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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.

Limbic encephalitis is a disease included in the group of autoimmune encephalitis triggered by different factors, including paraneoplastic, infectious, and pharmacological, among others. The main symptoms are memory impairment, seizures, and psychiatric symptoms. This disease can cause severe neuropsychiatric and cognitive sequelae if not treated in a timely manner, and, if underdiagnosed, it can worsen the prognosis when an underlying unidentified tumor exists. Given the importance of this condition, we wrote this article to provide an update on the diagnostic and therapeutic approach for these patients, according to possible findings in imaging, serum, and cerebrospinal fluid studies. Antibody detection tests can be used to identify, according to the location of the antigen (cellular surface, intracelular or synaptic), the relationship with tumors, response to treatment and prognosis. In case of paraneoplastic encephalitis, the therapeutic approach includes specific oncological treatment, immunotherapy, and symptom management, generally simultaneously.

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/m 2 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.

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. 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. 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. 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.

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.

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.

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 hMutS[alpha] and hMutSß in electromobility shift assays (EMSA) and further analyzed binding using surface plasmon resonance. MTT and clonogenic assays after 5-FU treatment demonstrated the most cytotoxicity in cells with both hMutS[alpha] and hMutSß, intermediate cytotoxicity in cells with hMutS[alpha] 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 hMutS[alpha]. Cytotoxicity induced by 5-FU is dependent on intact DNA MMR, with relative cell death correlating directly with hMutS[alpha] and/or hMutSß 5-FU binding ability (hMutS[alpha]>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.

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.sup.+ 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.sup.+ 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.sup.+ 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.sup.+ T cell infiltration which may contribute towards their higher mortality from colon cancer.

La encefalitis límbica es una enfermedad incluida en el grupo de encefalitis autoinmunes desencadenada por diferentes causas incluidas paraneoplásicas, infecciosas, farmacológicas, entre otras. Los síntomas principales son alteraciones de la memoria, convulsiones y síntomas psiquiátricos. Esta enfermedad puede provocar secuelas neuropsiquiátricas y cognitivas graves si no se hace un tratamiento oportuno y si se subdiagnostica puede empeorar el pronóstico cuando existe un tumor subyacente no identificado. Dada la importancia de esta condición, desarrollamos este artículo para proporcionar una actualización sobre el enfoque diagnóstico y terapéutico de estos pacientes, de acuerdo con los posibles hallazgos en estudios de imágenes, de suero y de líquido cefalorraquídeo. Las pruebas de detección de anticuerpos permiten identificar, según la ubicación del antígeno (superficie celular, intracelular o sináptico), la relación con tumores, la respuesta al tratamiento y el pronóstico; en caso de que se trate de una encefalitis paraneoplásica, el abordaje terapéutico incluye el tratamiento oncológico específico, la inmunoterapia y el manejo para control de los síntomas, generalmente de forma simultánea. INFORMACIÓN ARTÍCULO RESUMEN Palabras clave Anticuerpos; Encefalitis Límbica; Enfermedades Autoinmunes; Manifestaciones Neurológicas; Síndromes Paraneoplásicos del Sistema Nervioso Limbic encephalitis is a disease included in the group of autoimmune encephalitis triggered by different factors, including paraneoplastic, infectious, and pharmacological, among others. The main symptoms are memory impairment, seizures, and psychiatric symptoms. This disease can cause severe neuropsychiatric and cognitive sequelae if not treated in a timely manner, and, if underdiagnosed, it can worsen the prognosis when an underlying unidentified tumor exists. Given the importance of this condition, we wrote this article to provide an update on the diagnostic and therapeutic approach for these patients, according to possible findings in imaging, serum, and cerebrospinal fluid studies. Antibody detection tests can be used to identify, according to the location of the antigen (cellular surface, intracellular or synaptic), the relationship with tumors, response to treatment and prognosis. In case of paraneoplastic encephalitis, the therapeutic approach includes specific oncological treatment, immunotherapy, and symptom management, generally simultaneously. ARTICLE INFORMATION Keywords Antibodies; Autoimmune Diseases; Limbic Encephalitis; Neurological Manifestations Paraneoplastic Syndromes, Nervous System