FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study.

BACKGROUND: Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells. PATIENTS AND METHODS: Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile. RESULTS: From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent. CONCLUSIONS: Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials. CLINICALTRIALS.GOV NUMBER: NCT01197885.

A self-administered screening instrument for psychogenic nonepileptic seizures.

BACKGROUND: Delay in distinguishing psychogenic nonepileptic seizures (PNES) from epilepsy may result in significant health and economic burdens. Screening tools are needed to facilitate earlier identification of patients with PNES, thereby maximizing cost-effective use of video electroencephalography (VEEG), the expensive gold standard for differentiating PNES from epilepsy. We developed and prospectively validated a self-administered PNES screening questionnaire using variables known to distinguish PNES from epilepsy patients. METHODS: Adults referred for inpatient VEEG monitoring at two epilepsy centers were prospectively invited to complete a preliminary 209-item questionnaire assessing demographic, clinical, seizure-related, and psychosocial information that appeared in the literature as potentially useful indicators of PNES. A hybrid neural-bayesian classifier was trained to predict PNES using a sample at one center, and was prospectively validated on a separate set of naive patients from both centers. RESULTS: Of 211 enrolled subjects from the training center, 181 met the study criteria for either PNES (n = 48, 27%), epilepsy (n = 116, 64%), or coexisting PNES and epilepsy (n = 17, 9%). Variable reduction procedures identified 53 questionnaire items that were necessary to accurately predict PNES diagnosis. The hybrid classifier predicted PNES diagnosis with 94% sensitivity and 83% specificity at the training center, and 85% sensitivity and 85% specificity at the second center (n = 46; 17 PNES, 26 epilepsy, 3 with coexisting PNES and epilepsy). CONCLUSIONS: We developed and prospectively validated a self-administered psychogenic nonepileptic seizure screening questionnaire that could hasten referral for video electroencephalography and reduce the health and economic burdens from delayed diagnosis or misdiagnosis.

Relation between literacy and HIV treatment knowledge among patients on HAART regimens.

Successful management of HIV requires patient understanding and ability to act on treatment information. We examined the relationship between patient literacy and understanding of HIV treatment. Literacy, knowledge of CD4 count and viral load, and correct identification of HIV medications in regimen were evaluated in 204 patients receiving care in Shreveport, Louisiana and Chicago, Illinois. One-third of patients had limited literacy skills. These patients were less able to describe CD4 count (p < 0.001), viral load (p < 0.001) and to correctly identify medications in their regimen (p < 0.001). In the multivariate analysis, limited literacy was an independent predictor of poor understanding of CD4 count (OR 2.9, 95% CI: 1.3-6.3) and viral load (OR 4.1, 95% CI: 1.9-8.8). For correct medication identification, a significant interaction was found between number of HIV medications and literacy level. Among patients taking only 1-2 HIV medications, 100% of higher literate patients were able to identify their medications, compared to none of the lower literate patients prescribed three or more HIV medications. Patients with limited literacy skills may lack essential knowledge related to their HIV treatment. Clinicians may require additional training for improving communication with these patients.

Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery.

BACKGROUND: Pneumonia is a common postoperative complication associated with substantial morbidity and mortality. OBJECTIVE: To develop and validate a preoperative risk index for predicting postoperative pneumonia. DESIGN: Prospective cohort study with outcome assessment based on chart review. SETTING: 100 Veterans Affairs Medical Centers performing major surgery. PATIENTS: The risk index was developed by using data on 160 805 patients undergoing major noncardiac surgery between 1 September 1997 and 31 August 1999 and was validated by using data on 155 266 patients undergoing surgery between 1 September 1995 and 31 August 1997. Patients with preoperative pneumonia, ventilator dependence, and pneumonia that developed after postoperative respiratory failure were excluded. MEASUREMENTS: Postoperative pneumonia was defined by using the Centers for Disease Control and Prevention definition of nosocomial pneumonia. RESULTS: A total of 2466 patients (1.5%) developed pneumonia, and the 30-day postoperative mortality rate was 21%. A postoperative pneumonia risk index was developed that included type of surgery (abdominal aortic aneurysm repair, thoracic, upper abdominal, neck, vascular, and neurosurgery), age, functional status, weight loss, chronic obstructive pulmonary disease, general anesthesia, impaired sensorium, cerebral vascular accident, blood urea nitrogen level, transfusion, emergency surgery, long-term steroid use, smoking, and alcohol use. Patients were divided into five risk classes by using risk index scores. Pneumonia rates were 0.2% among those with 0 to 15 risk points, 1.2% for those with 16 to 25 risk points, 4.0% for those with 26 to 40 risk points, 9.4% for those with 41 to 55 risk points, and 15.3% for those with more than 55 risk points. The C-statistic was 0.805 for the development cohort and 0.817 for the validation cohort. CONCLUSIONS: The postoperative pneumonia risk index identifies patients at risk for postoperative pneumonia and may be useful in guiding perioperative respiratory care.

Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. The National Veterans Administration Surgical Quality Improvement Program.

OBJECTIVE: To develop and validate a preoperative risk index for predicting postoperative respiratory failure (PRF). SUMMARY BACKGROUND DATA: Respiratory failure is an important postoperative complication. METHOD: Based on a prospective cohort study, cases from 44 Veterans Affairs Medical Centers (n = 81,719) were used to develop the models. Cases from 132 Veterans Affairs Medical Centers (n = 99,390) were used as a validation sample. PRF was defined as mechanical ventilation for more than 48 hours after surgery or reintubation and mechanical ventilation after postoperative extubation. Ventilator-dependent, comatose, do not resuscitate, and female patients were excluded. RESULTS: PRF developed in 2,746 patients (3.4%). The respiratory failure risk index was developed from a simplified logistic regression model and included abdominal aortic aneurysm repair, thoracic surgery, neurosurgery, upper abdominal surgery, peripheral vascular surgery, neck surgery, emergency surgery, albumin level less than 30 g/L, blood urea nitrogen level more than 30 mg/dL, dependent functional status, chronic obstructive pulmonary disease, and age. CONCLUSIONS: The respiratory failure risk index is a validated model for identifying patients at risk for developing PRF and may be useful for guiding perioperative respiratory care.

A new preadmission staging system for predicting inpatient mortality from HIV-associated Pneumocystis carinii pneumonia in the early highly active antiretroviral therapy (HAART) era.

A common severe complication of human immunodeficiency virus (HIV) infection has been Pneumocystis carinii pneumonia (PCP). Recently, with increasing use of PCP prophylaxis and multidrug antiretroviral therapy, the clinical manifestations of HIV infection have changed dramatically and the predictors of inpatient mortality for PCP may have also changed. We developed a new staging system for predicting inpatient mortality for patients with HIV-associated PCP admitted between 1995 and 1997. Trained abstractors performed chart reviews of 1,660 patients hospitalized with HIV-associated PCP between 1995 and 1997 at 78 hospitals in seven metropolitan areas in the United States. The overall inpatient mortality rate was 11.3%. Hierarchically optimal classification tree analysis identified an ordered five-category staging system based on three predictors: wasting, alveolar-arterial oxygen gradient (AaPO(2)), and serum albumin level. The mortality rate increased with stage: 3.7% for Stage 1, 8.5% for Stage 2, 16.1% for Stage 3, 23.3% for Stage 4, and 49.1% for Stage 5. This new staging system may be useful for severity of illness adjustment in the current era while exploring current variation in HIV-associated PCP inpatient mortality rates among hospitals and across cities.

Racial variation in the use of laparoscopic cholecystectomy in the Department of Veterans Affairs medical system.

BACKGROUND: While studies have found racial differences in the rates of use of established invasive cardiac and cerebrovascular procedures, no study has evaluated racial variation in the rates of adoption of new surgical procedures. For patients undergoing laparoscopic cholecystectomy, the procedure represents a new and safe option that shortens the duration of postoperative hospitalization by almost one week. In this study, we evaluated whether, in the equal access Veterans Affairs (VA) medical system, the rate of adoption of this procedure and improvements in the duration of postoperative hospitalization differed between African-American and Caucasian patients. STUDY DESIGN: Data were obtained from two sources-administrative claims files and prospectively compiled dinical data from medical records and patient interviews. In both data sets, frequency of use, length of stay, and outcomes for African-American and Caucasian patients undergoing minimally invasive and open gallbladder surgery were analyzed for the first four years of use of the procedure in the VA system (1992 to 1995). RESULTS: Analyses based on claims files indicated that, after adjustment for potentially confounding variables, African-American patients who underwent cholecystectomy in VA medical centers were 25% less likely to undergo a minimally invasive cholecystectomy during the first 4 years of use of the new procedure (adjusted odds ratio, 0.74; 95% confidence interval, 0.66-0.83). Shortening of the average postoperative length of stay from 9 days or more in the prelaparoscopic era to less than 4.5 days for patients undergoing the laparoscopic procedure occurred in the first year for Caucasian patients, but did not occur until the fourth year for African-American patients (p<0.001). The overall difference in postoperative length of stay between African-American and Caucasian patients more than doubled from 1.7 days before introduction of laparoscopic cholecystectomy to 3.8 days in the fourth year. In comparison, analyses based on nurse-compiled clinical data indicated that, after adjustment for relevant clinical factors, racial variations in the rate of laparoscopic surgery were even larger (adjusted odds ratio for laparoscopic versus open cholecystectomy for African-American versus Caucasian veterans, 0.68; 95% confidence interval, 0.55-0.84). CONCLUSIONS: Compared to Caucasian patients, African-American patients who underwent cholecystectomy in VA medical centers had an approximately 25% to 32% lower likelihood of undergoing minimally invasive cholecystectomy procedures. The differences in rates of adoption of laparoscopic surgery did not appear to be from more comorbid illnesses among African-American patients. African-American and Caucasian veterans may differ in their preference for new surgical procedures like laparoscopic cholecystectomy. Conversely, VA physicians may have been less likely to recommend laparoscopic cholecystectomies to African-American patients.