Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial.

BACKGROUND: Immune checkpoint inhibitors (ICIs) to date have demonstrated limited activity in advanced ovarian cancer (OC). Folate receptor alpha (FRα) is overexpressed in the majority of OCs and presents an attractive target for a combination immunotherapy to potentially overcome resistance to ICI in OCs. The current study sought to examine clinical and immunologic responses to TPIV200, a multiepitope FRα vaccine administered with programmed death ligand 1 (PD-L1) inhibitor durvalumab in patients with advanced platinum-resistant OC. METHODS: Following Simon two-stage phase II trial design, 27 patients were enrolled. Treatment was administered in 28-day cycles (intradermal TPIV200 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 cycles and intravenous durvalumab for 12 cycles). Primary endpoints included overall response rate and progression-free survival at 24 weeks. Translational parameters focused on tumor microenvironment, PD-L1 and FRα expression, and peripheral vaccine-specific immune responses. RESULTS: Treatment was well tolerated, with related grade 3 toxicity rate of 18.5%. Increased T cell responses to the majority of peptides were observed in all patients at 6 weeks (p<0.0001). There was one unconfirmed partial response (3.7%) and nine patients had stable disease (33.3%). Clinical benefit was not associated with baseline FRα or PD-L1 expression. One patient with prolonged clinical benefit demonstrated loss of FRα expression and upregulation of PD-L1 in a progressing lesion. Despite the low overall response rate, the median overall survival was 21 months (13.5-∞), with evidence of benefit from postimmunotherapy regimens. CONCLUSIONS: Combination of TPIV200 and durvalumab was safe and elicited robust FRα-specific T cell responses in all patients. Unexpectedly durable survival in this heavily pretreated population highlights the need to investigate the impact of FRα vaccination on the OC biology post-treatment.

A phase 1 dose-escalation study of intraperitoneal cisplatin, intravenous/intraperitoneal paclitaxel, bevacizumab, and olaparib for newly diagnosed ovarian cancer.

OBJECTIVE: We assessed the safety and maximum tolerated dose (MTD) of the poly ADP-ribose polymerase (PARP) inhibitor olaparib with intravenous (IV)/intraperitoneal (IP) cisplatin/paclitaxel and IV bevacizumab, followed by olaparib and bevacizumab maintenance, in patients with newly diagnosed ovarian cancer who had undergone primary debulking surgery. METHODS: Treatment included: (Cycles 1-6) Day 1, IV paclitaxel 135 mg/m2/3 h + (from Cycle 2 onward) bevacizumab 15 mg/kg; Day 2, IP cisplatin 75 mg/m2; Days 2-8, olaparib (50/100/200 mg BID); Day 8, IP paclitaxel 60 mg/m2 of a 21-day cycle. Maintenance (Cycles 7-22) included: olaparib 300 mg BID and bevacizumab 15 mg/kg Day 1. The primary endpoint was MTD of olaparib, chemotherapy, and bevacizumab. RESULTS: Seventeen women were treated (Cohort 1 [50 mg olaparib], 8 patients; Cohort 2 [100 mg], 3 patients; and Cohort 3 [200 mg], 6 patients). Median age was 57 years (47-73); 94% had stage III disease; 29% had a germline BRCA mutation. Two of 6 patients in Cohort 3 experienced a dose-limiting toxicity (DLT). Grade 3/4 toxicities included: neutropenia (56%), lymphopenia (31%), anemia (25%), and fatigue (19%). Most patients started (88%, 81%) and completed (75%, 50%) maintenance olaparib and bevacizumab, respectively; 36% of patients on olaparib maintenance required a dose reduction. Median PFS was 33 months (26.2-NA). CONCLUSIONS: The MTD of intermittently dosed olaparib with concurrent IV/IP cisplatin/paclitaxel and bevacizumab is 100 mg BID. Non-hematologic toxicities were predominantly low grade. One-third of patients on olaparib maintenance required dose reduction.

Ultra-brief Screeners for Detecting Delirium Superimposed on Dementia.

OBJECTIVE: Delirium superimposed on dementia (DSD) is common, morbid, and costly, yet frequently undiagnosed. Our study aimed to develop a brief screening test to improve health care worker recognition of DSD. DESIGN/SETTING/PARTICIPANTS: Older hospitalized adults with dementia were prospectively enrolled from medical and surgical inpatient units of 3 hospitals (2 in Pennsylvania, 1 in Tennessee). MEASURES: The reference standard delirium assessment used Confusion Assessment Method (CAM) criteria and was based on a structured interview including the Mini-Mental State Examination, interviewer observations, and medical record review. To develop the screening test, 1-, 2-, and 3-item combinations from the reference standard assessment were analyzed to determine their sensitivity and specificity in diagnosing delirium presence in a dementia population compared to the reference standard. For multiple-item screeners, error on 1 or more items was considered a positive screen. RESULTS: Overall, 391 older adults with dementia were enrolled (mean age: 83.9 years, 71.1% female), and 95 (24.4%) developed DSD during their hospitalization, based on the reference standard. The best single-item screen for DSD was "What day of the week is it?" with 84% sensitivity [95% confidence interval (CI): 0.75, 0.91] and 41% specificity (CI: 0.35, 0.47). The best 2-item screen was "list the days of the week backwards" and "What day of the week is it?" with 93% sensitivity (CI: 0.85, 0.97) and 30% specificity (CI: 0.25, 0.36). The best 3-item screen was "list the days of the week backwards," "What type of place is this? [hospital]" and "Does the patient appear sleepy?" with 94% sensitivity (CI: 0.87, 0.98) and 42% specificity (CI: 0.36, 0.48). CONCLUSIONS/IMPLICATIONS: We identified a 3-item DSD screener with excellent sensitivity but limited specificity. This screener can be used to quickly rule out DSD in populations with a high prevalence of dementia and is a promising step toward developing efficient tools for DSD recognition among care providers.

Postoperative Delirium and Postoperative Cognitive Dysfunction: Overlap and Divergence.

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up. METHODS: This study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method-based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months. RESULTS: One hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07-1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72-1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71-2.09). CONCLUSIONS: Delirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

Use of an expert panel to identify domains and indicators of delirium severity.

PURPOSE: Our purpose was to create a content domain framework for delirium severity to inform item development for a new instrument to measure delirium severity. METHODS: We used an established, multi-stage instrument development process during which expert panelists discussed best approaches to measure delirium severity and identified related content domains. We conducted this work as part of the Better ASsessment of ILlness (BASIL) study, a prospective, observational study aimed at developing and testing measures of delirium severity. Our interdisciplinary expert panel consisted of twelve national delirium experts and four expert members of the core research group. Over a one-month period, experts participated in two rounds of review. RESULTS: Experts recommended that the construct of delirium severity should reflect both the phenomena and the impact of delirium to create an accurate, patient-centered instrument useful to interdisciplinary clinicians and family caregivers. Final content domains were Cognitive, Level of consciousness, Inattention, Psychiatric-Behavioral, Emotional dysregulation, Psychomotor features, and Functional. Themes debated by experts included reconciling clinical geriatrics and psychiatric content, mapping symptoms to one specific domain, and accurate capture of unclear clinical presentations. CONCLUSIONS: We believe this work represents the first application of instrument development science to delirium. The identified content domains are inclusive of various, wide-ranging domains of delirium severity and are reflective of a consistent framework that relates delirium severity to potential clinical outcomes. Our content domain framework provides a foundation for development of delirium severity instruments that can help improve care and quality of life for patients with delirium.

Perspectives on the Delirium Experience and Its Burden: Common Themes Among Older Patients, Their Family Caregivers, and Nurses.

BACKGROUND AND OBJECTIVES: While there are qualitative studies examining the delirium-related experiences of patients, family caregivers, and nurses separately, little is known about common aspects of delirium burden among all three groups. We describe common delirium burdens from the perspectives of patients, family caregivers, and nurses. RESEARCH DESIGN AND METHODS: We conducted semistructured qualitative interviews about delirium burden with 18 patients who had recently experienced a delirium episode, with 16 family caregivers, and with 15 nurses who routinely cared for patients with delirium. We recruited participants from a large, urban teaching hospital in Boston, Massachusetts. Interviews were recorded and transcribed. We used interpretive description as the approach to data analysis. RESULTS: We identified three common burden themes of the delirium experience: Symptom Burden (Disorientation, Hallucinations/Delusions, Impaired Communication, Memory Problems, Personality Changes, Sleep Disturbances); Emotional Burden (Anger/Frustration, Emotional Distress, Fear, Guilt, Helplessness); and Situational Burden (Loss of Control, Lack of Attention, Lack of Knowledge, Lack of Resources, Safety Concerns, Unpredictability, Unpreparedness). These burdens arise from different sources among patients, family caregivers, and nurses, with markedly differing perspectives on the burden experience. DISCUSSION AND IMPLICATIONS: Our findings advance the understanding of common burdens of the delirium experience for all groups and offer structure for instrument development and distinct interventions to address the burden of delirium as an individual or group experience. Our work reinforces that no one group experiences delirium in isolation. Delirium is a shared experience that will respond best to systemwide approaches to reduce associated burden.

Delirium Burden in Patients and Family Caregivers: Development and Testing of New Instruments.

BACKGROUND AND OBJECTIVES: Delirium creates distinct emotional distress in patients and family caregivers, yet there are limited tools to assess the experience. Our objective was to develop separate patient and family caregiver delirium burden instruments and to test their content and construct validity. RESEARCH DESIGN AND METHODS: Two hundred forty-seven patients and 213 family caregivers were selected from an ongoing prospective cohort of medical-surgical admissions aged ≥70 years old. New patient and family caregiver delirium burden instruments were developed and used to measure the subjective experiences of in-hospital delirium. Delirium and delirium severity were measured by the Confusion Assessment Method (CAM) and CAM-Severity (long form). RESULTS: Both Delirium Burden (DEL-B) instruments consist of eight questions and are measured on a 0 - 40 point scale. Final questions had good clarity and relevancy, as rated by the expert panel, and good internal consistency (Cronbach's α = .82-.86). In the cohort validation, Patient DEL-B (DEL-B-P) was 5.1 points higher and Family Caregiver DEL-B (DEL-B-C) was 5.8 points higher, on average, for patients who developed delirium compared to those who did not (p < .001). Test-retest reliability of DEL-B-C at baseline and 1 month was strong (correlation = .73). Delirium severity was mildly-moderately correlated with DEL-B-P (correlation = .34) and DEL-B-C (correlation = .26), suggesting contribution of other factors. DISCUSSION AND IMPLICATIONS: We created instruments to reliably measure and evaluate the burden of delirium for patients and their family caregivers. Although additional validation is indicated, these instruments provide a key first step toward measuring and improving the subjective experience of delirium for patients and their families.

The Association Between C-Reactive Protein and Postoperative Delirium Differs by Catechol-O-Methyltransferase Genotype.

OBJECTIVE: Catechol-O-methyltransferase (COMT), a key enzyme in degrading catecholamines associated with the stress response, may influence susceptibility to delirium. Individuals with the COMT (rs4680) Val/Val genotype (designated "warriors") withstand the onset of neuropsychiatric disorders and cognitive decline, whereas individuals with Met/Met and Val/Met genotypes ("nonwarriors") are more susceptible to these conditions. We evaluated whether COMT genotype modifies the established association between acute phase reactant (stress marker) C-reactive protein (CRP) and postoperative delirium. METHODS: This was a prospective cohort study conducted at two academic medical centers. The study involved 547 patients aged 70 or older undergoing major noncardiac surgery. We collected blood, extracted DNA, and performed COMT genotyping using allele-specific polymerase chain reaction assays, considering warriors versus nonwarriors. High plasma CRP, measured on postoperative day 2 using enzyme-linked immunosorbent assay, was defined by the highest sample-based quartile (≥234.12 mg/L). Delirium was determined using the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and race/ethnicity, stratified by COMT genotype, to determine whether the association between CRP and delirium differed by COMT. RESULTS: Prevalence of COMT warriors was 26%, and postoperative delirium occurred in 23%. Among COMT warriors, high CRP was not associated with delirium (relative risk [RR] 1.0, 95% confidence interval [CI] 0.4-2.6). In contrast, among nonwarriors, we found the expected relationship of high CRP and delirium (RR 1.5, 95% CI 1.1-2.2). CONCLUSION: COMT warriors may be protected against the increased risk of delirium associated with high CRP on postoperative day 2. With further confirmation, COMT genotype may help target interventions for delirium prevention in the vulnerable nonwarrior group.

The Better Assessment of Illness Study for Delirium Severity: Study Design, Procedures, and Cohort Description.

BACKGROUND/OBJECTIVES: To describe the design, procedures, and cohort for the Better ASsessment of ILlness -(BASIL) study, which is conducted to develop and test new delirium severity measures, compare them with existing measures, and examine related clinical outcomes. METHODS: Prospective cohort study with 1 year follow-up of study participants at a large teaching hospital in Boston, Massachusetts. After brief cognitive testing and the Delirium Symptom Interview, delirium and delirium severity were rated daily in the hospital using the Confusion Assessment Method (CAM) and CAM-Severity score, the Delirium Rating Scale-Revised-98 (DRS-R-98), and the Memorial Delirium Assessment Scale (MDAS). Other key study variables included comorbidity, physical function (basic and instrumental activities of daily living [ADL]), ratings of subjective health and well-being, and clinical outcomes (length of stay, 30 day rehospitalization, nursing home admission, healthcare utilization). Follow-up interviews occurred at 1- and 12-month with patients and families. In 42 patient interviews, inter-rater reliability for key variables was assessed. RESULTS: Of 768 eligible patients approached, 469 were screened and 352 enrolled, yielding an overall study response rate of 67% for potentially eligible participants. The mean participant was 80.3 years old (SD 6.8) and 203 (58%) were female. The majority of patients were medically complex with Charlson Comorbidity Scores ≥2 (192 patients, 55%), and 102 (29%) met criteria for dementia. Inter-rater reliability assessments (n = 42 pairs) were high for overall ratings of presence or absence of delirium by CAM (κ = 1.0), delirium severity by DRS-R-98 and MDAS (weighted kappa, κ = 1.0 for each) and for ADL impairment (κ = 1.0). For eligible participants at each time point, 278 out of 308 (90%) completed the 1-month follow-up and 132 out of 256 (53%) have completed the 12-month follow-up to date, which is still in progress. Among those who completed interviews, there was only 1-3% missing data on most major outcomes (delirium, basic ADL, and readmission). CONCLUSION: The BASIL study presents an innovative effort to advance the conceptualization and measurement of delirium severity. Unique strengths include the diverse cohort with complete high quality data and longitudinal follow-up, along with detailed collection of multiple delirium measures daily during hospitalization.

Detection of Delirium in Hospitalized Older General Medicine Patients: A Comparison of the 3D-CAM and CAM-ICU.

BACKGROUND: Delirium is common in older hospitalized patients and is associated with poor outcomes, yet most cases go undetected. The best approach for systematic delirium identification outside the intensive care unit remains unknown. OBJECTIVE: To conduct a comparative effectiveness study of the Confusion Assessment Method for the ICU (CAM-ICU) and the newly developed 3-minute diagnostic assessment for delirium using the Confusion Assessment Method (3D-CAM) in general medicine inpatients. DESIGN: Cross-sectional comparative effectiveness study. SETTING: Two non-intensive care general medicine units at a single academic medical center. PARTICIPANTS: Hospitalized general medicine patients aged ≥75 years. MEASUREMENTS: Clinicians performed a reference standard assessment for delirium that included patient interviews, family interviews, and review of the medical record. An expert panel determined the presence or absence of delirium using DSM-IV criteria. Two blinded research assistants administered the CAM-ICU and the 3D-CAM in random order, and we determined their diagnostic test characteristics compared to the reference standard. RESULTS: Among the 101 participants (mean age 84 ± 5.5 years, 61 % women, 25 % with dementia), 19 % were classified as delirious based on the reference standard. Evaluation times for the 3D-CAM and CAM-ICU were similar. The sensitivity [95 % confidence interval (CI)] of delirium detection for the 3D-CAM was 95 % [74 %, 100 %] and for the CAM-ICU was 53 % [29 %, 76 %], while specificity was >90 % for both instruments. Subgroup analyses showed that the CAM-ICU had sensitivity of 30 % in patients with mild delirium vs. 100 % for the 3D-CAM. CONCLUSIONS: In this comparative effectiveness study, we found that the 3D-CAM had substantially higher sensitivity than the CAM-ICU in hospitalized older general medicine patients, and similar administration time. Therefore, the 3D-CAM may be a superior screening tool for delirium in this patient population.

Treatment outcomes in completely resected stage I to stage IV uterine carcinosarcoma with rhabdomyosarcoma differentiation.

OBJECTIVE: To evaluate overall survival (OS) and progression-free survival (PFS) after adjuvant therapy in stage I to stage IV uterine carcinosarcoma with rhabdomyosarcoma differentiation. METHODS: Memorial Sloan-Kettering Cancer Center medical records from 1990 to 2012 were reviewed. Patients who received chemotherapy with or without radiation therapy (RT), or RT alone, for completely resected stage I to stage IV uterine carcinosarcoma with rhabdomyosarcoma differentiation were included. RESULTS: Of 53 patients, International Federation of Gynecology and Obstetrics stage distribution was as follows: I, 13 (24.5%); II, 8 (15.1%); III, 13 (24.5%); and IV, 19 (35.9%). Forty-one (77.4%) of 53 patients received adjuvant chemotherapy, and 34% of the patients who received chemotherapy also received pelvic RT or intravaginal brachytherapy (IVRT). Twelve (22.6%) of the 53 patients received only pelvic RT with/without IVRT. Paclitaxel-carboplatin was the most commonly used adjuvant chemotherapy treatment. The median PFS for the entire cohort was 13.4 months (95% confidence interval [CI], 10.5-17.0). The median OS for the entire cohort was 23.0 months (95% CI, 16.9-34.3). The median PFS periods by stage were 15.9 months for stages I/II versus 11.2 months for stages III/IV (P = 0.012). Median OS was not reached in the early-stage cohort. The median OS for the late-stage cohort was 20.9 months (P = 0.004). The median PFS periods by treatment were 10.4 months for pelvic RT with/without IVRT group versus 13.1 months for chemotherapy with/without pelvic RT with/without IVRT group (P = 0.498). The median OS periods by treatment were 23.6 months for chemotherapy with/without pelvic RT with/without IVRT group versus 16.9 months for pelvic RT with/without IVRT group (P = 0.501). CONCLUSION: The results suggest that chemotherapy alone or in combination with RT is associated with longer PFS and OS compared to RT alone. Only the stage of disease significantly affected PFS and OS.

Conversando con las madres: Una guía para la crianza de los niños. Lecciones para la vida / Talking with mothers: A guide for growing children. Lessons for life

Contiene: El embarazo, su significado, el parto; Las ventajas de la lactancia materna; La crianza de los niños; Conceptos de nutrición, los mejores alimentos disponibles; La pirámide, guía de los alimentos; Aspectos psicológicos del niño en edad escolar; La obesidad, sus riesgos para la vida; Qué podemos hacer para proteger a nuestros niños de las enfermedades más frecuentes? Los síntomas de esas enfermedades que se pueden detectar fácilmente; Qué hacer mientras llega la asistencia profesional; Los entretenimientos; La prevención de los accidentes; La adolescencia; Primeros auxilios; Las funciones de los médicos; La evaluación del crecimiento de los niños; La evaluación del crecimiento de los niños; El programa de salud reproductiva; La enfermedad diarréica aguda en la infancia; La desnutrición infantil