Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of ...three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies.
Patients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts.
Of 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab).
In this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.
We investigated the magnetoterahertz response of the Dirac semimetal Cd3As2 and observed a particularly low frequency optical phonon as well as a very prominent and field-sensitive cyclotron ...resonance. As the cyclotron frequency is tuned with the field to pass through the phonon, the phonon becomes circularly polarized, as shown by a notable splitting in its response to right- and left-hand polarized light. This splitting can be expressed as an effective phonon magnetic moment that is approximately 2.7 times the Bohr magneton, which is almost 4 orders of magnitude larger than ab initio calculations predict for phonon magnetic moments in nonmagnetic insulators. This exceedingly large value is due to the coupling of the phonons to the cyclotron motion and is controlled directly by the electron–phonon coupling constant. This field-tunable circular-polarization-selective coupling provides new functionality for nonlinear optics to create light-induced topological phases in Dirac semimetals.
The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus ...letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.
A total of 668 postmenopausal women with HR+, HER2– recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point.
At the time of the second interim analysis, the median duration of follow-up was 26.4months. Median PFS was 25.3months 95% confidence interval (CI) 23.0–30.3 for ribociclib plus letrozole and 16.0months (95% CI 13.4–18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457–0.704; log-rank P=9.63×10−8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517–1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.
The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.
NCT01958021
The enhancement of the functional properties of materials at reduced dimensions is crucial for continuous advancements in nanoelectronic applications. Here, we report that the scale reduction leads ...to the emergence of an important functional property, ferroelectricity, challenging the long-standing notion that ferroelectricity is inevitably suppressed at the scale of a few nanometers. A combination of theoretical calculations, electrical measurements, and structural analyses provides evidence of room-temperature ferroelectricity in strain-free epitaxial nanometer-thick films of otherwise nonferroelectric strontium titanate (SrTiO3). We show that electrically induced alignment of naturally existing polar nanoregions is responsible for the appearance of a stable net ferroelectric polarization in these films. This finding can be useful for the development of low-dimensional material systems with enhanced functional properties relevant to emerging nanoelectronic devices.
Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, ...human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib’s safety profile should inform adverse event (AE) management and enhance patient care.
AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management.
Patients were randomly assigned to receive fulvestrant plus alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of ≥248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo.
Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management.
NCT02437318.
•Hyperglycemia, rash, and diarrhea were the most common grade 3/4 adverse events in patients receiving alpelisib.•These adverse events were predictable, manageable with concomitant medications, and generally reversible.•Implementation of more detailed AE management guidelines improved various markers of safety during the study.
Abstract
STUDY QUESTION
Is a protocol that combines in vitro maturation of germinal vesicle-stage oocytes and their vitrification with freezing of cortical ovarian tissue feasible for use in ...fertility preservation for both chemotherapy-naive paediatric patients as well as patients after initiation of cancer therapy?
SUMMARY ANSWER
Follicle-containing ovarian tissue as well as oocytes that can undergo maturation in vitro can be obtained from paediatric patients (including prepubertal girls) both before and after cancer therapy.
WHAT IS KNOWN ALREADY
Anticancer therapy reduces the number of follicles/oocytes but this effect is less severe in young patients, particularly the paediatric age group. Autotransplantation of ovarian tissue has yielded to date 60 live births, including one from tissue that was cryostored in adolescence. However, it is assumed that autografting cryopreserved-thawed ovarian cortical tissue poses a risk of reseeding the malignancy. Immature oocytes can be collected from very young girls without hormonal stimulation and then matured in vitro and vitrified. We have previously shown that there is no difference in the number of ovarian cortical follicles between paediatric patients before and after chemotherapy.
STUDY DESIGN, SIZE, DURATION
A prospective study was conducted in a cohort of 42 paediatric females with cancer (before and after therapy initiation) who underwent fertility preservation procedures in 2007–2014 at a single tertiary medical centre.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The study group included girls and adolescent females with cancer: 22 before and 20 after chemotherapy. Following partial or complete oophorectomy, immature oocytes were either aspirated manually ex vivo from visible small antral follicles or filtered from spent media. Oocytes were incubated in oocyte maturation medium, and those that matured at 24 or 48 h were vitrified. Ovarian cortical tissue was cut and prepared for slow-gradual cryopreservation. Anti-Mullerian hormone (AMH) levels were measured in serum before and after oophorectomy.
MAIN RESULTS AND ROLE OF CHANCE
Ovarian tissue was successfully collected from 78.7% of the 42 patients. Oocytes were obtained from 20 patients before chemotherapy and 13 after chemotherapy. The youngest patients from whom oocytes were retrieved were aged 2 years (two atretic follicles) and 3 years. Of the 395 oocytes collected, ∼30% were atretic (29.6% in the pre-chemotherapy group, 37% in the post-chemotherapy group). One hundred twenty-one oocytes (31%) were matured in vitro and vitrified: 67.8% from patients before chemotherapy, the rest after chemotherapy. Mature oocytes suitable for vitrification were obtained from 16/20 patients before chemotherapy and from 12/13 patients after chemotherapy (maturation rate, 32 and 26.4%, respectively). There were significant correlations of the number of vitrified oocytes with patient age (more matured oocytes with older age) (P = 0.001) and with pre-oophorectomy AMH levels (P = 0.038 pre-chemotherapy group, P = 0.029 post-chemotherapy group). Oocytes suitable for vitrification were obtained both by manual aspiration of antral follicles (45%) and from rinse solutions after dissection. There were significantly more matured oocytes in the pre-chemotherapy group from aspiration than in the post-chemotherapy group after both aspiration (P < 0.033) and retrieval from rinsing fluids (P < 0.044). The number of pre-antral follicles per histological section did not differ in the pre- versus post-chemotherapy. AMH levels dropped by approximately 50% after ovarian removal in both groups, with a significant correlation between pre- and post-oophorectomy levels (P = 0.002 pre-chemotherapy group, P = 0.001 post-chemotherapy group).
LIMITATIONS, REASONS FOR CAUTION
There were no patients between 5 years and 10 years old in the post-chemotherapy group, which might have affected some results and correlations. Oocytes from patients soon after chemotherapy might be damaged, and caution is advised when using them for fertility-restoration purposes. The viability, development capability and fertilization potential of oocytes from paediatric patients, especially prepubertal and after chemotherapy, are unknown, in particular oocytes recovered from the media after the tissue dissection step.
WIDER IMPLICATIONS OF THE FINDINGS
Although more oocytes were collected and matured from chemotherapy-naïve paediatric patients, ovarian tissue and immature oocytes were also retrieved from young girls in whom cancer therapy has already been initiated. Our centre has established a protocol for potential maximal fertility preservation in paediatric female patients with cancer. Vitrified-in vitro-matured oocytes may serve as an important gamete source in paediatric female patients with cancer because the risk of reseeding the disease is avoided. Further studies are needed on the fertility-restoring potential of oocytes from paediatric and prepubertal patients, especially after exposure to chemotherapy.
STUDY FUNDING/COMPETING INTEREST(S)
The study was conducted as part of the routine procedures for fertility preservation at our IVF unit. No funding outside of the IVF laboratory was received. Funding for the AMH measurements was obtained by a research grant from the Israel Science Foundation (to B.-A.I., ISF 13-1873). None of the authors have competing interests.
TRIAL REGISTRATION NUMBER
N/A.
Recent epidemiological studies indicate the rate of gastrointestinal (GI) malignancies among younger patients is increasing, mainly due to colorectal cancer. There is a paucity of data regarding the ...magnitude of treatment-related symptoms, psychosocial issues and potential unmet needs in this population. We aimed to characterize the needs of this population to evaluate whether unmet needs could be targeted by potential intervention.
Female and male patients diagnosed with cancer of the gastrointestinal tract <40y retrospectively completed a questionnaire to evaluate symptoms, daily function and unmet needs at pre-treatment, during and post-treatment. Comparisons were made by gender, disease stage and treatment modality. Multiple linear regression models evaluated effects of demographics, symptoms and needs on multiple domains of health-related-quality-of-life (using Short-Form Health Survey-12 and CARES).
Fifty patients were enrolled (52 % female) to a pilot study. Median age at diagnosis was 35.5y (range, 21-40y). The symptoms that significantly increased from baseline to during and post-treatment were: diarrhea (37 %), sleeping disorder (32 %) and sexual dysfunction (40 %). Patients also reported significant deterioration in occupational activities and coping with children compared with baseline. Female patients reported significant unmet need for nutritional counseling and psychosocial support compared to male patients (p < 0.05). Patients treated with multimodality-treatment presented higher rates of unmet needs (p = 0.03).
Young patients with GI cancers represent a group with unique characteristics and needs compared with published evidence on other young-onset malignancies. The distinctive symptoms and areas of treatment-related functional impairments indicate there are unmet needs, especially in the area of psychosocial support and nutritional counseling.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The 80% mortality rate of pancreatic-cancer (PC) makes early diagnosis a challenge. Oral fluids (OF) may be considered the ultimate body fluid for non-invasive examinations. We have developed ...techniques to improve visualization of minor OF proteins thereby overcoming major barriers to using OF as a diagnostic fluid. The aim of this study was to establish a short discriminative panel of OF biomarkers for the detection of PC. Unstimulated OF were collected from PC patients and controls (n = 30). High-abundance-proteins were depleted and the remaining proteins were analyzed by two-dimensional-gel-electrophoresis and quantitative dimethylation-liquid-chromatography-tandem mass-spectrometry. Label-free quantitative-mass-spectrometry analysis (qMS) was performed on 20 individual samples (n = 20). More than 100 biomarker candidates were identified in OF samples, and 21 had a highly differential expression profile. qMS analysis yielded a ROC-plot AUC value of 0.91 with 90.0% sensitivity and specificity for a combination of five biomarker candidates. We found a combination of five biomarkers for PC. Most of these proteins are known to be related to PC or other gastric cancers, but have never been detected in OF. This study demonstrates the importance of novel OF depletion methodologies for increased protein visibility and highlights the clinical applicability of OF as a diagnostic fluid.
HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib ...monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T.
Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing.
ORR for 57 N + F + T-treated patients was 39% 95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response.
The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.
•The phase II SUMMIT basket study evaluated neratinib-based therapy in patients with solid tumors harboring HER2 mutations.•57 MBC patients received N + F + T, including 7 of 21 randomized 1:1:1 to F, F + T, or N + F + T.•The ORR for patients who received N + F + T was 39% (95% CI 26% to 52%); this included 1 complete and 21 partial responses.•Responses were seen in ductal (ORR 39%) and lobular (ORR 41%) MBC, one or more HER2 mutations, or co-occurring HER3 mutation.•Responses after cross-over from F or F + T to N + F + T support the requirement of neratinib for efficacy of the triplet.
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