A Path to High-Value Gastric Cancer Surgery Care Delivery.

Objective: To evaluate the feasibility, safety, and effectiveness of a comprehensive regional program, including the Minimally Invasive Recovery and Empowerment Care (MIREC) pathway, that can significantly reduce hospital stays after laparoscopic gastrectomy without increasing adverse events. Background: Cost-effectiveness and improving patient outcomes are crucial in providing quality gastric cancer care worldwide. Methods: To compare the outcomes of gastric cancer surgery using 2 different models of care within an integrated healthcare system from February 2012 to March 2023. The primary endpoint was the length of hospital stay. The secondary endpoints were the need for intensive care unit care, emergency room (ER) visits, readmission, reoperation, and death within 30 days after surgery. Results: There were 553 patients, 167 in the pre-(February 2012-April 2016) and 386 in the post-MIREC period (May 2016-March 2023). Perioperative chemotherapy utilization increased from 31.7% to 76.4% (P < 0.0001). Laparoscopic gastrectomy increased from 17.4% to 97.7% (P < 0.0001). Length of hospitalization decreased from 7 to 2 days (P < 0.0001), with 32.1% and 88% of patients discharged home on postoperative day 1 and postoperative day 2, respectively. When comparing pre- and post-MIREC, intensive care unit utilization (10.8% vs. 2.9%, P < 0.0001), ER visits (34.7% vs. 19.7%, P = 0.0002), and readmission (18.6% vs. 11.1%, P = 0.019) at 30 days were also considerably lower. In addition, more patients received postoperative adjuvant chemotherapy (31.4% to 63.5%, P < 0.0001), and the time between gastrectomy and starting adjuvant chemotherapy was also less (49-41 days; P = 0.002). Conclusion: This comprehensive regional program, which encompasses regionalization care, laparoscopic approach, modern oncologic care, surgical subspecialization, and the MIREC pathway, can potentially improve gastric cancer surgery outcomes. These benefits include reduced hospital stays and lower complication rates. As such, this program can revolutionize how gastric cancer surgery is delivered, leading to a higher quality of care and increased value to patients.

Medicaid Expansion: the impact of health policy on bariatric surgery.

BACKGROUND: Underutilization of bariatric surgery in uninsured and marginalized communities is well-documented. When discussing population health, healthcare access and equity are crucial components often influenced by health policy. OBJECTIVES: This study aims to determine if disparities in the use of bariatric surgery were influenced by changes in healthcare policy from the Affordable Care Act's 2014 expansion of Medicaid. SETTING: A retrospective analysis of the 2012-2018 Healthcare Cost and Utilization Project National Inpatient Sample was performed for elective Roux-en-Y gastric bypass and sleeve gastrectomy surgeries performed within the United States. METHODS: States were grouped into regions as defined by the U.S. Census Bureau. Medicaid as the primary payor for bariatric surgery was compared by region and year, as well as utilization by marginalized populations. RESULTS: Analysis included 212,776 bariatric surgeries. Medicaid as the primary payor increased from 9% to 19% from 2012 to 2018. A greater share of bariatric surgeries with Medicaid as the primary payor was located in the Northeast and West, as compared with those located in the Midwest and South. Medicaid beneficiaries in marginalized communities (Black race, Hispanic race, lowest income quartile, rural communities) made up a larger share of the bariatric surgery population over time. CONCLUSIONS: The Affordable Care Act's Medicaid Expansion improved health coverage and access to care, including bariatric surgery. An increase in bariatric surgeries among Medicaid beneficiaries correlated with the 2014 expansion of Medicaid. Social and economic disparities regarding bariatric surgery have improved though more progress may be seen with the adoption of Medicaid Expansion by the remaining U.S. states.

Same-Day Home Recovery for Benign Foregut Surgery.

Importance: Same-day home recovery (SHR) is now the standard of care for many major surgical procedures and has the potential to become standard practice for benign foregut procedures (eg, hiatal hernia repair, fundoplication, and Heller myotomy). Objective: To determine whether SHR for patients undergoing benign foregut surgery is feasible, safe, and effective. Design, Setting, and Participants: This prospective cohort study took place across 19 medical centers within an integrated health care system in northern California from January 2019 through September 2021. Participants included consecutive patients undergoing elective benign foregut surgery. Exposures: Standardized SHR program. Main Outcomes and Measures: The primary end point was the rate of SHR. The secondary end points were 7-day and 30-day rates of postoperative emergency department visits, hospital readmissions, and reoperations. Results: Of 1248 patients who underwent benign foregut surgery from January 2017 through September 2021, 558 were patients before implementation of the SHR program and 690 were patients postimplementation. The mean age of patients was 60 years, and 759 (59%) were female. The preimplementation SHR rate was 64 of 558 patients (11.5%) in 2018 and increased to 82 of 113 patients (72.6%) by 2021 (94/350 [26.9%] in 2019 and 112/227 [49.3%] in 2020; P < .001). There were no statistical differences in the 7-day and 30-day rates of postoperative emergency visits, hospital readmissions, and reoperations or 30-day mortality in the SHR vs non-SHR groups in the postimplementation era. Conclusions and Relevance: In this study, implementation of a regional SHR program among patients undergoing elective benign foregut surgery was feasible, safe, and effective. The changes in perioperative care require comprehensive patient education and full multidisciplinary support. An SHR program for benign foregut procedures has the potential to improve patient care and cost-effectiveness in care delivery.

Clinical Outcomes Following Regionalization of Gastric Cancer Care in a US Integrated Health Care System.

PURPOSE: In 2016, Kaiser Permanente Northern California regionalized gastric cancer care, introducing a regional comprehensive multidisciplinary care team, standardizing staging and chemotherapy, and implementing laparoscopic gastrectomy and D2 lymphadenectomy for patients eligible for curative-intent surgery. This study evaluated the effect of regionalization on outcomes. METHODS: The retrospective cohort study included gastric cancer cases diagnosed from January 2010 to May 2018. Information was obtained from the electronic medical record, cancer registry, state vital statistics, and chart review. Overall survival was compared in patients with all stages of disease, stage I-III disease, and curative-intent gastrectomy patients using annual inception cohorts. For the latter, the surgical approach and surgical outcomes were also compared. RESULTS: Among 1,429 eligible patients with gastric cancer with all stages of disease, one third were treated after regionalization, 650 had stage I-III disease, and 394 underwent curative-intent surgery. Among surgical patients, neoadjuvant chemotherapy utilization increased from 35% to 66% (P < .0001), laparoscopic gastrectomy increased from 18% to 92% (P < .0001), and D2 lymphadenectomy increased from 2% to 80% (P < .0001). Dissection of ≥ 15 lymph nodes increased from 61% to 95% (P < .0001). Surgical complication rates did not appear to increase after regionalization. Length of hospitalization decreased from 7 to 3 days (P < .001). Overall survival at 2 years was as follows: all stages, 32.8% pre and 37.3% post (P = .20); stage I-III cases with or without surgery, 55.6% and 61.1%, respectively (P = .25); and among surgery patients, 72.7% and 85.5%, respectively (P < .03). CONCLUSION: Regionalization of gastric cancer care within an integrated system allowed comprehensive multidisciplinary care, conversion to laparoscopic gastrectomy and D2 lymphadenectomy, increased overall survival among surgery patients, and no increase in surgical complications.

Small Cell Lung Carcinoma and Synchronous Rectal Adenocarcinoma and Jejunal Gastrointestinal Stromal Tumor Present in a Patient With History of Laryngeal Squamous Cell Carcinoma.

BACKGROUND: The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. CASE REPORT: We report such a case of a 67-year-old male smoker with a history of laryngeal squamous cell carcinoma. He was incidentally identified through follow up computed tomography to have three masses in the lung, rectum and jejunum, respectively. Biopsies were performed and demonstrated synchronous lung small cell carcinoma (pT1bN0) and rectal adenocarcinoma. The patient underwent fractionated stereotactic radiation (FSRT) to the pulmonary tumor and chemotherapy with cisplatin and etoposide followed by laparoscopic rectum low anterior resection and small bowel segmental resection. Final pathology diagnoses confirmed synchronous microsatellite stable (MMS) moderately differentiated adenocarcinoma of the rectum (pT3N1b) and jejunal gastrointestinal stromal tumor (GIST), spindle cell type (pT2N0). At 8 months follow up postsurgery, the patient was doing well and no tumor recurrences were identified. CONCLUSION: To the best of our knowledge, this is the first documented case of synchronous primary small cell lung carcinoma, rectal adenocarcinoma, and GIST in the English literature. The rarity, diagnosis and treatment challenges of these entities are discussed.

Intraoperative assessment of the effects of laparoscopic sleeve gastrectomy on the distensibility of the lower esophageal sphincter using impedance planimetry.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has emerged as an effective weight-loss procedure for morbid obesity that is also effective for treating comorbidities such as diabetes. However, it has been associated with the development of GERD postoperatively. The pathophysiology of post-LSG GERD is unknown, and current studies have shown conflicting results. The aim of our study is to shed light on this issue by investigating the effect of LSG on the lower esophageal sphincter (LES) function and the relationship of LES function to GERD symptoms. METHODS: A prospective study of patients undergoing LSG from 10/2013 to 8/2014 at a single academic tertiary referral center was carried out. Patients undergoing a concomitant procedure such as hiatal hernia repair or laparoscopic gastric band removal were excluded. Distensibility of the LES was measured after pneumoperitoneum and after LSG. Baseline GERD-HRQL was obtained with follow-up GERD-HRQL and weight at 3 and 6 months. The primary outcomes measured were LES distensibility and GERD-HRQL scores after LSG. Our secondary outcome was a correlation between LES distensibility and GERD-HRQL scores after LSG. RESULTS: Fifteen subjects were enrolled (5M/10F). Mean age was 51 years (30-71 years), and mean BMI 45 kg/m2 (30-58). We were able to obtain follow-up data for all patients at 3 months. Mean LES distensibility increased from 1.2 before LSG to 2.2 after LSG (p = 0.017). Median GERD-HRQL was 0 before LSG and remained essentially negative at 1 and 0 (3 and 6 months postoperatively, respectively). Three (27 %) of the patients had de novo GERD at 3 months following LSG. One (25 %) patient had remission of GERD. There was no correlation between LES distensibility and GERD symptoms. CONCLUSION: While LSG weakens the LES immediately, it does not predictably affect postoperative GERD symptoms; therefore, distensibility is not the only factor affecting development of postoperative GERD, confirming the multifactorial nature of post-LSG GERD.

Possible influence of variant of the P-glycoprotein gene (MDR1/ABCB1) on clinical response to guanfacine in children with pervasive developmental disorders and hyperactivity.

OBJECTIVE: Guanfacine has been shown to reduce hyperactive behaviors in children with attention-deficit/hyperactivity disorder (ADHD) and possibly in children with pervasive developmental disorder (PDD) and hyperactivity. The aim of this exploratory study was to examine whether gene variants encoding the multidrug resistance protein (MDR1 or ABCB1) , a drug transporter at the blood-brain barrier, are associated with variability in the efficacy of guanfacine in children with PDD and hyperactivity. METHODS: Children with PDD who participated in an 8-week open-label trial of guanfacine were genotyped for the C3435T single-nucleotide polymorphism (SNP) variant of the MDR1 gene, a variant reported to alter function of the transporter. The decrease from baseline to 8 weeks in parent-rated Aberrant Behavior Checklist (ABC) hyperactivity and Swanson, Nolan, and Pelham (SNAP) scores were analyzed by MDR1 genotype. Response was compared between subjects homozygous for the minor allele T of the C34535T MDR1 variant (T/T) versus other genotypes (C/T and C/C). RESULTS: Disruptive behavior decreased during guanfacine treatment as assessed by several end points in the 25 enrolled children (23 boys and 2 girls). Genotype data were available from 22 children. Subjects with either C/T or C/C (n = 16) genotypes showed a three-fold greater improvement than T/T MDR1 C3435T genotype (n = 6) (mean decrease of 15.1 +/- 12.6, or 50.7% from baseline, versus 4.5 +/- 5.1, or 15.6% from baseline) in parent-rated ABC Hyperactivity scores over 8 weeks (p = 0.03). Parent-rated ADHD SNAP scores also differed by genotype (p = 0.05). CONCLUSIONS: Gene variants in MDR1 may influence guanfacine response on hyperactive-impulsive behaviors via altered membrane transport. If replicated in larger samples, additional studies would be important to clarify the mechanisms underlying this effect and to determine its clinical significance. 2.

Pancreatic-pleural fistula is best managed by early operative intervention.

BACKGROUND: Pancreatic-pleural fistula is an uncommon complication of chronic pancreatitis occurring as a result of disruption of the main pancreatic duct and tracking of pancreatic fluid through the retroperitoneum into 1 or both thoracic cavities. The optimal treatment strategy for pancreatic-pleural fistula is unknown; it has traditionally been medical management followed by operative therapy for patients who fail to respond to conservative treatment. Our objective was to compile the case reports of pancreatic-pleural fistula in the literature in order to better define clinical management strategy. METHODS: The case management of pancreatic-pleural fistula was reviewed and a structured MEDLINE search for published studies was performed. Descriptive statistical analysis was performed on compiled data. RESULTS: Review of the literature revealed 63 adult patients with pancreatic-pleural fistula published in English between 1970 and 2008. The majority of patients were male (71%) and there was a predominance of alcohol-associated chronic pancreatitis (51%). There were 10 complications (16%) and 2 deaths (3%) reported. Most patients were treated initially with medical therapy (87%). Medical therapy was deemed to have failed after an average period of 35+/-5 days. Total duration of therapy for patients in whom operative intervention was required after attempted medical management was 40+/-6 days, which was greater than the surgery alone cohort. In total, operative treatment was successful more often than medical therapy (94% vs 31%). CONCLUSION: Analysis from this series indicates that a majority of patients recover from pancreatic-pleural fistula without sequelae (81%). Attempts at prolonged periods of medical therapy tend to delay the resolution of the fistula compared with patients who undergo definitive operative intervention early in the course of treatment.

External validation of the San Francisco Syncope Rule.

STUDY OBJECTIVE: We externally validate the ability of the San Francisco Syncope Rule to accurately identify syncope patients who will experience a 7-day serious clinical event. METHODS: Patients who presented to a single academic emergency department (ED) between 8 am and 10 pm with syncope or near-syncope were prospectively enrolled. Treating physicians recorded the presence or absence of all San Francisco Syncope Rule risk factors. Patients were contacted by telephone at 14 days for a structured interview. A 3-physician panel, blinded to the San Francisco Syncope Rule score, reviewed ED medical records, hospital records, and telephone interview forms to identify predefined serious clinical events. The primary outcome was the ability of the San Francisco Syncope Rule to predict any 7-day serious clinical event. A secondary outcome was the ability of the San Francisco Syncope Rule to predict 7-day serious clinical events that were not identified during the initial ED evaluation. RESULTS: Of 592 eligible patients, 477 (81%) provided informed consent. Direct telephone contact or admission/outpatient records were successfully obtained for 463 (97%) patients. There were 56 (12%) patients who had a serious 7-day clinical event, including 16 (3%) who received a diagnosis after the initial ED evaluation. Sensitivity and specificity of the San Francisco Syncope Rule for the primary outcome were 89% (95% confidence interval [CI] 81% to 97%) and 42% (95% CI 37% to 48%), respectively, and 69% (95% CI 46% to 92%) and 42% (95% CI 37% to 48%), respectively, for the secondary outcome. Estimates of sensitivity were minimally affected by missing data and most optimistic assumptions for missing follow-up information. CONCLUSION: In this external validation cohort, the San Francisco Syncope Rule had a lower sensitivity and specificity than in previous reports.

Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens.

CONTEXT: Preclinical studies demonstrate that nicotine administration leads to dopamine release in the ventral striatum. However, human studies reveal considerable interindividual variability in the extent of smoking-induced dopamine release. OBJECTIVE: To determine whether common gene variants of the brain dopamine pathway explain this observed phenotypic variability in humans. DESIGN: Blood samples were drawn to determine gene variants of dopamine system components, and positron emission tomography scanning with the radiotracer raclopride labeled with radioactive carbon (11C) was performed to measure smoking-induced dopamine release. SETTING: Academic brain imaging center. PARTICIPANTS: Forty-five tobacco-dependent smokers. INTERVENTIONS: Subjects either smoked a cigarette (n = 35) or did not smoke (n = 10) during positron emission tomography scanning. MAIN OUTCOME MEASURES: Gene variants of dopamine system components (the dopamine transporter variable nucleotide tandem repeat, D2 receptor Taq A1/A2, D4 receptor variable nucleotide tandem repeat, and catechol-O-methyltransferase Val158Met polymorphisms) and change in [11C]raclopride binding potential in the ventral caudate/nucleus accumbens on positron emission tomography scans. RESULTS: For subjects who smoked during scanning, those with at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype had greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes. An overall decrease in ventral caudate/nucleus accumbens binding potential in those who smoked compared with those who did not smoke was also found but was smaller in magnitude than previously reported. CONCLUSIONS: Smokers with genes associated with low resting dopamine tone have greater smoking-induced (phasic) dopamine release than those with alternate genotypes. These findings suggest that dopamine system genotype variabilities explain a significant proportion of the interindividual variability in smoking-induced dopamine release and indicate that smoking-induced dopamine release has a genetic predisposition.

Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies.

Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC50 > 5-10 micromol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y >> D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations.

Anti-recoverin antibodies induce an increase in intracellular calcium, leading to apoptosis in retinal cells.

Autoantibodies against recoverin, a Ca2+-binding protein found in patients with cancer-associated retinopathy (CAR syndrome), penetrate retinal cells and induce their apoptosis via a mitochondrial pathway. The goal of this study was to investigate whether the entry of anti-recoverin antibody into E1A.NR3 retinal cells causes a change in intracellular Ca2+. Intracellular Ca2+ was measured using the Ca2+-sensitive fluorescent dye Fura-2 AM in living E1A.NR3 retinal cells treated with anti-recoverin antibody Rec-1, patients' autoantibodies, and control rat and human IgG. The exposure of retinal cells to Rec-1 antibody and to the CAR patients' autoantibodies in vitro caused a significant increase in intracellular Ca2+, while non-specific antibodies did not induce such an effect. Co-treatment of the E1A.NR3 cells with Rec-1 in the presence of nifedipine, a L-type Ca2+ channel blocker, significantly suppressed the increase of Ca2+. Treatment with nifedipine also blocked changes in the anti-apoptotic protein bcl-xL and in expressions of the pro-apoptotic protein bax. Nifedipine-treated cells also showed a decrease in cytosolic cytochrome c release and a decrease in caspase 3 activation, compared to cells treated only with Rec-1 antibody. The increase in the antibody-induced Ca2+ is at least in part dependent on extracellular Ca2+. Nifedipine was found to inhibit the entry of Ca2+ into the cells and to protect them from Rec-1-induced apoptosis. Increased levels of intracellular Ca2+ may lead to retinal dysfunction and degeneration in the CAR syndrome. Our results provide a molecular basis for the use of Ca2+ blockers in the treatment of the CAR syndrome.

PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.

PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. MATERIALS AND METHODS: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. RESULTS: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. CONCLUSION: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.

Anti-apoptotic effects of CNTF gene transfer on photoreceptor degeneration in experimental antibody-induced retinopathy.

Autoantibodies against recoverin are found in the sera of patients with cancer-associated retinopathy syndrome, a paraneoplastic disease associated with retinal degeneration. We have previously shown that anti-recoverin autoantibodies induced photoreceptor apoptotic cell death after injection into the vitreous of Lewis rats. Ciliary neurotrophic factor (CNTF) has been shown to promote the survival of a number of neuronal cell types, including photoreceptors. In this study, we examined whether an adeno-associated virus (AAV)-mediated delivery of gene encoding the human CNTF protected photoreceptor cells from anti-recoverin antibody-induced death. One month after subretinal injection of the AAV-CNTF gene into one eye and a control vector into the other eye, an anti-recoverin antibody was injected to induce retinal cell death in Lewis rats. Subretinal administration of the virus led to an efficient transduction of photoreceptors, as indicated by immunostaining of retinas with anti-CNTF. Histological examination of the corresponding retinas showed that photoreceptor cells were significantly protected from apoptotic death in the CNTF-treated eyes. CNTF treatment of the retinas resulted in a time-dependent activation of STAT 3. The present study shows that an AAV-mediated delivery of CNTF may protect photoreceptors from antibody-induced cell death through the activation of STAT3 and the suppression of caspase 3 activity, a key caspase leading to apoptosis. Thus, CNTF may be a useful treatment for human antibody-mediated retinal degeneration.

Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway.

Anti-recoverin autoantibodies have been associated with cancer-associated retinopathy (CAR), a paraneoplastic blinding disease. Those antibodies have been shown to induce apoptotic death of photoreceptor cells. The objective was to ascertain the mechanisms of retinal death induced by anti-recoverin antibody in vitro by examining the apoptotic pathway involved in retinal cell death. Internalization of anti-recoverin antibody or its Fab fragments by retinal cells mediated by endocytosis lead to cytotoxicity. Antibody cellular translocation induced the increase of bcl-x(s) and bax and the decrease in the bcl-x(L) protein. We detected the release of cytochrome c and down-regulation of the apaf-1 protein. This correlated with the sequential activation of caspase 9 and caspase 3, as well as the degradation of the caspase substrate PARP and the fragmentation of DNA. Our data show that anti-recoverin antibodies are inducers of apoptosis through the mitochondrial pathway involving caspases 9 and 3. We propose that a similar mechanism may be in place in patients with CAR syndrome where high levels of circulating antibodies have been associated with retinal degeneration.