Brazil-TNT: A Randomized Phase 2 Trial of Neoadjuvant Chemoradiation Followed by FOLFIRINOX Versus Chemoradiation for Stage II/III Rectal Cancer.

BACKGROUND: Neoadjuvant radiation and oxaliplatin-based systemic therapy (total neoadjuvant therapy-TNT) have been shown to increase response and organ-preservation rates in localized rectal cancer. However, trials have been heterogeneous regarding treatment protocols and few have used a watch-and-wait (WW) approach for complete responders. This trial evaluates if conventional long-term chemoradiation followed by consolidation of FOLFIRINOX increases complete response rates and the number of patients managed by WW. METHODS: This was a pragmatic randomized phase II trial conducted in 2 Cancer Centers in Brazil that included patients with T3+ or N+ rectal adenocarcinoma. After completing a long-course 54 Gy chemoradiation with capecitabine patients were randomized 1:1 to 4 cycles of mFOLFIRINOX (Oxaliplatin 85, irinotecan 150, 5-FU 2400)-TNT-arm-or to the control arm, that did not include further neoadjuvant treatment. All patients were re-staged with dedicated pelvic magnetic resonance imaging and sigmoidoscopy 12 weeks after the end of radiation. Patients with a clinical complete response were followed using a WW protocol. The primary endpoint was complete response: clinical complete response (cCR) or pathological response (pCR). RESULTS: Between April 2021 and June 2023, 55 patients were randomized to TNT and 53 to the control arm. Tumors were 74% stage 3, median distance from the anal verge was 6 cm, 63% had an at-risk circumferential margin, and 33% an involved sphincter. The rates of cCR + pCR were (31%) for TNT versus (17%) for controls (odds ratio 2.19, CI 95% 0.8-6.22 P = .091) and rates of WW were 16% and 9% (P = ns). Median follow-up was 8.1 months and recurrence rates were 16% versus 21% for TNT and controls (P = ns). CONCLUSIONS: TNT with consolidation FOLFIRINOX is feasible and has high response rates, consistent with the current literature for TNT. This trial was supported by a grant from the Brazilian Government (PROADI-SUS - NUP 25000.164382/2020-81).

Pembrolizumab para personas menores de 18 años con cáncer colorrectal y metástasis sincrónica abdominoperitoneal irresecable con inestabilidad microsatelital, elegibles para terapia intensiva, quienes progresan a esquemas quimioterápicos que contienen 5-fluorouracilo (5-FU), capecitabina, oxaliplatino e irinotecán / Pembrolizumab for people under 18 years of age with colorectal cancer and irresectable synchronic abdominoperitoneal metastasis with microsatellite instability, eligible for intensive therapy, who progress to chemotherapy regimens containing 5-fluorouracil (5-FU), capecitabine, oxaliplatin and irinotecán

INTRODUCCIÓN: Cuadro clínico: El cáncer colorrectal es una neoplasia maligna del colon o del recto. Según la Organización Mundial de la Salud es la tercera neoplasia más frecuente y la segunda neoplasia con mayor mortalidad. En el año 2020, el Observatorio Global de Cáncer de la Agencia Internacional para la Investigación en Cáncer (GLOBOCAN) reportó 1 931 590 casos nuevos de cáncer colorrectal en todo el mundo y una incidencia estandarizada por edad de 19.6 por 100 000 personas-año. En cuanto a la mortalidad, en todo el mundo se reportó 935 173 muertes atribuibles a cáncer colorrectal y una incidencia de mortalidad estandarizada por edad de 9 por 100 000 personas-año. En América Latina, se reportó un total de 103 954 nuevos casos de cáncer colorrectal, una incidencia estandarizada por edad de 18.5 por 100 000 personasaño, 52 013 muertes atribuibles a cáncer colorrectal y una incidencia de mortalidad estandarizada por edad de 8.9 por 100 000 personas-año. En Perú, para el año 2019, se reporta una prevalencia de cáncer colorrectal de 2.1 por 100 000 y una incidencia de 0.3 por 100 000 entre las personas menores de 20 años. Entre los peruanos con cáncer colorrectal menores de 20 años de edad se reportó 5.04 años de vida saludable perdidos (AVISA) por 100 000 y 0.19 años vividos con discapacidad (AVD) por 100

Changes on food intake, body weight and salivary amylase synthesis in the submandibular gland of wistar rats treated with bevacizumab and cytostatics / Cambios en la ingesta de alimentos, peso corporal y síntesis de amilasa salival en la glándula submandibular de ratas wistar tratadas con bevacizumab y citostáticos

Background: Bevacizumab together with 5-fluorouracil and oxaliplatin inhibit microvascular growth of tumor blood vessels and tumor proliferation. Few reports state the effect of these therapeutic schemes on salivary glands. Materials and Methods: Food consumption, body weight and salivary amylase activity were assessed in the submandibular gland of rats. Adult male Wistar rats, of three months old with 350/400 grams body weight, under 12-hour light/dark cycles respectively, were divided into the following experimental groups: G1) Control group, G2) 5-Fluorouracil and leucovorin calcium treated group, G3) Bevacizumab treated group, G4) Oxaliplatin treated group, G5) Bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin calcium treated group and G6) Drug-free paired feeding treated group. Assessment of treatment effect was performed by one-way ANOVA. A value of p<0.05 was set for statistical significance. Results: Salivary amylase activity in gland homogenate was G1: 137.9 ± 4.64, G2: 60.95±4.64, G3: 120.93 ± 4.96, G4: 26.17 ±4.64, G5: 10.77 ±4.64 and G6: 82.87 ±4.64 U/mg protein (mean ± S.D.) Amylase activity in the G1 group was higher relative to the other experimental groups p<0.0001. Conclusions: The drugs 5-fluorouracil and oxaliplatin altered salivary amylase activity by serous granules of the submandibular gland interpreted as a mechanism of impaired acinar function. Bevacizumab administered in isolation did not alter salivary amylase activity compared to the control group. While the lower intake of the matched feeding group affected salivary amylase activity compared to the control group, the effect was significantly greater in animals treated with the oncology drugs used in the present animal model.

Antecedentes: Bevacizumab, junto con 5-fluorouracilo y oxaliplatino, inhiben el crecimiento microvascular de los vasos sanguíneos tumorales y la proliferación tumoral. Pocos reportes establecen el efecto de estos esquemas terapéuticos sobre las glándulas salivales. Materiales y Métodos: Se evaluaron el consumo de alimentos, el peso corporal y la actividad de amilasa salival en la glándula submandibular de ratas Wistar macho adultas, de tres meses de edad con 350/400 gramos de peso corporal, bajo ciclos de luz/oscuridad de 12 horas respectivamente, se dividieron en los siguientes grupos experimentales: G1) Grupo control, G2) Grupo tratado con 5-Fluorouracilo y Leucovorina cálcica. , G3) Grupo tratado con bevacizumab, G4) Grupo tratado con oxaliplatino, G5) Grupo tratado con bevacizumab, oxaliplatino, 5-fluorouracilo y leucovorina cálcica y G6) Grupo tratado con alimentación emparejada sin fármacos. La evaluación del efecto del tratamiento se realizó mediante ANOVA unidireccional. Se estableció un valor de p<0,05 para significación estadística. Resultado: La actividad de amilasa salival en homogeneizado de glándula fue G1: 137,9 ± 4,64, G2: 60,95 ± 4,64, G3: 120,93 ± 4,96, G4: 26,17 ± 4,64, G5: 10,77 ± 4,64 y G6: 82,87 ± 4,64 U/mg de proteína (media ± S.E.). La actividad de amilasa en el grupo G1 fue mayor en relación con los otros grupos experimentales p<0,0001. Conclusión: Los fármacos 5-fluorouracilo y oxaliplatino alteraron la actividad de la amilasa salival mediante gránulos serosos de la glándula submandibular interpretados como un mecanismo de deterioro de la función acinar. Bevacizumab administrado de forma aislada no alteró la actividad de la amilasa salival en comparación con el grupo de control. Mientras que la menor ingesta del grupo de alimentación combinada afectó la actividad de la amilasa salival en comparación con el grupo de control, el efecto fue significativamente mayor en los animales tratados con los medicamentos oncológicos utilizados en el grupo. modelo animal actual.

Cetuximab más FOLFOX en pacientes con cáncer colorrectal metastásico no resecable con tumor primario de localización izquierda, con expresión de EGFR, gen RAS no mutado y sin tratamiento sistémico previo / Cetuximab plus FOLFOX in patients with unresectable metastatic colorectal cancer with a primary tumor located on the left side, with EGFR expression, unmutated RAS gene and without previous systemic treatment

INTRODUCCIÓN: Cuadro clínico: El cáncer colorrectal (CCR) es el 4° cáncer más frecuente y es la 3° causa de muerte por cáncer a nivel mundial. En Perú, el CCR es el 5° cáncer más frecuente y la 6° causa de muerte por cáncer a nivel nacional. El 20 % es diagnosticado en etapa metastásica. De los pacientes con CCR en etapa metastásica hasta un 30 % tienen metástasis hepática. A nivel molecular, la presencia de mutaciones RAS se reporta entre el 12 % y 75 % (las proteínas RAS participan en la activación del EGFR que conduce a la tumorigénesis de colon) y a nivel histológico, las características del tumor primario del lado izquierdo son distintas a la del lado opuesto. Sobre la carga de enfermedad, los reportes nacionales informan que el cáncer colorrectal genera 19,955 años de vida saludables perdidos (AVISA). Con respecto al tratamiento, siendo el CCR metastásico (CCRM) una enfermedad incurable, el objetivo del tratamiento es prolongar la vida, maximizando la calidad de vida y seguridad del paciente. Dentro de las opciones de terapias sistemáticas, la quimioterapia sigue siendo una de las alternativas recomendadas, entre ellas el esquema denominado FOLFOX (compuesto por 5-fluorouracilo con leucovorina y oxaliplatino). Tecnología sanitária: El cetuximab un anticuerpo monoclonal quimérico de tipo IgG1, contra el EGFR. En Perú, el cetuximab cuenta con registro sanitario (N°BE00609), otorgado por la

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry.

BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

The rational modulation of autophagy sensitizes colorectal cancer cells to 5-fluouracil and oxaliplatin.

Colorectal cancer (CRC) is the third most common and deadliest cancer globally. Regimens using 5-fluorouracil (5FU) and Oxaliplatin (OXA) are the first-line treatment for CRC, but tumor recurrence is frequent. It is plausible to hypothesize that differential cellular responses are triggered after treatments depending on the genetic background of CRC cells and that the rational modulation of cell tolerance mechanisms like autophagy may reduce the regrowth of CRC cells. This study proposes investigating the cellular mechanisms triggered by CRC cells exposed to 5FU and OXA using a preclinical experimental design mimicking one cycle of the clinical regimen (i.e., 48 h of treatment repeated every 2 weeks). To test this, we treated CRC human cell lines HCT116 and HT29 with the 5FU and OXA, combined or not, for 48 h, followed by analysis for two additional weeks. Compared to single-drug treatments, the co-treatment reduced tumor cell regrowth, clonogenicity and stemness, phenotypes associated with tumor aggressiveness and poor prognosis in clinics. This effect was exerted by the induction of apoptosis and senescence only in the co-treatment. However, a week after treatment, cells that tolerated the treatment had high levels of autophagy features and restored the proliferative phenotype, resembling tumor recurrence. The pharmacologic suppression of early autophagy during its peak of occurrence, but not concomitant with chemotherapeutics, strongly reduced cell regrowth. Overall, our experimental model provides new insights into the cellular mechanisms that underlie the response and tolerance of CRC cells to 5FU and OXA, suggesting optimized, time-specific autophagy inhibition as a new avenue for improving the efficacy of current treatments.

Mitotherapy prevents peripheral neuropathy induced by oxaliplatin in mice.

Oxaliplatin (OXA) is an antineoplastic agent used for the treatment of cisplatin-resistant tumours, presenting lower incidence of nephrotoxicity and myelotoxicity than other platinum-based drugs. However, OXA treatment is highly associated with painful peripheral neuropathy, a well-known and relevant side effect caused by mitochondrial dysfunction. The transfer of functional exogenous mitochondria (mitotherapy) is a promising therapeutic strategy for mitochondrial diseases. We investigated the effect of mitotherapy on oxaliplatin-induced painful peripheral neuropathy (OIPN) in male mice. OIPN was induced by i.p. injections of oxaliplatin (3 mg/kg) over 5 consecutive days. Mechanical (von Frey test) and cold (acetone drop test) allodynia were evaluated between 7 and 17 days after the first OXA treatment. Mitochondria was isolated from donor mouse livers and mitochondrial oxidative phosphorylation was assessed with high resolution respirometry. After confirming that the isolated mitochondria were functional, the organelles were administered at the dose of 0.5 mg/kg of mitochondrial protein on days 1, 3 and 5. Treatment with OXA caused both mechanical and cold allodynia in mice that were significant 7 days after the initial injection of OXA and persisted for up to 17 days. Mitotherapy significantly prevented the development of both sensory alterations, and attenuated body weight loss induced by OXA. Mitotherapy also prevented spinal cord ERK1/2 activation, microgliosis and the increase in TLR4 mRNA levels. Mitotherapy prevented OIPN by inhibiting neuroinflammation and the consequent cellular overactivity in the spinal cord, presenting a potential therapeutic strategy for pain management in oncologic patients undergoing OXA treatment.

An Unexpected Presentation of a Maxillary Non-Hodgkin Lymphoma in an Elderly Hispanic Patient.

Extranodal NK/T-cell lymphoma (ENKTL), nasal type and aggressive NK cell leukemia are rare in Western World been less than 1% in USA to 8% in Asia among Non-Hodgkin's lymphomas. It is aggressive, with poor outcome and optimal treatment is unclear. A combination therapy that includes Peg-Asparaginase (SMILE) has been employed in young patients. An 85-year-old Puerto Rican male presented with anorexia, epistaxis, vertigo and involuntary facial movements. He was treated with injectable Onabotulinum toxin A due to suspicion of a hemifacial spasm. However, a CT scan demonstrated a left maxillary sinus lesion extending into the left middle turbinate with biopsy consistent with ENKTL. We adjusted therapy to patient's age and performance receiving Gemcitabine-Oxaliplatin (Gemox) with radiation obtaining a complete response with persistent negative Epstein Barr DNA titers. ENKTL is a rare disease initially misdiagnosed in our elderly patient, who demonstrated adequate response with a modified therapeutic regime.

A multi-centre randomized controlled trial investigating Consolidation Chemotherapy with and without oxaliplatin in distal rectal cancer and Watch & Wait.

BACKGROUND: Neoadjuvant chemoradiation(nCRT) has been considered the preferred initial treatment strategy for distal rectal cancer. Advantages of this approach include improved local control after radical surgery but also the opportunity for organ preserving strategies (Watch and Wait-WW). Consolidation chemotherapy(cCT) regimens using fluoropyrimidine-based with or without oxalipatin following nCRT have demonstrated to increase complete response and organ preservation rates among these patients. However, the benefit of adding oxaliplatin to cCT compared to fluoropirimidine alone regimens in terms of primary tumor response remains unclear. Since oxalipatin-treatment may be associated with considerable toxicity, it becomes imperative to understand the benefit of its incorporation into standard cCT regimens in terms of primary tumor response. The aim of the present trial is to compare the outcomes of 2 different cCT regimens following nCRT (fluoropyrimidine-alone versus fluoropyrimidine + oxaliplatin) for patients with distal rectal cancer. METHODS: In this multi-centre study, patients with magnetic resonance-defined distal rectal tumors will be randomized on a 1:1 ratio to receive long-course chemoradiation (54 Gy) followed by cCT with fluoropyrimidine alone versus fluoropyrimidine + oxaliplatin. Magnetic resonance(MR) will be analyzed centrally prior to patient inclusion and randomization. mrT2-3N0-1 tumor located no more than 1 cm above the anorectal ring determined by sagittal views on MR will be eligible for the study. Tumor response will be assessed after 12 weeks from radiotherapy(RT) completion. Patients with clinical complete response (clinical, endoscopic and radiological) may be enrolled in an organ-preservation program(WW). The primary endpoint of this trial is decision to organ-preservation surveillance (WW) at 18 weeks from RT completion. Secondary endpoints are 3-year surgery-free survival, TME-free survival, distant metastases-free survival, local regrowth-free survival and colostomy-free survival. DISCUSSION: Long-course nCRT with cCT is associated with improved complete response rates and may be a very attractive alternative to increase the chances for organ-preservation strategies. Fluoropyrimidine-based cCT with or without oxaliplatin has never been investigated in the setting of a randomized trial to compare clinical response rates and the possibility of organ-preservation. The outcomes of this study may significantly impact clinical practice of patients with distal rectal cancer interested in organ-preservation. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT05000697; registered on August 11th, 2021.

Synergistic effects of dendrosomal nanocurcumin and oxaliplatin on oncogenic properties of ovarian cancer cell lines by down-expression of MMPs.

BACKGROUND: Contrary to the advantageous anticancer activities of curcumin (Cur), limited bioavailability and solubility hindered its efficacy. Here, nontoxic dendrosomal nano carrier with Cur was used to overcome these problems. Despite considerable antitumor properties of Oxaliplatin (Oxa), the limiting factors are drug resistance and adverse side-effects. The hypothesis of this study was to evaluate the possible synergism between dendrosomal nanocurcumin (DNC) and Oxa and these agents showed growth regulatory effects on SKOV3 and OVCAR3 cells. METHODS AND MATERIALS: In the present study, colony formation, wound healing motility, cell adhesion, transwell invasion and migration assay and cell cycle arrest with or without DNC, Oxa and Combination were defined. In addition to, real time PCR and Western blot were used to analyze AKT, PI3K, PKC, JNK, P38 and MMPs mRNAs and proteins expressions. Docking of MMP-2-Cur, MMP-2-DNC and MMP-2-Oxa was performed and the results of all three complexes were simulated by molecular dynamics. RESULTS: Our findings illustrated that DNC had the greatest effect on cell death as compared to the Cur alone. Moreover, the growth inhibitory effects (such as cell death correlated to apoptosis) were more intense if Oxa was added followed by DNC at 4 h interval. However, insignificant effects were observed upon simultaneous addition of these two agents in both cell lines. Besides, a combination of agents synergistically alters the relative expression of MMP-9. CONCLUSIONS: The docking results showed that His70 and Asp100 may play a key role at the MMP-2 binding site. The matrigel invasion as well as cell viability of ovarian cancer cell lines SKOV3 and OVCAR3 by DNC alone or in combination with Oxa was inhibited significantly. The inhibitory effects of these agents were due to the differential expression levels of MMP 2 and MMP 9 regulated by multiple downstream signaling cascades. From the molecular dynamic simulation studies, it was confirmed that DNC established a strong interaction with MMP-2.

Oxaliplatin inhibits colorectal cancer progression by inhibiting CXCL11 secreted by cancer-associated fibroblasts and the CXCR3/PI3K/AKT pathway.

PURPOSE: Colorectal cancer (CRC) is a malignant tumor. Oxaliplatin (OXA) can inhibit cancer-associated fibroblasts (CAFs)-induced cancer progression. This study sought to explore the mechanism of OXA in CAFs-induced CRC development. METHODS: CRC cell lines (Caco-2, SW620), normal fibroblasts (NFs), and CAFs were treated with OXA. NFs and CAFs were cultured. CAFs were treated with/without OXA (0.4 mM), and the supernatant was extracted as the conditioned medium (CM) to culture CRC cells. Cell malignant episodes, E-cadherin and Vimentin levels, CXCL1, CXCL2, CXCL3, CXCL8, and CXCL11 mRNA levels, CXCL11 protein level, and extracellular release were assessed. CAFs were transfected with interfering RNA sh-CXCL11 to silence CXCL11 or transfected with CXCL11 overexpression plasmids and treated with OXA to explore the role of CXCL11 in OXA-mediated CRC cells through CAFs. CXCL11 receptor CXCR3 levels in CRC cells and the PI3K/AKT pathway changes were examined. The xenogeneic tumor was transplanted in nude mice. CXCL11 and CXCR3 levels in tumor tissues, tumor volume, shape, size, weight, and Ki67 positive expressions were assessed. RESULTS: CRC cell growths and epithelial-mesenchymal transformation were stimulated after culture with CAFs-CM, while OXA averted these trends. CXCL11 mRNA level was elevated most significantly, and its protein and extracellular secretion levels were raised, while OXA diminished the levels. CXCL11 silencing weakened the effects of CAFs-CM on promoting CRC proliferation and malignant episodes and CXCL11 overexpression averted OXA property on inhibiting CAFs-promoted CRC cell growth. CXCR3 and PI3K and AKT1 phosphorylation levels were raised in the CAFs-CM group but diminished by OXA. CXCL11 overexpression in CAFs averted OXA property on inhibiting CAFs-activated CXCR3/PI3K/AKT in CRC cells. OXA also inhibited the progression of xenograft tumors by limiting CAFs-secreted CXCL11. CONCLUSIONS: OXA repressed CRC progression by inhibiting CAFs-secreted CXCL11 and the CXCR3/PI3K/AKT pathway.

Modulatory effect of myricitrin against chromosome instability and cytostasis induced by bleomycin and oxaliplatin in CHO-K1 cells.

Myricitrin (MYR), a flavonol consumed in the leaves and fruits of plants of the Myrtaceae family, presents anti-proliferative, anti-inflammatory, anti-diabetic, and antioxidant properties in humans. However, there are few studies regarding the cyto-genotoxicity and the chemopreventive potential of MYR. Using the in vitro Micronucleus test, the cytostasis, mutagenicity, and modulatory effect of MYR in CHO-K1 cells were assessed. The concentrations of 39 and 78 µg/mL (p < 0.001.) of MYR decrease the cytokinesis-block proliferation index (CBPI) in the short exposure treatment (4 h), while in the extended treatment (24 h), concentrations of 4.8, 9.7, 19.5, 39 and 78 µg/mL (p < 0.001.) decreased the CBPI. MYR associated with oxaliplatin decreased CBPI at all tested concentrations in the pre-(p < 0.001) and post-treatments (p < 0.001), but there was no decrease when associated with bleomycin. As for chromosome instability, MYR did not increase the frequency of micronuclei (MNi), nucleoplasmic bridges (NPBs), or nuclear buds (NBUDs) in the 4 h exposure time, however, in the 24 h treatment, MYR increased the frequency of MNi and NPBs at concentration 19.5 µg/mL (p < 0.001). As for the modulatory effect, MYR associated with bleomycin decreased the frequency of MNi, NPBs, and NBUDs at all concentrations in the pretreatment (MNi and NPBs p < 0.001, NBUDs p < 0.05) and simultaneously (MNi, NPBs and NBUDs p < 0.001). When associated with oxaliplatin, the simultaneous treatment decreased the frequency of MNi (p < 0.001) and NBUDs (p < 0.01) at all concentrations, however, in the post-treatment, MYR increased MNi (p < 0.001) and NPBs p < 0.05) in CHO-K1 cells, when compared to oxaliplatin alone. The results demonstrated that MYR could modulate the mutagenic and cytostatic actions of bleomycin and oxaliplatin, demonstrating distinct behaviors, depending on the mechanism of action of the chemotherapeutic agent.

Changes in the expression of endocannabinoid system components in an experimental model of chemotherapy-induced peripheral neuropathic pain: Evaluation of sex-related differences.

Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism. Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits. Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes. Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.

Synergistic effects of dendrosomal nanocurcumin and oxaliplatin on oncogenic properties of ovarian cancer cell lines by down-expression of MMPs

BACKGROUND: Contrary to the advantageous anticancer activities of curcumin (Cur), limited bioavailability and solubility hindered its efficacy. Here, nontoxic dendrosomal nano carrier with Cur was used to overcome these problems. Despite considerable antitumor properties of Oxaliplatin (Oxa), the limiting factors are drug resistance and adverse side-effects. The hypothesis of this study was to evaluate the possible synergism between dendrosomal nanocurcumin (DNC) and Oxa and these agents showed growth regulatory effects on SKOV3 and OVCAR3 cells. METHODS: and materials In the present study, colony formation, wound healing motility, cell adhesion, transwell invasion and migration assay and cell cycle arrest with or without DNC, Oxa and Combination were defined. In addition to, real time PCR and Western blot were used to analyze AKT, PI3K, PKC, JNK, P38 and MMPs mRNAs and proteins expressions. Docking of MMP-2-Cur, MMP-2-DNC and MMP-2-Oxa was performed and the results of all three complexes were simulated by molecular dynamics. RESULTS: Our findings illustrated that DNC had the greatest effect on cell death as compared to the Cur alone. Moreover, the growth inhibitory effects (such as cell death correlated to apoptosis) were more intense if Oxa was added followed by DNC at 4 h interval. However, insignificant effects were observed upon simultaneous addition of these two agents in both cell lines. Besides, a combination of agents synergistically alters the relative expression of MMP-9. CONCLUSIONS: The docking results showed that His70 and Asp100 may play a key role at the MMP-2 binding site. The matrigel invasion as well as cell viability of ovarian cancer cell lines SKOV3 and OVCAR3 by DNC alone or in combination with Oxa was inhibited significantly. The inhibitory effects of these agents were due to the differential expression levels of MMP 2 and MMP 9 regulated by multiple downstream signaling cascades. From the molecular dynamic simulation studies, it was confirmed that DNC established a strong interaction with MMP-2.

Long-term resistance to 5-fluorouracil promotes epithelial-mesenchymal transition, apoptosis evasion, autophagy, and reduced proliferation rate in colon cancer cells.

The drug, 5-fluorouracil (5FU) is a standard first-line treatment for colorectal cancer (CRC) patients. However, drug resistance acquisition remains an important challenge for effective clinical outcomes. Here, we established a long-term drug-resistant CRC model and explored the cellular events underlying 5FU resistance. We showed that 5FU-treated cells (HCT-116 5FUR) using a prolonged treatment protocol were significantly more resistant than parental cells. Likewise, cell viability and IC50 values were also observed to increase in HCT-116 5FUR cells when treated with increasing doses of oxaliplatin, indicating a cross-resistance mechanism to other cytotoxic agents. Moreover, HCT-116 5FUR cells exhibited metabolic and molecular changes, as evidenced by increased thymidylate synthase levels and upregulated mRNA levels of ABCB1. HCT-116 5FUR cells were able to overcome S phase arrest and evade apoptosis, as well as activate autophagy, as indicated by increased LC3B levels. Cells treated with low and high doses displayed epithelial-mesenchymal transition (EMT) features, as observed by decreased E-cadherin and claudin-3 levels, increased vimentin protein levels, and increased SLUG, ZEB2 and TWIST1 mRNA levels. Furthermore, HCT-116 5FUR cells displayed enhanced migration and invasion capabilities. Interestingly, we found that the 5FU drug-resistance gene signature is positively associated with the mesenchymal signature in CRC samples, and that ABCB1 and ZEB2 co-expressed at high levels could predict poor outcomes in CRC patients. Overall, the 5FU long-term drug-resistance model established here induced various cellular events, and highlighted the importance of further efforts to identify promising targets involved in more than one cellular event to successfully overcome drug-resistance.

Sex-related differences in oxaliplatin-induced changes in the expression of transient receptor potential channels and their contribution to cold hypersensitivity.

Transient receptor potential (TRP) channels are involved in the development of oxaliplatin-induced neuropathic pain, a frequent and debilitating side effect of cancer therapy. Here we explored whether oxaliplatin-induced changes in the expression of TRP channels, as well as the development of pain-related behaviours, differed between male and female animals. Adult rats were injected with oxaliplatin or saline and mechanical and cold allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels of TRPV1, TRPM8 and TRPA1 were assessed in lumbar ganglia and spinal cord by using real time RT-PCR. Oxaliplatin administration induced mechanical and cold hypersensitivity and allodynia in both sexes, with more severe responses to cold stimulation detected in females. Oxaliplatin also induced a significant increase in the expression of TRPV1, TRPM8 and TRPA1 in lumbar dorsal root ganglia. Interestingly, while TRPV1 and TRPA1 upregulation showed no sex difference, the increase in TRPM8 mRNA levels was more pronounced in female ganglia, correlating with the increased sensitivity to innocuous cold stimuli observed in females. TRPV1 and TRPM8 were also found to be upregulated in the spinal cord of animals of both sexes. Our results reveal previously undescribed changes in the expression of TRP channels occurring in peripheral ganglia and spinal cord of both male and female oxaliplatin-treated animals, with some of these changes exhibiting sex-related differences that could underlie the development of sex-specific patterns of pain-related behaviours.

Oxaliplatin versus Irinotecan no câncer colorretal avançado / Oxaliplatin versus Irinotecan in advanced colorectal cancer

O câncer colorretal é uma neoplasia com alta prevalência e letalidade. A razão desse elevado número de mortes é a detecção da doença em estágios metastáticos, de difícil cura e que necessitam de terapia quimioterápica adjuvante ou paliativa. Na atualidade, o principal tratamento quimioterápico dessa neoplasia tem como base as drogas Oxaliplatina ou Irinotecano, isolados ou combinados com outros medicamentos. O objetivo desta revisão sistemática é avaliar se há superioridade do esquema quimioterápico com Irinotecano sobre o regime com Oxaliplatina. Foi realizada a análise de ensaios clínicos randomizados, fase II ou III, nas bases de dados eletrônicas Central e PubMed. Critérios de inclusão: ensaios clínicos randomizados comparando regimes à base de irinotecano ou oxaliplatina como tratamentos de primeira linha para câncer colorretal metastático. O desfecho primário analisado foi a superioridade entre os quimioterápicos sobre a sobrevida global. Os desfechos secundários incluíram sobrevida livre de progressão, taxa de resposta e efeitos colaterais. Registro na PROSPERO: CRD42019130339. Não houve diferença significativa nos 13 estudos sobre a sobrevida dos pacientes. Sobre os efeitos colaterais dos medicamentos, os regimes baseados em irinotecano foram associados a uma alta incidência de neutropenia e diarreia grave. Já os associados com oxaliplatin cursaram com alta incidência de neuropatia sensitiva. Não houve diferença estatisticamente significativa sobre a sobrevida global, sobrevivência livre de progressão e na taxa de resposta quando comparamos os pacientes que receberam oxaliplatina e irinotecano (AU)

Colorectal cancer is a highly prevalent and lethal neoplasm. The reason for this high number of deaths is the detection of the disease in metastatic stages, which are difficult to cure and require adjuvant or palliative chemotherapy therapy. Currently, the main chemotherapeutic treatment of this neoplasm is based on the drugs Oxaliplatin or Irinotecan, alone or combined with other drugs. The objective of this systematic review is to evaluate whether there is superiority of the chemotherapy regimen with Irinotecan over that with Oxaliplatin. Analysis of randomized clinical trials, phase II or III, was performed in the electronic databases Central and PubMed. Inclusion criteria: randomized clinical trials comparing irinotecan- or oxaliplatin-based regimens as first-line treatments for metastatic colorectal cancer. The primary endpoint analyzed was the superiority between chemotherapies on overall survival. Secondary endpoints included progression-free survival, response rate, and side effects. PROSPERO registration: CRD42019130339. There was no significant difference in the 13 studies on patient survival. On drug side effects, irinotecan-based regimens were associated with a high incidence of neutropenia and severe diarrhea. Those associated with oxaliplatin were associated with a high incidence of sensory neuropathy. There was no statistically significant difference in overall survival, progression-free survival, and response rate when comparing patients receiving oxaliplatin and irinotecan (AU)

Eficacia y seguridad de bevacizumab más capecitabina para el tratamiento de pacientes adultos mayores con cáncer colorrectal metastásico, ECOG 0-2, sin tratamiento previo, no tributario a quimioterapia basada en platino (oxaliplatino) ni irinotecán / Efficacy and safety of bevacizumab plus capecitabine for the treatment of older adult patients with metastatic colorectal cancer, ECOG 0-2, treatment-naïve, not amenable to platinum-based chemotherapy (oxaliplatin) or irinotecan

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021, se ha elaborado el presente dictamen que expone la evaluación de la eficacia y seguridad de bevacizumab más capecitabina para el tratamiento de pacientes adultos mayores con cáncer colorrectal metastásico, ECOG 0-2, sin tratamiento previo, no tributario a quimioterapia basada en platino (oxaliplatino) ni irinotecán. Así, el médico Nelson Cuevas Muñoz, especialista en oncología médica del Hospital Nacional Edgardo Rebagliati Martins, siguiendo la Directiva N° 003-IETSIESSALUD-2016, envió al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de uso por fuera del Petitorio Farmacológico de EsSalud el producto farmacéutico producto bevacizumab más capecitabina. ASPECTOS GENERALES: En el Dictamen Preliminar N° 002-SDEPFYOTS-DETS-IETSI-2017 se detallan los aspectos generales del cáncer colorrectal metastásico (CCRM). Brevemente, en Perú, en el 2020, el CCR fue la quinta causa de muerte por cáncer en pacientes mayores de 65 años, con una tasa de muerte estandarizada por edad de 52 muertes por cada 100000 habitantes, y una incidencia ajustada por edad de 95 casos por cada 100000 habitantes (GLOBOCAN, 2020). En Estados Unidos, se ha estimado que el 20 % de los pacientes con CCR presentan enfermedad metastásica (Siegel et al., 2022), y que la sobrevida de cinco años en pacientes con CCRM es del 15 %, siendo la más baja comparada con el CCR localizado o regional (NIH, 2022). METODOLOGÍA: La búsqueda bibliográfica exhaustiva se llevó a cabo con el objetivo de identificar la mejor evidencia disponible sobre la eficacia y seguridad de bevacizumab más capecitabina para el tratamiento de pacientes adultos mayores con cáncer colorrectal metastásico, ECOG 0-2, sin tratamiento previo, no tributario a quimioterapia basada en platino (oxaliplatino) ni irinotecán. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library y LiLACS. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como: The National Institute for Health and Care Excellence (NICE), The National Comprehensive Cancer Network (NCCN), The European Society for Medical Oncology (ESMO), The American Society of Clinical Oncology (ASCO), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), Scottish Medicines Consortium (SMC), Haute Autorité de Santé (HAS), lnstitute for Clinical and Economic Review (ICER), Agency for Healthcare Research and Quality's (AHRQ), National Health and Medical Research Council (NHMRC), New Zealand Guidelines Group (NZGG), Canadian Medical Association (CMA), American College of Physicians Clinical Practice Guidelines, Registered Nurses Association of Ontario (RNAO), y Comissáo nacional de incorporagáo de tecnologías no sus (CONITEC). Adicionalmente, se realizó una búsqueda manual en las bases The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y el repositorio institucional de la Dirección General de .... V Medicamentos, Insumos y Drogas (DIGEMID). Finalmente, se realizó una búsqueda ... A manual en el portal ClinicalTrials.govdel National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. RESULTADOS: Luego de la búsqueda bibliográfica, se incluyeron seis GPC elaboradas por The Cancer Council Australia Colorectal Cancer Guidelines Working Party (CCACCGWP) (Nott et al., 2017), ASCO (Chiorean et al., 2020), The Japanese Society for Cancer of the Colon and Rectum (JSCCR) (Hashiguchi et al., 2020), SIGN (SIGN, 2016), y la NCCN, que elaboró dos GPC, una para pacientes con cáncer de colon (NCCN, 2022a) y otra para pacientes con cáncer rectal (NCCN, 2022b). Además, se incluyó una ETS elaborada por CADTH (CADTH, 2015), y el ECA de fase III, denominado AVEX (Cunningham et al., 2013). CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación no aprueba el uso de bevacizumab más capecitabina para el tratamiento de pacientes adultos mayores con cáncer colorrectal metastásico, ECOG 0-2, sin tratamiento previo, no tributario a quimioterapia basada en platino (oxaliplatino) ni irinotecán.

Caracterización clínico-epidemiológica de la urolitiasis / Clinical-epidemiological description of urolithiasis

Introducción: Las urolitiasis ocasionan dolor, deterioro funcional renal y notorias erogaciones económicas. Objetivos: Identificar las características clínico-epidemiológicas de la nefrolitiasis. Métodos: Estudio descriptivo, transversal. Se estudiaron 2 923 personas pertenecientes a tres consultorios del Policlínico Plaza; municipio Plaza de la Revolución, provincia La Habana, Cuba., seleccionados por muestreo simple aleatorio de los 16 con que cuenta el área de salud. Los datos se obtuvieron mediante encuesta y entrevista estructurada. La información fue procesada de forma automatizada (IBMSPSS 22.0). Se utilizó análisis de distribución de frecuencias, se calcularon tasas de prevalencia, y fue empleado el test de homogeneidad. Resultados: La prevalencia de urolitiasis fue de 4,99 por cada 100 habitantes, de 6,3 entre los varones y de 5,7 en los de piel blanca. La edad promedio al diagnóstico fue de 39,3 años. Entre los factores de riesgo de litiasis predominó la alta ingestión de oxalatos (97,3 por ciento). La ecografía fue la forma de diagnóstico más usada (67,8 por ciento). La fitoterapia fue el tratamiento médico más utilizado (69,2 por ciento). Al 16,4 por ciento de los pacientes se les expidió certificado médico en los últimos dos años. Conclusiones: La prevalencia de litiasis urinaria en el Policlínico Docente Plaza de la Revolución es elevada, con predominio en el sexo masculino, en sujetos de piel blanca y en las edades medias de la vida. La alta ingestión de oxalato es el factor de riesgo de litiasis urinaria más frecuente encontrado. La forma de diagnóstico más utilizada es la ecografía y el tratamiento más empleado es la fitoterapia(AU)

Introduction: Urolithiasis causes pain, renal functional deterioration and notorious economic expenses. Objectives: To identify the clinical-epidemiological characteristics of nephrolithiasis. Methods: A descriptive, cross-sectional study was conducted in a total of 2,923 people from to three clinics of Plaza de la Revolution Teaching Community Clinic, Plaza de la Revolution municipality, Havana province, Cuba. They were selected by simple random sampling from the 16 clinics that the health area has. The data was obtained through a survey and structured interview. The information was processed automatically (IBMSPSS 22.0). Frequency distribution analysis was used, prevalence rates were calculated and the homogeneity test was used. Results: The prevalence of urolithiasis was 4.99 per 100 inhabitants, 6.3 among men and 5.7 among white-skinned men. The average age at diagnosis was 39.3 years. Among the risk factors for lithiasis, the high intake of oxalates prevailed (97.3 percent). Ultrasound was the most used form of diagnosis (67.8 percent). Phytotherapy was the most used medical treatment (69.2 percent). A medical permit was issued to 16.4 percent of the patients in the last two years. Conclusions: The prevalence of urinary lithiasis in Plaza de la Revolution Teaching Community Clinic is high, prevailing in males, in white-skinned and middle aged subjects. High oxalate intake is the most common risk factor for urinary lithiasis found. The most used form of diagnosis is ultrasound and the most used treatment is phytotherapy(AU)

Oxaliplatin related multiple focal nodular hyperplasia mimicking metastasis from a gastric cancer.

INTRODUCTION: The FOLFOX6 scheme is a combination drug chemotherapy that contains calcium leucovorin (folinic acid), fluorouracil, and oxaliplatin, the chronic use of chemotherapy with oxaliplatin can progress to focal nodular hyperplasia (FNH), which is a benign hepatic lesion. CASE REPORT: We present a case of a 26- year-old female diagnosed with an ovarian mixed germ cell tumor with extension to the peritoneum, treated with 12 cycles in 9 months with neoadjuvant chemotherapy FOLFOX 6 scheme and oophorectomy. A three-year follow-up CT showed three nodular and hypervascular hepatic lesions suspicious of metastatic disease; an MRI with liver-specific contrast confirmed the diagnosis of FNH. MANAGEMENT AND OUTCOME: The patient continued her follow-up without other treatment and metastatic disease. DISCUSSION: While most multiple liver lesions in a patient with cancer will be suspicious of metastasis, a careful drug history should be obtained, as an oxaliplatin-related side effect to develop FNH has been reported. MRI with liver-specific contrast has a positive predictive value of 95% because of the biliary excretion through OATP1B3 transporter, expressed in functional hepatocytes and overexpressed in some liver tumors such as FNH, so it should be performed when FNH is suspected.