activity, via movement of companion animals, having a significant role in establishing new populations of this species. Dermacentor variabilis is a vector of several pathogens of medical and agricultural importance but is not considered to be a competent vector for Borrelia burgdorferi, the etiological agent of Lyme disease; our molecular analysis of a subset of D. variabilis for both B. burgdorferi and B. miyamotoi did not confirm any with Borrelia. This study spans the initial establishment of this tick species and documents the pattern of introduction, providing a relatively unique opportunity to examine the first stages of range expansion of a tick species.

Disordered eating and considerations for the transgender community: a review of the literature and clinical guidance for assessment and treatment.

BACKGROUND: It has been well established that individuals who identify as lesbian, gay, bisexual, transgender, and queer are at increased risk for mental health pathology, including eating disorders/disordered eating behaviors (ED/DEB). However, less is understood about the unique experiences of transgender and gender diverse (TGD) people who struggle with ED/DEB. AIMS: The purpose of this literature review is to examine the literature regarding the unique risk factors for TGD individuals who experience ED/DEB through a lens informed by the minority stress model. Additionally, guidance around the assessment and clinical management of eating disorders for TGD individuals will be presented. RESULTS: TGD people are at increased risk for developing ED/DEB due to a number of factors including: gender dysphoria, minority stress, the desire to pass, and barriers to gender affirming care. CONCLUSION: While guidance around assessment and treatment of ED/DEB for TGD individuals is still limited, adhering to a gender affirmative care model is essential.

People who identify as lesbian, gay, bisexual, transgender, and queer (LGBTQ) are more likely to have mental health difficulties, including eating disorders/disordered eating behaviors (ED/DEB). Much of the existing literature has focused on LGBTQ populations and not on the unique experiences of transgender and gender diverse (TGD) people. This literature review seeks to examine the unique risk factors for TGD people who experience ED/DEB. The minority stress model is used to better understand these risk factors, which include gender dysphoria, minority stress, the desire to pass, and barriers to gender affirming care. Research offering guidance for assessing and treating ED/DEB with TGD people is still limited but it is clear that a gender affirmative care model provides robust support for this population.

Young Adult Patients with Testosterone Management Concerns after Gender-Affirming Hysterectomy and Bilateral Oophorectomy: A Case Series.

Many transgender and gender diverse adolescents and young adults will pursue hysterectomy for the purpose of gender affirmation. This procedure often includes bilateral salpingo-oophorectomy (BSO), which has potential implications for long-term health should individuals choose to stop, or lose access to, exogenous testosterone. Although most of these individuals intend to remain on testosterone indefinitely, not all do, and little information exists on such cases following bilateral oophorectomy to guide counseling and practice. This case series documents 3 individuals who had interruptions in their testosterone use after hysterectomy with BSO for reasons including external barriers, internal barriers, and concerns about side effects. Patients should be appropriately counseled on hysterectomy options as bilateral oophorectomy is not required in the absence of specific indications.

Cardiac Morbidity Following Chemoradiation in Stage III Non-small Cell Lung Cancer Patients: A Population-Based Cohort Study.

AIMS: To assess the risk of cardiac toxicity following radical radiotherapy in advanced lung cancer patients. MATERIALS AND METHODS: Patients with a diagnosis of stage III non-small cell lung cancer (NSCLC) receiving chemoradiotherapy were extracted from a population-based cohort in Ontario, Canada. The primary outcome of cardiac toxicity, defined as cardiac events or congestive heart failure, was assessed at 1 and 5 years following chemoradiotherapy. Secondary outcomes included overall survival, survival in relationship to post-treatment cardiac events and the effect of radiotherapy technique on cardiac toxicity. RESULTS: In total, 2031 NSCLC patients were included. The cumulative incidence of cardiac toxicity at 5 years was 20.3% (18.4-22.3). The median survival was 13.7 months in NSCLC patients who had a cardiac event post-chemoradiotherapy compared with 23.4 months in those who did not (P = 0.012). There was a trend towards increased cumulative cardiac toxicity (hazard ratio 3.37, P = 0.14) with three-dimensional conformal radiotherapy compared with intensity-modulated or volumetric arc radiotherapy techniques. CONCLUSION: The risk of cardiac events and congestive heart failure 5 years after radical thoracic radiotherapy appears high and survival is inferior at 1 year in those patients who experience a cardiac event post-treatment. More conformal radiotherapy techniques may help reduce cardiac toxicity. Further studies should investigate adaptive treatment planning and close monitoring and intervention in this high-risk group after chemoradiotherapy.

Comparison of transcriptome responses of the liver, tail fin, and olfactory epithelium of Rana [Lithobates] catesbeiana tadpoles disrupted by thyroid hormones and estrogen.

Thyroid hormones (THs) are important developmental regulators in vertebrates, including during the metamorphosis of a tadpole into a frog. Metamorphosis is a post-embryonic developmental period initiated by TH production in the tadpole thyroid gland. The two main bioactive forms of TH are L-thyroxine (T4) and 3,5,3'-triiodothyronine (T3); these hormones have overlapping but distinct mechanisms of action. Premetamorphic tadpoles are highly responsive to TH and can be induced to metamorphose through exogenous TH exposure, making them an important model for both the study of vertebrate TH signaling and endocrine disrupting chemicals (EDCs). It is important to differentiate TH-mediated responses from estrogenic responses in premetamorphic tadpoles when assessing dysregulation by EDCs as crosstalk between the two endocrine systems is well-documented. Herein, we compare the RNA-sequencing-derived transcriptomic profiles of three TH-responsive tissues (liver, olfactory epithelium, and tail fin) in premetamorphic bullfrog (Rana [Lithobates] catesbeiana) tadpoles exposed to T3, T4, and estradiol (E2). These profiles were generated using the latest available genome assembly for the species. The data indicate that there is a clear distinction, and little overlap, between the transcriptomic responses elicited by E2 and the THs. In contrast, within the THs, the T3- and T4-induced transcriptomic profiles generally show considerable overlap; however, the degree of overlap is highly tissue-dependent, illustrating the importance of distinguishing the two THs and the affected signaling pathways within the target tissue type when evaluating hormone active agents. The data herein also show that E2 and TH treatment can uniquely induce significant changes in expression of their respective "classic" bioindicator transcripts vtg (E2) and thra, thrb, and thibz (THs). However, care must be taken in the interpretation of increased vep or esr1 transcripts as a change in transcript levels can be induced by THs rather than solely E2.

Final results of the global and Asia cohorts of KAMILLA, a phase IIIB safety trial of trastuzumab emtansine in patients with HER2-positive advanced breast cancer.

BACKGROUND: KAMILLA is a single-arm safety study of trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC; NCT01702571). We report the final analysis of cohort 2 (Asia) within the context of published cohort 1 (Global) findings. METHODS: Patients had HER2-positive, locally advanced, or metastatic BC progressing after chemotherapy and anti-HER2 therapy or ≤6 months after adjuvant therapy. The primary objective was to further evaluate T-DM1 (3.6 mg/kg, administered intravenously every 3 weeks) safety/tolerability, including the following adverse events of primary interest (AEPIs): grade ≥3 AEPIs (hepatic events, allergic reactions, thrombocytopenia, hemorrhage events), all grade ≥3 treatment-related AEs, and all-grade pneumonitis. RESULTS: KAMILLA enrolled 2185 patients (cohort 1, n = 2003; cohort 2, n = 182) as of 31 July 2019. Of these, 2002 and 181 per cohort were treated and included in the safety population. Approximately 70% of patients had two or more previous treatment lines in the metastatic setting. Median T-DM1 exposure was 5.6 and 5.0 months per cohort; median follow-up was 20.6 and 15.1 months. The overall AEPI rate was higher in cohort 2 (93/181; 51.4%) versus cohort 1 (462/2002; 23.1%), mostly driven by a higher grade ≥3 thrombocytopenia rate in cohort 2. In cohort 2, grade ≥3 thrombocytopenia was not associated with grade ≥3 hemorrhagic events and most (128/138) fully resolved. Grade ≥3 treatment-related AEPI rates were 18.4% (cohort 1) and 48.6% (cohort 2), the latter mainly due to thrombocytopenia. Any-grade pneumonitis rates were 1.0% and 2.2%. No new safety signals were identified. Median (95% confidence interval) progression-free survival was 6.8 months (5.8-7.6 months) and 5.7 months (5.5-7.0 months) in cohorts 1 and 2, respectively; median overall survival was 27.2 months (25.5-28.7 months) and 29.5 months (21.1 months to non-estimable). In both cohorts, median progression-free survival and overall survival decreased with increasing prior therapy lines. CONCLUSIONS: Cohort 2 results aligned with previous findings in Asian patients, supporting the manageable safety profile and use of T-DM1 in advanced BC.

Using genomic prediction to detect microevolutionary change of a quantitative trait.

Detecting microevolutionary responses to natural selection by observing temporal changes in individual breeding values is challenging. The collection of suitable datasets can take many years and disentangling the contributions of the environment and genetics to phenotypic change is not trivial. Furthermore, pedigree-based methods of obtaining individual breeding values have known biases. Here, we apply a genomic prediction approach to estimate breeding values of adult weight in a 35-year dataset of Soay sheep (Ovis aries). Comparisons are made with a traditional pedigree-based approach. During the study period, adult body weight decreased, but the underlying genetic component of body weight increased, at a rate that is unlikely to be attributable to genetic drift. Thus cryptic microevolution of greater adult body weight has probably occurred. Genomic and pedigree-based approaches gave largely consistent results. Thus, using genomic prediction to study microevolution in wild populations can remove the requirement for pedigree data, potentially opening up new study systems for similar research.

Skin Tone and Perceived Discrimination: Health and Aging Beyond the Binary in NSHAP 2015.

OBJECTIVES: This paper introduces new measures of skin tone (self-reported) and perceived discrimination that are included in the third round of the National Social Life, Health, and Aging Project (NSHAP). We explain the rationale for these new measures, emphasizing, in particular, how they help researchers to conceptualize and measure the significance of race/ethnicity for health and aging beyond binary ethnoracial categories. METHOD: We describe new measures of skin tone and perceived discrimination for use in NSHAP 2015. We provide descriptive statistics on the distribution of skin tone (self-reported) by race/ethnicity. As a proof of concept, we use logistic and ordinary least squares regression analyses to examine the relationship between skin tone, perceived discrimination, and perceived stress among ethnoracial minorities. RESULTS: We find that there is significant variation in skin tone among non-White respondents in NSHAP 2015 (e.g., non-Hispanic Black and Latinx). We also find that skin tone (self-reported) is a significant predictor of the frequency of perceived discrimination and perceived stress among African American, but not Latinx respondents in NSHAP. DISCUSSION: The inclusion of new skin tone and discrimination measures in NSHAP 2015 provides a unique and novel opportunity for researchers to more deeply understand how race/ethnicity is connected to health and aging among ethnoracial minorities. Furthermore, it will enable analyses of how stress and perceived discrimination also affect patterns of health and aging among Whites against the backdrop of steadily increasing socioeconomic inequalities and shifting ethnoracial demographics in the United States.

ReIMAGINE: a prostate cancer research consortium with added value through its patient and public involvement and engagement.

BACKGROUND: ReIMAGINE aims to improve the current prostate specific antigen (PSA)/biopsy risk stratification for prostate cancer (PCa) and develop a new image-based method (with biomarkers) for diagnosing high/low risk PCa in men. ReIMAGINE's varied patient and public involvement (PPI) and engagement (PE) strategy maximises the impact of its scientific output by informing and shaping the different stages of research. AIMS: Through including the voice of patients and the public, the ReIMAGINE Consortium aims to translate these different perspectives into the design and implementation process. This will improve the overall quality of the research by: reflecting the needs and priorities of patients and the public, ensuring methods and procedures are feasible and appropriate ensuring information is relevant and accessible to those being recruited to the study identifying dissemination channels relevant to patients/the public and developing outputs that are accessible to a lay audience With support from our patient/user groups, the ReIMAGINE Consortium aims to improve our ability to derive prognostic information and allocate men to the most appropriate and effective therapies, using a novel image-based risk stratification with investigation of non-imaging biomarkers. FINDINGS: We have been working with patients and the public from initiation of the project to ensure that the research is relevant to men and their families. Our PPI Sub-Committee, led by a PCa patient, has been involved in our dissemination strategy, outreach activities, and study design recommendations. For example, the sub-committee have developed a variety of informative videos relevant and accessible to those being recruited, and organised multiple online research engagement events that are accessible to a lay audience. As quoted by one of the study participants, "the more we present the benefits and opportunities to patients and the public, the more research commitment we obtain, and the sooner critical clinical questions such as PCa diagnostics will be addressed".

One in eight men will be diagnosed with prostate cancer (PCa). Most will not die of it, but our ability to identify those men whose cancer poses the greatest threat to life has, thus far, been poor. Some men are diagnosed with small cancers which will never cause them a problem, some will have treatment which is unnecessary, others will have their cancers missed, and others will be misclassified as either having low risk cancer and will therefore miss out on the appropriate treatment, or told their cancer is high risk and have unnecessary treatment. Nowhere else in modern medicine are these errors of over-diagnosis, over-treatment, missed-diagnoses, and poor risk-stratification more common. The ReIMAGINE Consortium has been developed to undertake discoveries that will correct these four key errors in the PCa diagnostic pathway. We will investigate how to best identify which men have, or will develop, aggressive prostate cancer using imaging combined with advanced biomarker analyses of blood and urine (i.e., OMICs technologies such as whole genome sequencing, targeted sequencing (e.g.: = , methylation). We will achieve this by building on established partnerships between patients, advocacy organisations, clinicians, imaging experts, molecular biologists, methodologists, and a broad range of industrial partners.The Patient and Public Involvement (PPI) sub-committee is an integral part of the study workflow, contributing to study design and recruitment, results analysis, and dissemination. The committee, led by a funded PPI co-ordinator and a patient chair, have given invaluable insight into the study modifications due to COVID-19 restrictions.

Orientational Correlations in Active and Passive Nematic Defects.

We investigate the emergence of orientational order among +1/2 disclinations in active nematic liquid crystals. Using a combination of theoretical and experimental methods, we show that +1/2 disclinations have short-range antiferromagnetic alignment, as a consequence of the elastic torques originating from their polar structure. The presence of intermediate -1/2 disclinations, however, turns this interaction from antialigning to aligning at scales that are smaller than the typical distance between like-sign defects. No long-range orientational order is observed. Strikingly, these effects are insensitive to material properties and qualitatively similar to what is found for defects in passive nematic liquid crystals.

Laparoscopic and Robotic Surgery for Endometrial and Cervical Cancer.

Minimally invasive surgery (MIS) has many benefits, in the form of reduced postoperative morbidity, improved recovery and reduced inpatient stay. It is imperative, however, when new techniques are adopted, in the context of treating oncology patients, that the oncological efficacy and safety are established rigorously rather than assumed based on first principles. Here we have attempted to provide a comprehensive review of all the contentious and topical themes surrounding the use of MIS in the treatment of endometrial and cervix cancer following a thorough review of the literature. On the topic of endometrial cancer, we cover the role of laparoscopy in both early and advanced disease, together with the role and unique benefits of robotic surgery. The surgical challenge of patients with a raised body mass index and the frail and elderly are discussed and finally the role of sentinel lymph node assessment. For cervical cancer, the role of MIS for staging and primary treatment is covered, together with the interesting and highly specialist topics of fertility-sparing treatment, ovarian transposition and the live birth rate associated with this. We end with a discussion on the evidence surrounding the role of adjuvant hysterectomy following radical chemoradiation and pelvic exenteration for recurrent cervical cancer. MIS is the standard of care for endometrial cancer. The future of MIS for cervix cancer, however, remains uncertain. Current recommendations, based on the available evidence, are that the open approach should be considered the gold standard for the surgical management of early cervical cancer and that MIS should only be adopted in the context of research. Careful counselling of patients on the current evidence, discussing in detail the risks and benefits to enable them to make an informed choice, remains paramount.

Colorism and Physical Health: Evidence from a National Survey.

This study uses nationally representative data to extend a steadily growing body of research on the health consequences of skin color by comparatively examining the consequences of perceived ingroup and outgroup skin color discrimination (perceived colorism) for physical health among African Americans. Using a comprehensive set of measures of physical health, I find that perceived ingroup colorism is significantly associated with worse physical health outcomes among African Americans. Notably, the magnitude of ingroup colorism's associations with most of these outcomes rivals or even exceeds that of major lifetime discrimination, everyday discrimination, and perceived outgroup colorism. These findings compellingly suggest the inclusion of perceived colorism measures in future survey data collection efforts.

A systematic review of in vitro studies evaluating the inhibitory effects of polyphenol-rich fruit extracts on carbohydrate digestive enzymes activity: a focus on culinary fruits consumed in Europe.

Evidence shows that polyphenols can attenuate postprandial blood glucose responses to meals containing digestible carbohydrate. Polyphenol-rich plant extracts are emerging as potential ingredients in functional foods and/or beverages despite limited understanding of their physiological effects. Many studies have investigated the mechanisms of polyphenol-rich fruit extracts on inhibition of digestive enzymes. However, the evidence available has yet to be critically evaluated systematically. This report reviews the in vitro literature to quantify the effect of fruit polyphenol extracts on the activities of digestive carbohydrases. A systematic literature search was conducted using six science databases. Included studies, totaling 34 in number, were in vitro digestion models which quantified gut digestive enzyme(s) activity on starch digestion in the presence of fruit polyphenol extracts. Most studies assessed the effects of fruit extracts on either α-amylase (n = 30) or α-glucosidase (n = 30) activity. Studies were consistent overall in showing stronger inhibition of α-amylase compared to α-glucosidase by proanthocyanidin- and/or ellagitannin-rich fruit extracts. Recommendations are proposed for future reporting of this type of research to enable meaningful synthesis of the literature as a whole. Such knowledge could allow effective choices to be made for development of novel functional foods and beverages.

Linked fate and mental health among African Americans.

Linked fate, the feeling that what happens to one's group may indelibly shape one's own life, is variously conceptualized as an aspect of ethnoracial identity, expression of political solidarity, and/or sense of ethnoracial consciousness. In this study, I contend that, within the context of stigmatization, linked fate may also be compellingly conceptualized as an expression of collective threat and vulnerability with potential relevance for the mental health of African Americans, in particular. Nevertheless, existing research on race and mental health has remained silent on this issue, as linked fate has received little scholarly attention from researchers interested in mental health. Building on prior research on ethnoracial identity, stigmatization, and mental health among African Americans, I introduce linked fate as a neglected, yet important phenomenon among stigmatized minorities, which is deeply associated with ethnoracial identification and should also be considered when examining the consequences of ethnoracial identification on the mental health of African Americans. Using nationally-representative data and logistic regression, I find that linked fate not only fails to be health-protective but is significantly associated with poorer mental health among African Americans in the form of increased suffering from major depression, bipolar I, and anxiety disorders.

Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial☆.

BACKGROUND: Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. PATIENTS AND METHODS: KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post hoc, exploratory analysis. The main outcome measures were best overall response rate (complete response + partial response) and clinical benefit rate (complete response + partial response + stable disease lasting ≥6 months) by RECIST v1.1 criteria, progression-free survival, overall survival, and safety. RESULTS: Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the best overall response rate and clinical benefit rate were 21.4% [95% confidence interval (CI) 14.6-29.6] and 42.9% (95% CI 34.1-52.0), respectively. A reduction in the sum of the major diameters of BM ≥30% occurred in 42.9% (95% CI 34.1-52.0), including 49.3% (95% CI 36.9-61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median progression-free survival and overall survival were 5.5 (95% CI 5.3-5.6) months and 18.9 (95% CI 17.1-21.3) months, respectively. The adverse event profile was broadly similar in patients with and without baseline BM, although nervous system adverse events were more common in patients with [208 (52.3%)] versus without [701 (43.7%)] baseline BM. CONCLUSION: This exploratory analysis of patients with HER2-positive metastatic breast cancer and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01702571.

A Canadian cancer trials group phase IB study of durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) given concurrently or sequentially in patients with advanced, incurable solid malignancies.

Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.