Associations between diabetes mellitus and sensorineural hearing loss from humans and animal studies.

There is controversy regarding the association and etiopathogenesis of diabetes mellitus (DM) and sensorineural hearing loss (SNHL). Some studies support that SNHL develops because of angiopathy and/or neuropathy caused by DM, but many of the findings have been inconsistent. This review aims to highlight a select number of studies that effectively describe the relationship between DM and SNHL, thus bringing more attention and awareness to this area of research. This review also describes animal models to understand better the mechanisms of DM contributing to SNHL in the inner ear. The goal of this narrative review is for researchers and healthcare professionals to further their understanding and investigation of the etiopathogenesis of both DM and SNHL, therefore leading to the development of effective treatments for diabetic patients displaying symptoms of SNHL.

Effectiveness of repeated injections of botulinum toxin A on gait and fatigue in adults with spastic paraparesis secondary to multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is the most common neurologic disease in young adults. Spasticity is one of its most disabling symptoms, with botulinum toxin A type A (BoNT-A) being one of the treatments of choice for this symptom. OBJECTIVE: We assessed the response to abobotulinumtoxinA in improving walking ability and fatigue in patients with spastic paraparesis caused by MS. METHODS: We performed a real-world, multicenter, prospective, open-label low-intervention trial in 84 patients with MS and spastic paraparesis of the lower limbs infiltrated with abobotulinumtoxinA (LINITOX study). The response of spasticity, walking ability and fatigue is analyzed in 4 cycles of ultrasound-guided injection in the lower limbs. RESULTS: The patients improved their walking ability by an average of 11.34% meters measured with 6-Minute Walk Test (6MWT), and decreased the percentage of fatigue by 6.86% (4.66 percentage points less), in the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) 4 weeks after abobotulinumtoxinA injection, both values are statistically significant. This improvement seems to persist over time, throughout the cycles. CONCLUSION: We found improved walking ability and less fatigue in patients with MS-related spastic paresis of the lower limbs after injection of abobotulinumtoxinA.

Personalized peritoneal dialysis prescription-beyond clinical or analytical values.

Traditionally, dialysis adequacy has been assessed primarily by determining the clearance of a single small solute, urea. Nevertheless, it has become increasingly evident that numerous other factors play a crucial role in the overall well-being, outcomes and quality of life of dialysis patients. Consequently, in recent years, there has been a notable paradigm shift in guidelines and recommendations regarding dialysis adequacy. This shift represents a departure from a narrow focus only on the removal of specific toxins, embracing a more holistic, person-centered approach. This new perspective underscores the critical importance of improving the well-being of individuals undergoing dialysis while simultaneously minimizing the overall treatment burden. It is based on a double focus on both clinical outcomes and a comprehensive patient experience. To achieve this, a person-centered approach must be embraced when devising care strategies for each individual. This requires a close collaboration between the healthcare team and the patient, facilitating an in-depth understanding of the patient's unique goals, priorities and preferences while striving for the highest quality of care during treatment. The aim of this publication is to address the existing evidence on this all-encompassing approach to treatment care for patients undergoing peritoneal dialysis and provide a concise overview to promote a deeper understanding of this person-centered approach.

Dopamine-derived pigments in nature: Identification of decarboxybetalains in Amaranthaceae species.

A unique family of decarboxylated betalains derived from dopamine has recently been discovered. Due to the lack of chemical standards, the existence and distribution of decarboxylated betalains in nature remains unknown. Traditional betalains contain L-DOPA as the starting point of the biosynthetic pathway and betalamic acid as a structural and functional unit, while the recently discovered betalains rely on dopamine. Here, 30 dopamine-derived betalains were biotechnologically produced, purified, and characterized, creating an unprecedented library to explore their properties and presence in nature. The maximum absorbance wavelengths for the pigments ranged between 461nm and 485 nm. HPLC analysis showed retention times between 0.6-2.2 min higher than traditional betalains due to their higher hydrophobicity. The presence of decarboxybetalains in nature was screened using HPLC-ESI-Q-TOF mass spectrometry in various species of the Amaranthaceae family: beetroot (Beta vulgaris subsp. vulgaris), Swiss chard (B. vulgaris var. cicla), celosia (Celosia argentea var. plumosa) and quinoa (Chenopodium quinoa). The latter species had the highest content of decarboxybetalains (28 compounds in its POEQ-143 variety). 29 pigments were found distributed among the different analyzed plant sources. The abundance of decarboxybetalains demonstrated in this work highlights these pigments as an important family of phytochemicals in the order Caryophyllales.

Associations between various markers of intestinal barrier and immune function after a high-intensity exercise challenge.

Strenuous exercise can result in disruption of intestinal barrier function and occurrence of gastrointestinal symptoms. The aim of this exploratory study was to elucidate systemic effects of increased intestinal permeability after high-intensity exercise. Forty-one endurance-trained subjects performed a 60-min treadmill run at 80% VO2max. Small intestinal permeability was measured as urinary excretion ratio of lactulose/rhamnose (L/R). Blood, saliva and feces were analyzed for gut barrier and immune-related biomarkers. The exercise challenge increased several markers of intestinal barrier disruption, immune function and oxidative stress. We found a negative correlation between L/R ratio and uric acid (r = -0.480), as well as a positive correlation between the L/R ratio and fecal chromogranin A in male participants (r = 0.555). No significant correlations were found between any of the markers and gastrointestinal symptoms, however, perceived exertion correlated with the combination of IL-6, IL-10 and salivary cortisol (r = 0.492). The lack of correlation between intestinal permeability and gastrointestinal symptoms could be due to minor symptoms experienced in lab settings compared to real-life competitions. The correlation between L/R ratio and uric acid might imply a barrier-protective effect of uric acid, and inflammatory processes due to strenuous exercise seem to play an important role regarding physical exhaustion.

"You Are Not Wrong About Getting Strong:" An Insight Into the Impact of Age Group and Level of Competition on Strength in Spanish Football Players.

OBJECTIVE: This study aimed to compare the maximum and rapid force production of Spanish football players and explore the differences between age group and level of competition. METHODS: A cross-sectional study was developed to evaluate the peak force (PF), relative PF, and rate of force development over 250 ms (RFD0-250) during the isometric midthigh pull between groups of football players based on age group (senior vs junior) and level of competition (national vs regional). Using a portable isometric rig, 111 football players performed 2 isometric midthigh-pull trials on a force plate. Two-way analysis of variance with Bonferroni post hoc correction was applied, and statistical significance was set at P ≤ .05. The PF, relative PF, and RFD0-250 0, 25, 50, 75, and 100 percentiles were also calculated and descriptively reported, separated by age group and level of competition. RESULTS: The analysis of variance revealed a significant main effect of the level of competition for the PF (P < .001), relative PF (P = .003), and RFD0-250 (P < .001). There was a significant main effect of age group for the PF (P < .001). There was a significant interaction effect of the age group × level of competition for relative PF (P = .014). National players were stronger than regional players on the PF and RFD0-250 (P < .001). Senior players were stronger than junior players for the PF (P < .001). CONCLUSIONS: Maximum and rapid force production are crucial for Spanish football players as they progress in both level of competition and age group. Practitioners should encourage young football players to prioritize strength development to improve their athletic performance.

Enhancing the hypotensive effect of latanoprost by combining synthetic phosphatidylcholine liposomes with hyaluronic acid and osmoprotective agents.

The first line of glaucoma treatment focuses on reducing intraocular pressure (IOP) through the prescription of topical prostaglandin analogues, such as latanoprost (LAT). Topical ophthalmic medicines have low bioavailability due to their rapid elimination from the ocular surface. Nanotechnology offers innovative ways of enhancing the ocular bioavailability of antiglaucoma agents while reducing administration frequency. This study aims to combine LAT-loaded synthetic phosphatidylcholine liposomes with hyaluronic acid (0.2% w/v) and the osmoprotectants betaine (0.40% w/v) and leucine (0.90% w/v) (LAT-HA-LIP) to extend the hypotensive effect of LAT while protecting the ocular surface. LAT-HA-LIP was prepared as a mixture of 1,2-dioleoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol and α-tocopherol acetate. LAT-HA-LIP exhibited high drug-loading capacity (104.52 ± 4.10%), unimodal vesicle sizes (195.14 ± 14.34 nm) and a zeta potential of -13.96 ± 0.78 mV. LAT-HA-LIP was isotonic (284.00 ± 1.41 mOsm L-1), had neutral pH (7.63 ± 0.01) and had suitable surface tension (44.07 ± 2.70 mN m-1) and viscosity (2.69 ± 0.15 mPa s-1) for topical ophthalmic administration. LAT-HA-LIP exhibited optimal in vitro tolerance in human corneal and conjunctival epithelial cells. No signs of ocular alteration or discomfort were observed when LAT-HA-LIP was instilled in albino male New Zealand rabbits. Hypotensive studies revealed that, after a single eye drop, the effect of LAT-HA-LIP lasted 24 h longer than that of a marketed formulation and that relative ocular bioavailability was almost three times higher (p < 0.001). These findings indicate the potential ocular protection and hypotensive effect LAT-HA-LIP offers in glaucoma treatment.

Female GluA3-KO mice show early onset hearing loss and afferent swellings in ambient sound levels.

AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8-weeks of age. Since Gria3 is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis in Gria3KO females. Here, auditory brainstem responses (ABR) were similar in 3-week-old female Gria3WT and Gria3KO mice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older in Gria3KO. In contrast, these metrics were similar between genotypes when raised in quiet. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were increased in female Gria3KO mice in ambient sound compared to Gria3WT or to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative to Gria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3KO. Swollen afferent terminals were observed by 5-weeks only in Gria3KO females reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.

Long-range inhibitory neurons mediate cortical neurovascular coupling.

To meet the high energy demands of brain function, cerebral blood flow (CBF) parallels changes in neuronal activity by a mechanism known as neurovascular coupling (NVC). However, which neurons play a role in mediating NVC is not well understood. Here, we identify in mice and humans a specific population of cortical GABAergic neurons that co-express neuronal nitric oxide synthase and tachykinin receptor 1 (Tacr1). Through whole-tissue clearing, we demonstrate that Tacr1 neurons extend local and long-range projections across functionally connected cortical areas. We show that whisker stimulation elicited Tacr1 neuron activity in the barrel cortex through feedforward excitatory pathways. Additionally, through optogenetic experiments, we demonstrate that Tacr1 neurons are instrumental in mediating CBF through the relaxation of mural cells in a similar fashion to whisker stimulation. Finally, by electron microscopy, we observe that Tacr1 processes contact astrocytic endfeet. These findings suggest that Tacr1 neurons integrate cortical activity to mediate NVC.

SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability.

During genome duplication, replication forks (RFs) can be stalled by different obstacles or by depletion of replication factors or nucleotides. A limited number of histone post-translational modifications at stalled RFs are involved in RF protection and restart. Provided the recent observation that the SIN3A histone deacetylase complex reduces transcription-replication conflicts, we explore the role of the SIN3A complex in protecting RFs under stressed conditions. We observe that Sin3A protein is enriched at replicating DNA in the presence of hydroxyurea. In this situation, Sin3A-depleted cells show increased RF stalling, H3 acetylation, and DNA breaks at stalled RFs. Under Sin3A depletion, RF recovery is impaired, and DNA damage accumulates. Importantly, these effects are partially dependent on the MUS81 endonuclease, which promotes DNA breaks and MRE11-dependent DNA degradation of such breaks. We propose that chromatin deacetylation triggered by the SIN3A complex limits MUS81 cleavage of stalled RFs, promoting genome stability when DNA replication is challenged.

Towards transparent decision-making processes within museums: Case study of Museu Nacional d'Art de Catalunya (MNAC).

Understanding that good decision-making is paramount for the success of an organization and recognizing that strategic decision-making inside museums is a topic that has been over-passed by researchers, this paper intends to contribute to the relevance of the subject through the implementation of an innovative tool. Decision-making in museums is normally focused on the intuition, subjectivity, and experience of the curator, who brings all his knowledge to the exhibition programming. However, museums' management and environment are constantly changing, thus the application of this tool would aim to make decisions in a more democratic, transparent, inclusive, and accurate manner. Besides, it will be easier to understand how distinct subjects can work together, demonstrating successful results to improve the decision-making process when programming and measuring temporary exhibition seasons in museums. This paper describes the design and implementation of the Multi-Attribute Utility Theory (MAUT) for the Museu Nacional d'Art de Catalunya (MNAC). It also analyzes and evaluates the decision-making process when scheduling exhibitions for a season.

Detection of Anomalies in Daily Activities Using Data from Smart Meters.

The massive deployment of smart meters in most Western countries in recent decades has allowed the creation and development of a significant variety of applications, mainly related to efficient energy management. The information provided about energy consumption has also been dedicated to the areas of social work and health. In this context, smart meters are considered single-point non-intrusive sensors that might be used to monitor the behaviour and activity patterns of people living in a household. This work describes the design of a short-term behavioural alarm generator based on the processing of energy consumption data coming from a commercial smart meter. The device captured data from a household for a period of six months, thus providing the consumption disaggregated per appliance at an interval of one hour. These data were used to train different intelligent systems, capable of estimating the predicted consumption for the next one-hour interval. Four different approaches have been considered and compared when designing the prediction system: a recurrent neural network, a convolutional neural network, a random forest, and a decision tree. By statistically analysing these predictions and the actual final energy consumption measurements, anomalies can be detected in the undertaking of three different daily activities: sleeping, breakfast, and lunch. The recurrent neural network achieves an F1-score of 0.8 in the detection of these anomalies for the household under analysis, outperforming other approaches. The proposal might be applied to the generation of a short-term alarm, which can be involved in future deployments and developments in the field of ambient assisted living.

Relationship between Medication-Related Osteonecrosis of the Jaw and CDK4/6 Inhibitors in Breast Cancer.

OBJECTIVE: We aimed to evaluate the use of CDK4/6 inhibitors as a risk factor for medication-related osteonecrosis of the jaw (MRONJ) in a cohort of patients with metastatic breast cancer treated with denosumab. METHODS: This was a multicentre, retrospective, observational study. All patients with breast cancer treated with denosumab (January 2011-December 2022) were included. The relationship between CDK4/6 inhibitors and MRONJ was analysed. RESULTS: A total of 243 patients were included, ninety-five (44.2%) of whom used a CDK4/6 inhibitor. There were 21 patients with MRONJ. In patients treated with denosumab without CDK4/6 inhibitors, the incidence of MRONJ and mean time to the occurrence of MRONJ were 6.6% (8/120) and 16.8 months (SD 7.8), respectively; in patients treated with denosumab and CDK4/6 inhibitor, these values were 13.7% (13/95) and 15.4 months (SD 8.7), respectively. The difference in the incidence was not significant (p = 0.085). Among the 19 patients who used abemaciclib, the probability of MRONJ occurrence was significantly higher compared to patients not using CDK4/6 inhibitors (p = 0.0178). CONCLUSIONS: These results suggest that the incidence of MRONJ in patients with metastatic breast cancer treated with denosumab is higher, and the onset of MRONJ occurs earlier in the presence of CDK4/6 inhibitors. The differences were statistically significant in the patients who used abemaciclib. Given that the use of this combination is very common in routine clinical practice, it would be advisable to carry out larger prospective studies to clarify the risk of this association.

Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Analysis of Tumor Microenvironment Changes after Neoadjuvant Chemotherapy with or without Bevacizumab in Advanced Ovarian Cancer (GEICO-89T/MINOVA Study).

PURPOSE: The aim of our study was to elucidate the impact of bevacizumab added to neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment and correlate the changes with the clinical outcome of the patients. EXPERIMENTAL DESIGN: IHC and multiplex immunofluorescence for lymphoid and myeloid lineage markers were performed in matched tumor samples from 23 patients with ovarian cancer enrolled in GEICO 1205/NOVA clinical study before NACT and at the time of interval cytoreductive surgery. RESULTS: Our results showed that the addition of bevacizumab to NACT plays a role mainly on lymphoid populations at the stromal compartment, detecting a significant decrease of CD4+ T cells, an increase of CD8+ T cells, and an upregulation in effector/regulatory cell ratio (CD8+/CD4+FOXP3+). None of the changes observed were detected in the intra-epithelial site in any arm (NACT or NACT-bevacizumab). No differences were found in myeloid lineage (macrophage-like). The percentage of Treg populations and effector/regulatory cell ratio in the stroma were the only two variables significantly associated with progression-free survival (PFS). CONCLUSIONS: The addition of bevacizumab to NACT did not have an impact on PFS in the GEICO 1205 study. However, at the cellular level, changes in CD4+, CD8+ lymphocyte populations, and CD8+/CD4+FOXP3 ratio have been detected only at the stromal site. On the basis of our results, we hypothesize about the existence of mechanisms of resistance that could prevent the trafficking of T-effector cells into the epithelial component of the tumor as a potential explanation for the lack of efficacy of ICI in the first-line treatment of advanced epithelial ovarian cancer. See related commentary by Soberanis Pina and Oza, p. 12.

Dynamics of hemoglobins during nodule development, nitrate response, and dark stress in Lotus japonicus.

Legume nodules express multiple leghemoglobins (Lbs) and non-symbiotic hemoglobins (Glbs), but how they are regulated is unclear. Here, we study the regulation of all Lbs and Glbs of Lotus japonicus in different physiologically relevant conditions and mutant backgrounds. We quantified hemoglobin expression, localized reactive oxygen species (ROS) and nitric oxide (NO) in nodules, and deployed mutants deficient in Lbs and in the transcription factors NLP4 (associated with nitrate sensitivity) and NAC094 (associated with senescence). Expression of Lbs and class 2 Glbs was suppressed by nitrate, whereas expression of class 1 and 3 Glbs was positively correlated with external nitrate concentrations. Nitrate-responsive elements were found in the promoters of several hemoglobin genes. Mutant nodules without Lbs showed accumulation of ROS and NO and alterations of antioxidants and senescence markers. NO accumulation occurred by a nitrate-independent pathway, probably due to the virtual disappearance of Glb1-1 and the deficiency of Lbs. We conclude that hemoglobins are regulated in a gene-specific manner during nodule development and in response to nitrate and dark stress. Mutant analyses reveal that nodules lacking Lbs experience nitro-oxidative stress and that there is compensation of expression between Lb1 and Lb2. They also show modulation of hemoglobin expression by NLP4 and NAC094.

Adaptation of the Recreovía During COVID-19 Lockdowns: Making Physical Activity Accessible to Older Adults in Bogotá, Colombia.

The community restrictions during the coronavirus disease 2019 pandemic adversely impacted older adults' physical activity levels. This convergent mixed-method study assessed the adaptation of the Recreovía, a community-based physical activity program in Bogotá, and characterized physical activity levels among older adult participants. Our results showed how the Recreovía adapted during the pandemic to continue promoting physical activity, through indoor and outdoor strategies, including virtual physical activity sessions and safety protocols. During this time, 72%-79% of the older adults attending the adapted program were physically active. A greater proportion of park users (84.2%) and more people involved in vigorous physical activity were observed during Recreovía days. Older adults had positive experiences and perceptions of the Recreovía program related to their health and social well-being. Even though the older adults prefer being outdoors, the adapted program allowed participants to continue with their physical activity routines as much as possible during the pandemic.

Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial.

BACKGROUND: The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10-GEICO 68-C-JGOG1084-GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone. METHODS: In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle) with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death. Stratification factors were previous concomitant chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin vs carboplatin). Dual primary endpoints were investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumours version 1.1 and overall survival analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03556839, and is ongoing. FINDINGS: Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3-16·6) with atezolizumab and 10·4 months (9·7-11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49-0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3-36·8) versus 22·8 months (20·3-28·0), respectively (HR 0·68 [95% CI 0·52-0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1-2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab. INTERPRETATION: Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option. FUNDING: F Hoffmann-La Roche.

Light and shadow of watch-and-wait strategy in rectal cancer: oncological result, clinical outcomes, and cost-effectiveness analysis.

BACKGROUND: The watch-and-wait (WW) strategy is a potential option for patients with rectal cancer who obtain a complete clinic response after neoadjuvant therapy. The aim of this study is to analyze the long-term oncological outcomes and perform a cost-effectiveness analysis in patients undergoing this strategy for rectal cancer. MATERIAL AND METHODS: The data of patients treated with the WW strategy were prospectively collected from January 2015 to January 2020. A control group was created, matched 1:1 from a pool of 480 patients undergoing total mesorectal excision. An independent company carried out the financial analysis. Clinical and oncological outcomes were analyzed in both groups. Outcome parameters included surgical and follow-up costs, quality-adjusted life years (QALYs), and the incremental cost per QALY gained or the incremental cost-effectiveness ratio (ICER). RESULTS: Forty patients were included in the WW group, with 40 patients in the surgical group. During a median follow-up period of 36 months, metastasis-free survival (MFS) and overall survival (OS) were similar in the two groups. In the WW group, nine (22%) local regrowths were detected in the first 2 years. The permanent stoma rate was slightly higher after salvage surgery in the WW group compared to the surgical group (48.5% vs 20%, p < 0.01). The cost-effectiveness analysis was slightly better for the WW group, especially for low rectal cancer compared to medium-high rectal cancer (ICER = - 108,642.1 vs ICER = - 42,423). CONCLUSIONS: The WW strategy in locally advanced rectal cancer offers similar oncological outcomes with respect to the surgical group and excellent results in quality of life and cost outcomes, especially for low rectal cancer. Nonetheless, the complex surgical field during salvage surgery can lead to a high permanent stoma rate; therefore, the careful selection of patients is mandatory.