A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic Her2-negative breast cancer.

BACKGROUND: Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer. PATIENTS AND METHODS: Eligible patients had locally advanced, unresectable, or metastatic HER2- breast cancer with Eastern Cooperative Group performance status of 0-2 and without prior taxane therapy in the advanced setting. Study treatment included 600 mg of zilovertamab administered intravenously (IV) on Days 1 and 15 of Cycle 1 and then Day 1 of each 28-day cycle along with paclitaxel weekly at 80 mg/m2 IV. RESULTS: Study patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response. CONCLUSION: The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted. TRIAL REGISTRATION: NCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.

Treatment of cystinosis with delayed-release cysteamine: 6-year follow-up.

BACKGROUND: Patients with nephropathic cystinosis are required to take 6-hourly immediate-release cysteamine (Cystagon®) to reduce disease progression. This arduous regimen affects quality of life, disrupts sleep, and may result in non-compliance with therapy. Enteric-coated cysteamine bitartrate (EC-cysteamine) was developed as a "proof-of-concept" formulation for twice-daily ingestion. Previous reports have shown this therapy to be effective up to a mean of 14 months. CASE-DIAGNOSIS/TREATMENT: Two subjects (aged 13 and 15 years) received EC-cysteamine for 5-6 years at 60-65 % of their previous total daily dose of immediate-release cysteamine given at 6-h intervals. White blood cell (WBC) cystine levels were monitored every 1-3 months. CONCLUSION: The administration of EC-cysteamine did not result in any change in mean trough WBC cystine levels or any deterioration in the estimated glomerular filtration rate, thyroid, or liver function, suggesting that delayed-release, twice-daily EC-cysteamine is an effective long-term treatment alternative to immediate-release cysteamine given at 6-h intervals.

The effect of cysteamine bitartrate on adiponectin multimerization in non-alcoholic fatty liver disease and healthy subjects.

OBJECTIVE: To determine the effects of cysteamine on adiponectin multimerization in sera of patients with nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN: Sera from 10 children with biopsy-proven NAFLD treated with cysteamine were assayed for adiponectin multimers at baseline, after 24 weeks of treatment, and again 16 weeks after discontinuing treatment. Pretreatment sera from subjects with NAFLD and from adult controls without NAFLD controls (n = 8) were incubated in cysteamine and multimers were measured 1 hour later. A cysteamine/adiponectin multimer dose-response curve was created. RESULTS: Following 24 weeks of cysteamine therapy, the mean percentage increase for high, medium (MMW), and low (LMW) molecular weight multimers and total adiponectin from baseline was 53% (P = .02), 19% (P = .02), 29.4% (P = .03), and 49.3% (P = .05), respectively. Levels returned to baseline at 16 weeks after stopping therapy, unlike hepatic transaminase levels which remained low. Sera from 0 week, incubated in cysteamine for 1 hour, showed a significant mean percent increase in LMW adiponectin levels and a mean percent reduction in MMW levels compared with baseline in adults with and without NAFLD. CONCLUSIONS: Cysteamine impacts adiponectin multimerization. Long-term cysteamine therapy increases levels of all multimers, whereas, in vitro short-term exposure causes a rapid increase in LMW and reduction in MMW multimers in NAFLD and healthy controls. Cysteamine may be a potential therapeutic agent for conditions associated with insulin-resistance, oxidative stress, and depressed adiponectin levels.

Expression of GIV/Girdin, a metastasis-related protein, predicts patient survival in colon cancer.

Metastasis accounts for the majority of cancer-related deaths. Accurate prediction of metastatic potential of tumors has been elusive, and the search for clinically useful markers continues. We previously reported that GIV/Girdin triggers tumor cell migration by virtue of a C-terminal guanine-nucleotide exchange factor motif that activates Gαi. Here we identify GIV as a metastasis-related protein whose full-length transcript (GIV-fl) is expressed exclusively in highly invasive colon, breast, and pancreatic carcinoma cells and not in their poorly invasive counterparts. A prospective, exploratory biomarker study conducted on a cohort of 56 patients with stage II colorectal cancer revealed a significant correlation between GIV-fl expression in tumor epithelium and shortened metastasis-free survival. Survival rate for patients with GIV-fl-positive tumors is significantly reduced compared with the patients with GIV-fl-negative tumors [P<0.0001; hazard ratio=0.076; CI=0.052-0.30 (95%)]. At the 5-yr mark, survival is 100% in the GIV-fl-negative group and 62 ± 9% (mean±SE; P=6×10(-5)) in the GIV-fl-positive group. Furthermore, GIV-fl expression predicts a risk of mortality independent of the microsatellite stability status, a well-established prognosticator of colorectal cancers. We conclude that GIV-fl is a novel metastasis-related protein and an independent adverse prognosticator that may serve as a useful adjunct to traditional staging strategies in colorectal carcinoma.

Long-term treatment of cystinosis in children with twice-daily cysteamine.

OBJECTIVE: Cystinosis causes renal and other organ failure. Treatment with 6-hourly cysteamine bitartrate (Cystagon, Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A recent study showed that an enteric-release cysteamine required less frequent daily dosing. This report describes the long-term use of enteric-coated (EC) cysteamine bitartrate (Cystagon) in children with cystinosis. STUDY DESIGN: After a pharmacokinetic and pharmacodynamic study of EC-cysteamine in children with cystinosis, 5 patients remained on twice-daily treatment. White blood cell cystine levels were measured 12 hours after ingestion every 4 to 8 weeks. These levels were then compared with the patient's previous 6-h post-dose levels taken while on regular cysteamine bitartrate before entering the study. Blood chemistry was also measured. RESULTS: Five children with cystinosis (mean age, 9 years; range, 8 to 17 years) who previously took cysteamine bitartrate (mean dose, 47 mg/kg body wt), received EC-cysteamine for 10 to 27 months (mean dose, 25 mg/kg body wt) and had mean white blood cell cystine levels of 0.77 and 0.71 nmol half-cystine/mg protein, respectively. During the study period, patients maintained adequate growth and there was no significant deterioration in renal or thyroid function. Two children were required to restart acid suppression after 6 months on EC-cysteamine therapy. CONCLUSIONS: Long-term, twice-daily EC-cysteamine, given at approximately 60% of the previous daily dose of cysteamine bitartrate, was effective at maintaining white blood cell cystine levels within a satisfactory range. There was no significant deterioration in renal or thyroid function.

Pharmacokinetics of enteric-coated cysteamine bitartrate in healthy adults: a pilot study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for cysteamine. Regular cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients. WHAT THIS STUDY ADDS: This is the only study that provides pharmacokinetic data for cysteamine delivered in an enteric-release preparation in normal subjects. EC-cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. EC-cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective. AIMS: Cysteamine bitartrate (Cystagon) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated in normal healthy subjects. METHODS: Enteric-coated cysteamine was prepared. Following single doses of cysteamine bitartrate non-enteric-coated 450 mg and cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma cysteamine and gastrin concentrations were measured. Two subjects also received cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded. RESULTS: Six healthy adults (mean age 20.7 years, range 18-24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml(-1)). The tmax following cysteamine bitartrate non-enteric-coated (mean and SD is 75+/-19 min) was shorter than cysteamine bitartrate enteric-coated (220+/-74 min) (P=0.001), but only the Cmax and AUC estimates following 900 mg cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P<0.05). One patient had GI symptoms following both 900 mg cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated. CONCLUSION: Although patient numbers were low, single high doses of cysteamine bitartrate enteric-coated were better tolerated than similar doses of cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following cysteamine bitartrate enteric-coated suggested that the cysteamine was released enterically.

RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFbeta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFbeta surface receptors. Cells were treated with TGFbeta1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGFbeta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGFbeta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGFbeta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFbeta. TGFbeta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFbeta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.

Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery.

Cysteamine is approved for the treatment of cystinosis and is being evaluated for Huntington's disease and non-alcoholic fatty liver disease. Little is known about the bioavailability and biodistribution of the drug. The aim was to determine plasma, cerebrospinal fluid (CSF), and tissue (liver, kidney, muscle) cysteamine levels following intraduodenal delivery of the drug in rats pretreated and naïve to cysteamine and to estimate the hepatic first-pass effect on cysteamine. Healthy male rats (n = 66) underwent intraduodenal and portal (PV) or jugular (JVC) venous catheterization. Half were pretreated with cysteamine, and half were naïve. Following intraduodenal cysteamine (20 mg/kg), serial blood samples were collected from the PV or the JVC. Animals were sacrificed at specific time points, and CSF and tissue were collected. Cysteamine levels were determined in plasma, CSF, and tissue. The Cmax was achieved in 5-10 min from PV and 5-22.5 min from JVC. The PV-Cmax (P = 0.08), PV-AUC0-t (P = 0.16), JVC-Cmax (P = 0.02) and JVC-AUC0-t (P = 0.03) were higher in naive than in pretreated animals. Plasma cysteamine levels returned to baseline in ≤120 min. The hepatic first-pass effect was estimated at 40%. Peak tissue and CSF cysteamine levels occurred ≤22.5 min, but returned to baseline levels ≤180 min. There was no difference in CSF and tissue cysteamine levels between naïve and pretreated groups, although cysteamine was more rapidly cleared in the pretreated group. Cysteamine is rapidly absorbed from the small intestine, undergoes significant hepatic first-pass metabolism, crosses the blood brain barrier, and is almost undetectable in plasma, CSF, and body tissues 2 h after ingestion. Sustained-release cysteamine may provide prolonged tissue exposure.

Influence of race on microsatellite instability and CD8+ T cell infiltration in colon cancer.

African American patients with colorectal cancer show higher mortality than their Caucasian counterparts. Biology might play a partial role, and prior studies suggest a higher prevalence for microsatellite instability (MSI) among cancers from African Americans, albeit patients with MSI cancers have improved survival over patients with non-MSI cancers, counter to the outcome observed for African American patients. CD8+ T cell infiltration of colon cancer is postively correlated with MSI tumors, and is also related to improved outcome. Here, we utilized a 503-person, population-based colon cancer cohort comprising 45% African Americans to determine, under blinded conditions from all epidemiological data, the prevalence of MSI and associated CD8+ T cell infiltration within the cancers. Among Caucasian cancers, 14% were MSI, whereas African American cancers demonstrated 7% MSI (P = 0.009). Clinically, MSI cancers between races were similar; among microsatellite stable cancers, African American patients were younger, female, and with proximal cancers. CD8+ T cells were higher in MSI cancers (88.0 vs 30.4/hpf, P<0.0001), but was not different between races. Utilizing this population-based cohort, African American cancers show half the MSI prevalence of Caucasians without change in CD8+ T cell infiltration which may contribute towards their higher mortality from colon cancer.

The Effect of Food on Cysteamine Bitartrate Absorption in Healthy Participants.

OBJECTIVES: Treatment with cysteamine reduces the rate of progression to end-stage kidney disease in cystinosis. Although food is often taken with cysteamine to reduce associated gastrointestinal symptoms, this may alter the bioavailability of cysteamine. METHODS: This is a prospective, randomized, 3-treatment study to determine the effects of fasting and high-fat/calorie and high-protein meals on cysteamine absorption in healthy adult controls. On 3 separate days, serial plasma cysteamine levels were measured after cysteamine bitartrate 500 mg was ingested while fasting and also 30 minutes after high-fat/calorie and high-protein diets. Gastrointestinal (GI) symptoms were also monitored. RESULTS: Eight participants (5 men) were enrolled. Cysteamine absorption, as measured by area under the cysteamine concentration-time curve (AUC0-∞ ) while fasted and following high-fat/calorie and high-protein meals, was 3618 ± 372 min·µM, 2799 ± 405 min·µM (P = .04 vs fasted), and 2457 ± 353 min·µM (P = .005), respectively, and the mean Cmax values for participants were 26.3 ± 3.5 µM, 22.4 ± 5.6 µM (P = .16 vs fasted), and 17.2 ± 2.6 µM (P = .036 vs fasted), respectively. Mild GI symptoms were reported in 3 participants. CONCLUSIONS: Cysteamine absorption may be decreased by 30% when taken with food as compared with the fasting state. Food causes wide variation in tmax and Cmax for cysteamine.

Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity.

BACKGROUND: Patients with advanced microsatellite unstable colorectal cancers do not show a survival benefit from 5-fluorouracil (5-FU)-based chemotherapy. We and others have shown that the DNA mismatch repair (MMR) complex hMutSα binds 5-FU incorporated into DNA. Although hMutSß is known to interact with interstrand crosslinks (ICLs) induced by drugs such as cisplatin and psoralen, it has not been demonstrated to interact with 5-FU incorporated into DNA. Our aim was to examine if hMutSß plays a role in 5-FU recognition. METHODS: We compared the normalized growth of 5-FU treated cells containing either or both mismatch repair complexes using MTT and clonogenic assays. We utilized oligonucleotides containing 5-FU and purified baculovirus-synthesized hMutSα and hMutSß in electromobility shift assays (EMSA) and further analyzed binding using surface plasmon resonance. RESULTS: MTT and clonogenic assays after 5-FU treatment demonstrated the most cytotoxicity in cells with both hMutSα and hMutSß, intermediate cytotoxicity in cells with hMutSα alone, and the least cytotoxicity in cells with hMutSß alone, hMutSß binds 5-FU-modified DNA, but its relative binding is less than the binding of 5-FU-modified DNA by hMutSα. CONCLUSION: Cytotoxicity induced by 5-FU is dependent on intact DNA MMR, with relative cell death correlating directly with hMutSα and/or hMutSß 5-FU binding ability (hMutSα>hMutSß). The MMR complexes provide a hierarchical chemosensitivity for 5-FU cell death, and may have implications for treatment of patients with certain MMR-deficient tumors.

Relationship of EMAST and microsatellite instability among patients with rectal cancer.

BACKGROUND: Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a population-based cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers. METHODS: We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and National-Cancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration. RESULTS: Among this cohort of patients with rectal cancer (mean age 62.2 ± 10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p = 0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p = 0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p = 0.0001). CONCLUSIONS: EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development.

A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate.

Cells respond to growth factors by either migrating or proliferating, but not both at the same time, a phenomenon termed migration-proliferation dichotomy. The underlying mechanism of this phenomenon has remained unknown. We demonstrate here that Galpha(i) protein and GIV, its nonreceptor guanine nucleotide exchange factor (GEF), program EGF receptor (EGFR) signaling and orchestrate this dichotomy. GIV directly interacts with EGFR, and when its GEF function is intact, a Galpha(i)-GIV-EGFR signaling complex assembles, EGFR autophosphorylation is enhanced, and the receptor's association with the plasma membrane (PM) is prolonged. Accordingly, PM-based motogenic signals (PI3-kinase-Akt and PLCgamma1) are amplified, and cell migration is triggered. In cells expressing a GEF-deficient mutant, the Galphai-GIV-EGFR signaling complex is not assembled, EGFR autophosphorylation is reduced, the receptor's association with endosomes is prolonged, mitogenic signals (ERK 1/2, Src, and STAT5) are amplified, and cell proliferation is triggered. In rapidly growing, poorly motile breast and colon cancer cells and in noninvasive colorectal carcinomas in situ in which EGFR signaling favors mitosis over motility, a GEF-deficient splice variant of GIV was identified. In slow growing, highly motile cancer cells and late invasive carcinomas, GIV is highly expressed and has an intact GEF motif. Thus, inclusion or exclusion of GIV's GEF motif, which activates Galphai, modulates EGFR signaling, generates migration-proliferation dichotomy, and most likely influences cancer progression.

Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin.

BACKGROUND & AIMS: Colon cancers with high-frequency microsatellite instability (MSI-H) develop frameshift mutations in tumor suppressors as part of their pathogenesis. ACVR2 is mutated at its exon 10 polyadenine tract in >80% of MSI-H colon cancers, coinciding with loss of protein. ACVR2 transmits the growth effects of activin via phosphorylation of SMAD proteins to affect gene transcription. The functional effect of activin in colon cancers has not been studied. We developed and characterized a cell model in which we studied how activin signaling affects growth. METHODS: hMLH1 and ACVR2 mutant HCT116 cells were previously stably transferred with chromosome 2 (HCT116+chr2), restoring a single regulated copy of wild-type ACVR2 but not hMLH1. Both HCT116+chr2 and parental HCT116 cells (as well as HEC59 and ACVR2 and hMSH2 complemented HEC59+chr2 cells) were assessed for genetic complementation and biologic function. RESULTS: HCT116+chr2 cells and HEC59+chr2 cells, but not ACVR2-mutant HCT116 or HEC59 cells, acquired wild-type ACVR2 as well as expression of ACVR2 wild-type messenger RNA. Complemented ACVR2 protein complexed with ACVR1 with activin treatment, generating nuclear phosphoSMAD2 and activin-specific gene transcription. ACVR2-restored cells showed decreased growth and reduced S phase but increased cellular migration following activin treatment. ACVR2 small interfering RNA reversed these effects in complemented cells. CONCLUSIONS: ACVR2-complemented MSI-H colon cancers restore activin-SMAD signaling, decrease growth, and slow their cell cycle following ligand stimulation but show increased cellular migration. Activin is growth suppressive and enhances migration similar to transforming growth factor beta in colon cancer, indicating that abrogation of the effects of activin contribute to the pathogenesis of MSI-H colon cancers.

Complicaciones en el tratamiento quirúrgico de pacientes pediátricos conhidrocefalia operados en el Hospital Nacional Guillermo Almenara Irigoyen / Surgical complications in pediatric patients with hydrocephalus in Guillermo Almenara-Irigoyen Nacional Hospital

Objetivo: Determinar las principales complicaciones postquirúrgicas en pacientes pediátricos con hidrocefalia en el Hospital Nacional Guillermo Almenara Irigoyen. Material y método: Estudio descriptivo, de tipo serie de casos que incluyó las historias clínicas de pacientes post operados por hidrocefalia mediante la derivación ventriculoperitoneal, entre 0 y 14 años al momento de la primera intervención quirúrgica en la institución indicada. Los datos fueron recolectados en una ficha estandarizada. Se aceptó como significancia estadística p<0,05. Resultados: Se encontró complicaciones en 35,5% de los pacientes. De las complicaciones 54% fueron tempranas y 45% tardías. Las causas fueron: disfunción del sistema, infección y hematoma subdural debido a sobredrenaje, 54,5%, 27,3% y 18,2% respectivamente. De los pacientes con complicaciones: 54,5% tenían hidrocefalia adquirida y 45,5% congénita; 72,7% fueron intervenidos de emergencia y 27,3% de manera electiva. Se encontró asociación estadísticamente significativa entre la etiología de la hidrocefalia y las complicaciones registradas χ2 = 5,387 (p = 0,02). Conclusiones: Se encontró una frecuencia de 35,5% de complicaciones post quirúrgicas, siendo la disfunción del sistema la complicación más frecuente en este escenario. Los resultados indican que la hidrocefalia adquirida presenta mayor riesgo de presentar complicaciones postquirúrgicas que la congénita.

Objective: To determine the main surgical complications in pediatric patients with hydrocephalus in Guillermo Almenara Irigoyen National Hospital. Material and method: A descriptive case series reviewed the charts of pediatric patients with hydrocephalus who underwent a ventriculo-peritoneal shunt procedure. These patients were between 0 and 14 years old when they had their first surgery. Data was collected in a standardized chart. Statistical significance was established in p<0.05. Results: Approximately one third of patients (35.5%) developed complications. Fifty- four percent had early complications and 45% developed late complications. Causes for complications were: system malfunction, infection and subdural hematoma caused by overdrainage of VP shunts in 54.5%, 27.3% and 18.2%, respectively. Of all patients who developed complications, 54.5% had acquired and 45.5% had congenital hydrocephalus; 72.7% underwent emergency surgery and 27.3% underwent elective surgery. There was a statistically significant association between the origin of hydrocephalus and the development of complications, χ2 = 5.387 (p = 0.02). Conclusions: The frequency of complications after surgical therapy for hydrocephalus was 35.5%. The main cause was system malfunction. These results show that acquired hydrocephalus has a greater likelihood for developing post surgical complications compared to congenital hydrocephalus.

Bone morphogenetic protein signaling and growth suppression in colon cancer.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily, which utilize BMP receptors and intracellular SMADs to transduce their signals to regulate cell differentiation, proliferation, and apoptosis. Because mutations in BMP receptor type IA (BMPRIA) and SMAD4 are found in the germline of patients with the colon cancer predisposition syndrome juvenile polyposis, and because the contribution of BMP in colon cancers is largely unknown, we examined colon cancer cells and tissues for evidence of BMP signaling and determined its growth effects. We determined the presence and functionality of BMPR1A by examining BMP-induced phosphorylation and nuclear translocation of SMAD1; transcriptional activity via a BMP-specific luciferase reporter; and growth characteristics by cell cycle analysis, cell growth, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide metabolic assays. These assays were also performed after transfection with a dominant negative (DN) BMPR1A construct. In SMAD4-null SW480 cells, we examined BMP effects on cellular wound assays as well as BMP-induced transcription in the presence of transfected SMAD4. We also determined the expression of BMPR1A, BMP ligands, and phospho-SMAD1 in primary human colon cancer specimens. We found intact BMP signaling and modest growth suppression in HCT116 and two derivative cell lines and, surprisingly, growth suppression in SMAD4-null SW480 cells. BMP-induced SMAD signaling and BMPR1A-mediated growth suppression were reversed with DN BMPR1A transfection. BMP2 slowed wound closure, and transfection of SMAD4 into SW480 cells did not change BMP-specific transcriptional activity over controls due to receptor stimulation by endogenously produced ligand. We found no cell cycle alterations with BMP treatment in the HCT116 and derivative cell lines, but there was an increased G1 fraction in SW480 cells that was not due to increased p21 transcription. In human colon cancer specimens, BMP2 and BMP7 ligands, BMPRIA, and phospho-SMAD1 were expressed. In conclusion, BMP signaling is intact and growth suppressive in human colon cancer cells. In addition to SMADs, BMP may utilize SMAD4-independent pathways for growth suppression in colon cancers.

The mismatch repair complex hMutS alpha recognizes 5-fluorouracil-modified DNA: implications for chemosensitivity and resistance.

BACKGROUND & AIMS: Recent evidence suggests that patients with advanced microsatellite unstable (MSI) colorectal cancers lack a survival benefit with 5-fluorouracil (5-FU)-based chemotherapy. Additionally, tumor cells with MSI (caused by defective DNA mismatch repair) are more resistant to 5-FU in culture compared with microsatellite stable cells, despite similar amounts of 5-FU incorporation into the cell's DNA. We examined whether the component of the DNA mismatch repair (MMR) system that normally recognizes single base pair mismatches could specifically recognize 5-FU incorporated into DNA as a potential mechanism for chemosensitivity. METHODS: We synthesized oligonucleotides with and without incorporated 5-FU and created oligonucleotides with a single base pair mismatch (as a positive control) to perform electromobility gel shift assays (EMSA) with a purified, baculovirus-synthesized hMutS alpha MMR complex. We also utilized surface plasmon resonance to measure relative binding differences between the oligonucleotides and hMutS alpha in real time. RESULTS: Using EMSA, we demonstrate that hMutS alpha recognizes and binds 5-FU-modified DNA. The reaction is specific as added ATP dissociates the hMutS alpha complex from the 5-FU-modified strand. Using surface plasmon resonance, we demonstrate greater binding between hMutS alpha and 5-FU-modified DNA compared with complementary DNA or DNA containing a C/T mismatch. CONCLUSIONS: The MMR complex hMutS alpha specifically recognizes and binds to 5-FU-modified DNA. Because MMR components are required for the induction of apoptosis by many DNA-damaging agents, the chemosensitivity of 5-FU for patients with advanced colorectal cancer may be in part due to recognition of 5-FU incorporated into tumor DNA by the MMR proteins.

Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer.

BACKGROUND & AIMS: 5-Fluorouracil improves mortality in stage III colorectal cancer patients. In vitro studies suggest that microsatellite instability influences cell survival after 5-fluorouracil treatment. We investigated the survival influence of 5-fluorouracil in patients with microsatellite instability-high tumors. METHODS: We collected data and tumors on 204 consecutive stage II and III colorectal cancer patients from registries at the University of California and Veterans Administration hospitals in San Diego, California, from 1982 to 1999. Archival DNA was extracted, and microsatellite instability was assessed by National Cancer Institute-recommended markers. Cox proportional hazard modeling was used to determine survival associations for microsatellite instability and 5-fluorouracil treatment status. RESULTS: We identified 36 microsatellite instability-high (17.6%) and 168 non-microsatellite instability-high tumors (82.4%). Microsatellite instability-high tumors were significantly associated with proximal colon location, presence of mucin, and surrounding lymphoid reaction. Univariate and multivariate analyses showed no survival difference between microsatellite instability-high and non-microsatellite instability-high groups (hazard ratio, 1.04; P = 0.88). Dichotomized by use of 5-fluorouracil, there was increased risk of death in patients who received no adjuvant chemotherapy (hazard ratio, 2.02; P = 0.02). However, the benefit of 5-fluorouracil was different between microsatellite instability-high and non-microsatellite instability-high groups. Patients with non-microsatellite instability-high tumors who received 5-fluorouracil had better survival compared with patients who were not treated (P < 0.05). Conversely, patients with microsatellite instability-high tumors who were treated with 5-fluorouracil had no survival difference compared with patients without treatment (P = 0.52). CONCLUSIONS: There is improved survival in patients with non-microsatellite instability-high tumors after 5-fluorouracil-based chemotherapy that does not extend to patients with microsatellite instability-high tumors. The microsatellite instability status of a patient's colorectal cancer may indicate differences in 5-fluorouracil-based chemosensitivity; this is consistent with in vitro studies.

Postura en niños videntes e invidentes congénitos / Posture in children with normal vision and congenital blindness

Se realizó un exámen postural a 25 niños invidentes congénitos y se compararon resultados con los observados en 25 niños videntes. Los invidentes presentaron diferentes estadísticamente significativas en cuanto a la inclinación anterior del cuello, asimetría de hombros, alteración de escápular, prominencia abdominal, basculación anterior de pelvis y alteraciones de la columna vertebral. Consideramos que dichas diferencias pueden ser consecuencia de la ausencia de una vía fundamental del control postural como es una vía óptica.