In a trial evaluating two daily-dose levels of voxelotor, which binds to sickle hemoglobin and prevents polymerization under hypoxic conditions, hemoglobin levels increased by more than 1 g per ...deciliter in approximately half the patients who received the drug, and markers of hemolysis decreased. Toxic effects were mainly low grade and not different from those with placebo.
The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines
. The Ad26.COV2.S vaccine expresses a stabilized spike ...protein from the WA1/2020 strain of SARS-CoV-2, and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in several geographical regions-including in South Africa, where 95% of sequenced viruses in cases of COVID-19 were the B.1.351 variant
. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern.
The Malocclusion Impact Questionnaire (MIQ) is a condition-specific measure that assesses the impact of malocclusion on Oral Health-Related Quality of Life (OHRQoL). The aim of this study was to ...cross-culturally adapt the original version of MIQ into Spanish and to assess the acceptability, reliability and validity of this version in the Chilean population.
The MIQ was cross-culturally adapted for the Spanish language for Chile using recommended standards for the linguistic validation of instruments. To assess its psychometric properties, a cross-sectional study was carried out with 219 children aged 10 to 16 years from public schools in Puerto Montt, Chile, who completed the Chilean versions of the MIQ (MIQ
) and the Child Perceptions Questionnaire 11-14 (CPQ
). The presence and severity of malocclusions was determined through the Dental Aesthetic Index by a trained dentist. The MIQ was administrated a second time two weeks later. The reliability of the scale was assessed by analysis of its internal consistency (Cronbach's alpha) and reproducibility (Intraclass correlation coefficient - ICC). The validity of the construct was assessed by confirmatory factor analysis and known groups method. Criterion validity was assessed by calculating the Spearman correlation with the CPQ
.
The content comparison of the back-translation with the original MIQ showed that all items except two were conceptually and linguistically equivalent. The cognitive debriefing showed a suitable understanding of the Chilean version. The MIQ
demonstrated good reliability, with Cronbach's alpha coefficient of 0.85 and ICC of 0.91. A moderate correlation was found between the MIQ
and CPQ
(0.58). In the known groups comparison, children who felt that their teeth bothered them and/or affected their life obtained significantly higher scores on the MIQ
. The OHRQoL was worse when the severity of the malocclusion was greater (p = 0.03).
The results support the applicability, reliability and validity of the Spanish version of MIQ for assessing OHRQoL in Chilean children with malocclusions.
There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) ...longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status.
Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1).
DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration).
These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.
Estrogen receptor (ER)-positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway alterations in ...approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting.
We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months.
At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common ≥ grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response (
,
, and
mutations) or absence of response (
mutations), which require independent validation.
Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.
Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in ...vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell-rich and T cell-sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC-mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A-positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1-positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.
Abstract
Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the ...treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT.
Background
Some antipsychotic drugs elevate prolactin, and hyperprolactinaemia is associated with an increased risk of breast cancer. Women with schizophrenia have an increased incidence of breast ...cancer, but also multiple risk factors for the condition.
Method
This paper will critically review recent epidemiological studies concerning antipsychotics and breast cancer from a psychiatric perspective.
Results
Two recent epidemiological studies have found an association between use of prolactin-elevating antipsychotics and breast cancer in women with schizophrenia and other psychotic disorders. Prolactin-elevating drugs include paliperidone, risperidone, amisulpride and haloperidol, whilst prolactin-sparing antipsychotics included aripiprazole, brexpiprazole, cariprazine and quetiapine. In the two studies, estimated increased risks of breast cancer were disconcertingly high (up to 62%), but a third recent study found only a weak dose-response association. There are extensive methodological complications in this research, including the extent to which studies measure other risk factors for breast cancer and disagreement about the extent of prolactin elevation by some antipsychotics.
Conclusion
Although causation between prolactin elevating antipsychotics and breast cancer in women has not been demonstrated, recent epidemiological reports are worrying. For women on antipsychotics, informed consent should ideally include discussion of breast cancer concerns within the wider context of treatment benefits and risks.
Intravenous paclitaxel (IVpac) is complicated by neuropathy and requires premedication to prevent hypersensitivity-type reactions. Paclitaxel is poorly absorbed orally; encequidar (E), a novel ...P-glycoprotein pump inhibitor, allows oral absorption.
A phase III open-label study comparing oral paclitaxel plus E (oPac + E) 205 mg/m
paclitaxel plus 15 mg E methanesulfonate monohydrate 3 consecutive days per week versus IVpac 175 mg/m
once every 3 weeks was performed. Women with metastatic breast cancer and adequate organ function, at least 1 year from last taxane, were randomly assigned 2:1 to oPac + E versus IVpac. The primary end point was confirmed radiographic response using RECIST 1.1, assessed by blinded independent central review. Secondary end points included progression-free survival (PFS) and overall survival (OS).
Four hundred two patients from Latin America were enrolled (265 oPac + E, 137 IVpac); demographics and prior therapies were balanced. The confirmed response (intent-to-treat) was 36% for oPac + E versus 23% for IVpac (
= .01). The PFS was 8.4 versus 7.4 months, respectively (hazard ratio, 0.768; 95.5% CI, 0.584 to 1.01;
= .046), and the OS was 22.7 versus 16.5 months, respectively (hazard ratio, 0.794; 95.5% CI, 0.607 to 1.037;
= .08). Grade 3-4 adverse reactions were 55% with oPac + E and 53% with IVpac. oPac + E had lower incidence and severity of neuropathy (2%
15% > grade 2) and alopecia (49%
62% all grades) than IVpac but more nausea, vomiting, diarrhea, and neutropenic complications, particularly in patients with elevated liver enzymes. On-study deaths (8% oPac + E
9% IVpac) were treatment-related in 3% and 0%, respectively.
oPac + E increased the confirmed tumor response versus IVpac, with trends in PFS and OS. Neuropathy was less frequent and severe with oPac + E; neutropenic serious infections were increased. Elevated liver enzymes at baseline predispose oPac + E patients to early neutropenia and serious infections (funded by Athenex, Inc; ClinicalTrials.gov identifier: NCT02594371).
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