Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01).

BACKGROUND: Primary analysis of the multicenter, open-label, single-arm, phase II DESTINY-Breast01 trial (median follow-up 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with a median follow-up of 26.5 months (data cut-off 26 March 2021). PATIENTS AND METHODS: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included overall survival (OS), duration of response (DoR), progression-free survival (PFS), and safety. RESULTS: The ORR by ICR was 62.0% [95% confidence interval (CI) 54.5% to 69.0%] in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median OS was 29.1 months (95% CI 24.6-36.1 months). Median PFS and DoR were 19.4 months (95% CI 14.1-25.0 months) and 18.2 months (95% CI 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had one or more grade ≥3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5. CONCLUSIONS: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC.

The effectiveness of fascial closure with antimicrobial-coated sutures in preventing incisional surgical site infections in gastrointestinal surgery: a systematic review and meta-analysis.

The aim of this study was to conduct a systematic review and meta-analysis of the efficacy of fascial closure using antimicrobial-sutures specifically for the prevention of surgical site infections (SSIs) in gastrointestinal surgery, as part of the revision of the SSI prevention guidelines of the Japanese Society of Surgical Infectious Diseases (JSSI). We searched CENTRAL, PubMed and ICHUSHI-Web in May 2023, and included randomized controlled trials (RCTs) comparing antimicrobial-coated and non-coated sutures for fascial closure in gastrointestinal surgery (PROSPERO No. CRD42023430377). Three authors independently screened the RCTs. We assessed the risk of bias and the GRADE criteria for the extracted data. The primary outcome was incisional SSI and the secondary outcomes were abdominal wall dehiscence and the length of postoperative hospital stay. This study was supported partially by the JSSI. A total of 10 RCTs and 5396 patients were included. The use of antimicrobial-coated sutures significantly lowered the risk of incisional SSIs compared with non-coated suture (risk ratio: 0.79, 95% confidence intervals: 0.64-0.98). In subgroup analyses, antimicrobial-coated sutures reduced the risk of SSIs for open surgeries, and when monofilament sutures were used. Antimicrobial-coated sutures did not reduce the incidence of abdominal wall dehiscence and the length of hospital stay compared with non-coated sutures. The certainty of the evidence was rated as moderate according to the GRADE criteria, because of risk of bias. In conclusion, the use of antimicrobial-coated sutures for fascial closure in gastrointestinal surgery is associated with a significantly lower risk of SSI than non-coated sutures.

Quantitative measurement of airborne particles during endoscopic and microscopic ear surgery in the operating room.

OBJECTIVE: This study aimed to quantitatively investigate airborne particle load in the operating room during endoscopic or microscopic epitympanectomy or mastoidectomy. METHOD: In the transcanal endoscopic ear surgery group, drilling was performed underwater. A particle counter was used to measure the particle load before, during and after drilling during transcanal endoscopic ear surgery or microscopic ear surgery. The device counted the numbers of airborne particles of 0.3, 0.5 or 1.0 µm in diameter. RESULTS: The particle load during drilling was significantly higher in the microscopic ear surgery group (n = 5) than in the transcanal endoscopic ear surgery group (n = 11) for all particle sizes (p < 0.01). In the transcanal endoscopic ear surgery group, no significant differences among the particle load observed before, during and after drilling were seen for any of the particle sizes. CONCLUSION: Bone dissection carries a lower risk of airborne infection if it is performed using the endoscopic underwater drilling technique.

Comparison of clinical outcomes of osimertinib and first-generation EGFR-tyrosine kinase inhibitors (TKIs) in TKI-untreated EGFR-mutated non-small-cell lung cancer with leptomeningeal metastases.

BACKGROUND: Leptomeningeal metastases (LM) are devastating complications of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Although osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI), has better penetration into the central nervous system than first-generation EGFR-TKIs, data on the distinct activity of EGFR-TKIs in untreated advanced EGFR-mutated NSCLC with LM are lacking. PATIENTS AND METHODS: We retrospectively reviewed patients treated with EGFR-TKIs for TKI-untreated common EGFR-mutated NSCLC with LM between July 2002 and July 2021 at the National Cancer Center Hospital. The patients were divided into two groups: patients treated with osimertinib (Osi group) and those treated with gefitinib or erlotinib [first-generation (1G)-TKI group]. RESULTS: Of the 967 patients, 71 were eligible, including 29 in the Osi group and 42 in the 1G-TKI group. The median progression-free survival (PFS) and overall survival (OS) in the Osi group were better than those in the 1G-TKI group (PFS: 16.9 months versus 8.6 months, P = 0.007, and OS: 26.6 months versus 20.0 months, P = 0.158). The LM-overall response rate (ORR) and LM-PFS were significantly better in the Osi group than in the 1G-TKI group (LM-ORR: 62.5% versus 25.7%, P = 0.007; LM-PFS: 23.4 months versus 12.1 months, P = 0.021). In the subgroup analysis of EGFR mutation status, LM-PFS for patients with exon 19 deletion was significantly longer in the Osi group than in the 1G-TKI group (32.7 months versus 13.4 months, P = 0.013), whereas those with L858R mutation in exon 21 did not differ between the two groups. In the multivariate analysis, osimertinib and exon 19 deletion were significant factors for better LM-PFS and OS. CONCLUSION: Osimertinib can be more effective for untreated common EGFR-mutated NSCLC patients with LM, especially those with exon 19 deletion, compared to first-generation TKIs.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.

Muscular Echo-Intensity of the Quadriceps by Ultrasound Is More Related to Improvement of Gait Independence than Muscle Thickness in Older Inpatients.

OBJECTIVES: This study aimed to examine whether the decrease in muscular echo-intensity of the quadriceps by ultrasound in older inpatients is related to the improvement of gait independence than the increase of muscle thickness. DESIGN: Longitudinal study. SETTING: Hospital-based study. PARTICIPANTS: This study included 171 inpatients aged ≥ 65 years (median age: 84.0 [77.0-88.0], 56.1% female). Patients who were able to walk independently at hospital admission were excluded from the study. MEASUREMENTS: Improvement of gait independence during hospital stay was assessed using the change in Functional Independence Measure (FIM) gait score (i.e., FIM gait score at hospital discharge minus FIM gait score at hospital admission) and FIM gait score at hospital discharge. Muscular echo-intensity and muscle thickness of the quadriceps were assessed at hospital admission and discharge using ultrasound images, respectively. Muscular echo-intensity has been shown to be mainly related to intramuscular adipose tissue. Multiple linear regression analysis was performed to identify the factors independently associated with the change in FIM gait score and FIM gait score at discharge. RESULTS: Change in quadriceps echo-intensity was independently and significantly associated with the change in FIM gait score (ß = -0.22, p = 0.017) and FIM gait score at hospital discharge (ß = -0.21, p = 0.017). In contrast, change in quadriceps thickness was not independently and significantly associated with the change in FIM gait score (ß = 0.16, p = 0.050) and FIM gait score at hospital discharge (ß = 0.15, p = 0.050). CONCLUSIONS: Our study indicates that a decrease in muscular echo-intensity of the quadriceps by ultrasound is more related to the improvement of gait independence than an increase of muscle thickness in older inpatients. Intervention for intramuscular adipose tissue of the quadriceps may be important for improving gait independence in older inpatients.

Transarterial chemoembolisation for palliative treatment of renal cell carcinoma in two dogs with pulmonary metastasis.

Two dogs with anorexia and rapid weight loss were referred to our hospital due to a right renal mass and several pulmonary nodules. Both dogs underwent needle core biopsy of the mass, followed by transarterial chemoembolisation of the renal mass. A catheter was inserted from the femoral artery and advanced into the right renal artery. A suspension of carboplatin (100 mg/m2 ) and equivalent lipiodol was administered via the inserted multipurpose catheter. Immediately after, under fluoroscopic guidance, pulse injections of small amounts of gelatin particles (diameter 1 mm) dissolved in iohexol were administered until complete embolisation of the renal artery. Histopathologic diagnosis was renal cell carcinoma in both dogs. Clinical signs improved for 134 and 358 days after transarterial chemoembolisation. In addition, postoperative radiographs demonstrated a decrease in the tumour size. The dogs died 215 and 525 days after the initial evaluation, respectively. As a palliative treatment, transarterial chemoembolisation might help reduce the tumour volume and improve the quality of life in dogs with renal cell carcinoma and distant metastases.

Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial.

BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). CONCLUSIONS: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

Higher Body Mass Index in Hospitalized Older Patients Is Related to Higher Muscle Quality.

OBJECTIVES: This study aimed to examine the relationship between muscle mass, intramuscular adipose tissue, and body mass index (BMI) in older inpatients. DESIGN: Cross-sectional study. SETTING: Hospital-based study. PARTICIPANTS: This study included 413 inpatients aged ≥ 65 years (186 men and 227 women). MEASUREMENTS: Muscle mass and intramuscular adipose tissue of the quadriceps were assessed by measuring the muscle thickness and echo intensity on ultrasound images. To examine the relationship between quadriceps thickness and echo intensity and BMI in total participants and each sex, the Kendall rank correlation coefficient was used. Multiple regression analysis was performed to examine whether BMI was independently and significantly related to the quadriceps thickness and echo intensity, even after adjusting for other variables for total participants and each sex. The independent variables in multiple regression analyses were BMI, age, disease, days from onset disease. RESULTS: The results of the correlation analyses showed that BMI was significantly related to the quadriceps thickness (total participants, τ = 0.431; men, τ = 0.491; women, τ = 0.388) and echo intensity (total participants, τ = -0.239; men, τ = -0.318; women, τ = -0.188). In the multiple regression analysis, BMI was independently and significantly associated with the quadriceps thickness (total participants, ß = 0.535; men, ß = 0.548; women, ß = 0.519) and echo intensity (total participants, ß = -0.287; men, ß = -0.398; women, ß = -0.210). CONCLUSION: This study indicated that older inpatients with a higher BMI have greater muscle mass and less intramuscular adipose tissue of the quadriceps. These results suggested that a higher BMI in older inpatients is related to higher quadriceps muscle quality.

Generation of nonlinearity in the electrical response of yeast suspensions.

The mechanism through which nonlinearity is generated in the response waveform of the electric current obtained by applying alternating current voltage to yeast suspension has not yet been elucidated. In this paper, we showed that the response waveform depends on the applied voltage and frequency. The results showed that distortion (nonlinearity) in the waveform increases as the applied voltage increases and/or the frequency decreases. We suggest a model for the generation of nonlinearity based on the influx of potassium ions into the cell via potassium ion channels and transporters in the membrane due to the applied voltage. Furthermore, we validated this model by simulating an electrical circuit.

Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

Endometrial epithelial-mesenchymal transition (EMT) by menstruation-related inflammatory factors during hypoxia.

Endometriosis is characterised by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal haemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, hypoxia is a well-known inducer of fibrosis that may be associated with epithelial-mesenchymal transition (EMT). However, the complex molecular interactions between hypoxia and proinflammatory menstruation-related factors, PGE2 and thrombin, a PAR1 agonist, on EMT in endometriosis have not been fully characterised. To explore the effects of hypoxia and proinflammatory factors on EMT-like changes in endometrial cells, we determined the effects of PGE2 and thrombin (P/T) on EMT marker expression and cell migration in three dimensional cultured human endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Treatment of EECs with P/T under hypoxia stimulated cell migration, increased the expression of mesenchymal N-cadherin, vimentin and C-X-C chemokine receptor type 4 (CXCR4), and reduced the expression of epithelial E-cadherin. Furthermore, treatment with C-X-C motif chemokine ligand 12 (CXCL12), a ligand for CXCR4, increased EMT marker expression and cell migration. In ESCs, P/T or oestrogen treatment under hypoxic conditions increased the expression and secretion of CXCL12. Taken together, our data show that hypoxic and proinflammatory stimuli induce EMT, cell migration and inflammation in EECs, which was increased by CXCL12 derived from ESCs. These data imply that inflammatory mediators in retrograde menstrual fluid contribute to ectopic endometrial EMT and migration in the presence of peritoneal hypoxia.

Children's behavioural problems and its associations with socioeconomic position and early parenting environment: findings from the UK Millennium Cohort Study.

AIMS: To investigate behavioural problems throughout childhood and adolescent, and its relationship with socioeconomic position (SEP) and early parenting environment. METHODS: Using data from the Millennium Cohort Study conducted in the UK, behavioural problems of 14 452 children were analysed using a growth curve model. The children were followed from birth to adolescence, and their behavioural problems were measured by the Strengths and Difficulties Questionnaire (SDQ). The SDQ was sub-scaled into externalising and internalising problems. After assessing the general trajectory of children's behavioural problems, variables representing SEP and parenting environments were introduced to the model to analyse the association with children's outcomes. RESULTS: Overall, children's trajectories in externalising problems showed a decreasing trend while internalising problems increased as they aged. Household income and maternal education in early childhood were independently associated with children's behavioural problems, while the association for maternal occupation was significantly weaker. Positive early parenting environments attenuated the association between SEP and children's behavioural problems. Also, with regards to children's behavioural problems, positive parenting explained more variance between children compared to SEP. Favourable parent-child relationship buffered the income gradient in children's behavioural problems during early childhood, and although this buffering effect did not last until adolescence, those who had good parent-child relationships developed better outcomes regardless of their SEP. CONCLUSIONS: The results of the study emphasise the importance of a positive early parenting environment for improving and reducing the socioeconomic gap in children's behavioural problems and encourages policies to promote better parenting circumstances.

Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Visualization and quantification of anastomotic perfusion in colorectal surgery using near-infrared fluorescence.

BACKGROUND: Anastomotic leakage (AL) is one of the most troublesome complications in colorectal surgery. Recently, near-infrared fluorescence (NIRF) imaging has been used intraoperatively to detect sentinel lymph nodes and visualize the blood supply at the region of interest (ROI). The aim of this study was to evaluate the role of visualization and quantification of bowel perfusion around the anastomosis using NIRF system in predicting AL. METHODS: A prospective study was conducted on patients who had laparoscopic surgery for colorectal cancer at our institution. Perfusion of the anastomosis was evaluated with NIRF imaging after intravenous injection of indocyanine green (ICG). The time course of fluorescence intensity was recorded by an imaging analyzer We measured the time from ICG injection to the beginning of fluorescence (T0), maximum intensity (Imax), time to reach Imax (Tmax), time to reach Imax 50% ([Formula: see text]) and slope (S) after the anastomosis. RESULTS: Tumor locations were as follows; cecum: 2, ascending colon: 2, transverse colon: 7, descending colon: 1, sigmoid colon: 2, rectosigmoid colon: 3 and rectum: 6 (one case with synchronous cancer). All operations were performed laparoscopically. Four patients were diagnosed with or suspected to have AL (2 patients with grade B anastomotic leakage after low anterior resection, 1 patient with minor leakage in transverse colon resection and 1 patient needing re-anastomosis intraoperatively in transverse colon resection). T0 was significantly longer in the AL group than in patients without AL (64.3 ± 27.6 and 18.2 ± 6.6 s, p = 2.2 × 10-3). CONCLUSIONS: Perfusion of the anastomosis could be successfully visualized and quantified using NIRF imaging with ICG. T0 might be a useful parameter for prediction of AL.

Femoral morphology asymmetry in hip dysplasia makes radiological leg length measurement inaccurate.

AIMS: The aim of this study was to examine whether hips with unilateral osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH) have significant asymmetry in femoral length, and to determine potential related factors. PATIENTS AND METHODS: We enrolled 90 patients (82 female, eight male) with DDH showing unilateral OA changes, and 43 healthy volunteers (26 female, 17 male) as controls. The mean age was 61.8 years (39 to 93) for the DDH groups, and 71.2 years (57 to 84) for the control group. Using a CT-based coordinate measurement system, we evaluated the following vertical distances: top of the greater trochanter to the knee centre (femoral length GT), most medial prominence of the lesser trochanter to the knee centre (femoral length LT), and top of the greater trochanter to the medial prominence of the lesser trochanter (intertrochanteric distance), along with assessments of femoral neck anteversion and neck shaft angle. RESULTS: The percentages of hips with an absolute difference of > 5 mm in femoral GT and LT lengths were significantly larger in the DDH group (24% for both) compared with those of the control group (2% and 7%, respectively). The femoral length GT of the affected femur was significantly shorter in Crowe I and longer in Crowe IV than that of the unaffected side. The affected-to-unaffected difference of the intertrochanteric distance showed positive correlation with that of the femoral length GT in Crowe I and Crowe II/III, and negative correlation with that of the femoral length LT in the Crowe I and Crowe IV groups. CONCLUSION: Hips with unilateral end-stage OA secondary to DDH show significant asymmetry in femoral length between both the greater and lesser trochanter and the knee compared with controls. The intertrochanteric distance was a morphological factor related to femoral-length asymmetry. When undertaking total hip arthroplasty (THA) in the presence of DDH, long leg radiographs or CT measurements should be used to assess true leg-length discrepancy. Cite this article: Bone Joint J 2019;101-B:297-302.

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.

Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study.

BACKGROUND: Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. RESULTS: All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9-34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0-2.2), and median overall survival was 18.0 months (95% CI 12.9-23.0). CONCLUSIONS: Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.

Canine squamous cell carcinoma cell lines with high expression of survivin are sensitive to survivin inhibitor YM155.

Treatment of unresectable canine squamous cell carcinoma (SCC) remains challenging and new therapeutic strategies are needed. Survivin is a member of the inhibitor of apoptosis protein family and its inhibitor, YM155, is a potential anti-tumour agent. In the present study, 10 canine tumour cell lines (representing eight different tumour types) were screened for sensitivity to YM155; the drug potently inhibited the growth of the HAPPY SCC cell line. The growth inhibitory properties of YM155 were then examined in more detail using a panel of seven SCC cell lines. YM155 inhibited the growth of the cell lines HAPPY and SQ4; in contrast to the other lines in the panel, these two cell lines had high levels of expression of survivin. In HAPPY cells, YM155 inhibited expression of the survivin gene at the transcriptional level. In contrast, YM155 down-regulated survivin at the post-transcriptional level in SQ4 cells. YM155 suppressed cell growth in HAPPY cells, mostly via induction of apoptosis, but this was not the case in SQ4 cells. Two canine SCC cell lines with high cellular expression of survivin were sensitive to YM155. The possible underlying mechanisms of the cytotoxic effect of YM155 in these cell lines were different. One cell line had down-regulation of survivin mRNA and protein expression, associated with induction of apoptotic cell death. The other cell line had post-transcriptional down-regulation of survivin expression and subsequent induction of non-apoptotic cell death. Targeting survivin with YM155 is a potential approach for the treatment of canine SCCs with high expression of survivin.