Prognostic role for the derived neutrophil-to-lymphocyte ratio in early breast cancer: a GEICAM/9906 substudy

Purpose: Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer. Patients and methods: This was a retrospective analysis of 1246 patients with lymph node-positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis. Results: The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10 years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08-1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico-pathological factors. However, dNLR ≥ 1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p = 0.038) and in patients with one to three lymph node metastases (HR 1.32, p = 0.032). There was a non-significant association with worse DFS in non-luminal and in HER2-enriched tumors (HR 1.40, p = 0.085 and HR 1.53, p = 0.067). No significant interaction was observed between the treatment arm and dNLR. Conclusion: Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer

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Prognostic role for the derived neutrophil-to-lymphocyte ratio in early breast cancer: a GEICAM/9906 substudy.

PURPOSE: Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer. PATIENTS AND METHODS: This was a retrospective analysis of 1246 patients with lymph node-positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis. RESULTS: The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10 years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08-1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico-pathological factors. However, dNLR ≥ 1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p = 0.038) and in patients with one to three lymph node metastases (HR 1.32, p = 0.032). There was a non-significant association with worse DFS in non-luminal and in HER2-enriched tumors (HR 1.40, p = 0.085 and HR 1.53, p = 0.067). No significant interaction was observed between the treatment arm and dNLR. CONCLUSION: Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer. TRIAL REGISTRATION: EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). ClinicalTrials.gov Identifier: NCT00129922 (retrospectively registered 10/08/2005). Results of this study were presented in part at the 2016 ESMO conference October 7-11, 2016, Copenhagen, Denmark (oral presentation).

Outcomes of single versus double hormone receptor-positive breast cancer. A GEICAM/9906 sub-study.

BACKGROUND: Retrospective data suggest better outcomes for patients with double hormonal receptor (oestrogen [ER] and progesterone receptor [PgR])-positive (dHR+) early breast cancer, compared with single hormonal receptor-positive, sHR+, (ER+/PgR- or ER-/PgR+) disease. Here, we evaluate the classification according to intrinsic subtypes and clinical outcomes of sHR+ versus dHR+ in HER2-negative breast cancer patients enrolled in GEICAM/9906 study (NCT00129922). METHODS: Archival tumours were retrieved retrospectively for the analysis of ER, PgR and HER2 status and classified into intrinsic subtypes using the PAM50 gene expression assay. Disease-free survival (DFS) and overall survival (OS) were explored using a Cox proportional hazard analysis. RESULTS: Data on intrinsic subtypes were available in 571 (50%) patients with ER+ and/or PR+, and HER2-negative primary tumours. The incidence of luminal A and luminal B subtypes were 52%/36% in dHR+ tumours (ER+/PgR+), and 15%/58% in ER+/PgR-tumours. ER-/PgR+ tumours were mainly luminal A (52%). Compared with ER+/PgR+ patients, DFS was similar in ER-/PgR+ (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.57-2.34, p = 0.70) but worse in ER+/PgR- patients (HR 1.60, 95% CI 1.12-2.28, p < 0.01). Similar results were observed for OS (HR 1.50, p = 0.30 and HR 1.86, p < 0.01, respectively). CONCLUSIONS: The ER+/PgR- group is characterised by higher proliferation and worse outcomes. In spite of the ER-/PgR+ subgroup resembles ER+/PgR+ disease in terms of molecular subtypes and outcomes, the small number of patients in this subgroup prevents from drawing any conclusions. TRIAL REGISTRATION: EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). CLINICALTRIALS. GOV IDENTIFIER: NCT00129922 (retrospectively registered 10/08/2005).

Dataset reporting BCKDK interference in a BCAA-catabolism restricted environment.

This data article contains complementary figures to the research article "Mitochondrial response to the BCKDK-deficiency: some clues to understand the positive dietary response in this form of autism" [1]. Herein we present data relative to the effect of knocking down BCKDK gene on the real time oxygen consumption rate of fibroblasts obtained from a Maple Syrup Urine Disease (MSUD) patient. Interference of BCKDK expression on such cells showing a reduced branched-chain α-ketoacid dehydrogenase (BCKDHc) activity; let us generate a scenario to study the direct effect of BCKDK absence in an environment of high branched-chain amino acids (BCAAs) concentrations. Data relative to the effectiveness of the knockdown together with the potentiality of the BCKDK-knockdown to increase the deficient branched-chain α-ketoacid dehydrogenase activity detected in MSUD patients are also shown.

Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism.

Mutations on the mitochondrial-expressed Branched Chain α-Keto acid Dehydrogenase Kinase (BCKDK) gene have been recently associated with a novel dietary-treatable form of autism. But, being a mitochondrial metabolism disease, little is known about the impact on mitochondrial performance. Here, we analyze the mitochondrial response to the BCKDK-deficiency in patient's primary fibroblasts by measuring bioenergetics, ultra-structural and dynamic parameters. A two-fold increase in superoxide anion production, together with a reduction in ATP-linked respiration and intracellular ATP levels (down to 60%) detected in mutants fibroblasts point to a general bioenergetics depletion that could affect the mitochondrial dynamics and cell fate. Ultrastructure analysis of BCKDK-deficient fibroblasts shows an increased number of elongated mitochondria, apparently associated with changes in the mediator of inner mitochondria membrane fusion, GTPase OPA1 forms, and in the outer mitochondrial membrane, mitofusin 2/MFN2. Our data support a possible hyperfusion response of BCKDK-deficient mitochondria to stress. Cellular fate also seems to be affected as these fibroblasts show an altered proportion of the cells on G0/G1 and G2/M phases. Knockdown of BCKDK gene in control fibroblasts recapitulates most of these features. Same BCKDK-knockdown in a MSUD patient fibroblasts unmasks the direct involvement of the accelerated BCAAs catabolism in the mitochondrial dysfunction. All these data give us a clue to understand the positive dietary response to an overload of branched-chain amino acids. We hypothesize that a combination of the current therapeutic option with a protocol that considers the oxidative damage and energy expenditure, addressing the patients' individuality, might be useful for the physicians.

Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers.

Recent findings in colon cancer cells indicate that inhibition of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase by the ATPase inhibitory factor 1 (IF1) promotes aerobic glycolysis and a reactive oxygen species (ROS)-mediated signal that enhances proliferation and cell survival. Herein, we have studied the expression, biological relevance, mechanism of regulation and potential clinical impact of IF1 in some prevalent human carcinomas. We show that IF1 is highly overexpressed in most (>90%) of the colon (n=64), lung (n=30), breast (n=129) and ovarian (n=10) carcinomas studied as assessed by different approaches in independent cohorts of cancer patients. The expression of IF1 in the corresponding normal tissues is negligible. By contrast, the endometrium, stomach and kidney show high expression of IF1 in the normal tissue revealing subtle differences by carcinogenesis. The overexpression of IF1 also promotes the activation of aerobic glycolysis and a concurrent ROS signal in mitochondria of the lung, breast and ovarian cancer cells mimicking the activity of oligomycin. IF1-mediated ROS signaling activates cell-type specific adaptive responses aimed at preventing death in these cell lines. Remarkably, regulation of IF1 expression in the colon, lung, breast and ovarian carcinomas is exerted at post-transcriptional levels. We demonstrate that IF1 is a short-lived protein (t1/2 ∼100 min) strongly implicating translation and/or protein stabilization as main drivers of metabolic reprogramming and cell survival in these human cancers. Analysis of tumor expression of IF1 in cohorts of breast and colon cancer patients revealed its relevance as a predictive marker for clinical outcome, emphasizing the high potential of IF1 as therapeutic target.

Mitochondrial bioenergetics and dynamics interplay in complex I-deficient fibroblasts.

BACKGROUND: Complex I (CI) deficiency is the most frequent cause of OXPHOS disorders. Recent studies have shown increases in reactive oxygen species (ROS) production and mitochondrial network disturbances in patients' fibroblasts harbouring mutations in CI subunits. OBJECTIVES: The present work evaluates the impact of mutations in the NDUFA1 and NDUFV1 genes of CI on mitochondrial bioenergetics and dynamics, in fibroblasts from patients suffering isolated CI deficiency. RESULTS: Decreased oxygen consumption rate and slow growth rate were found in patients with severe CI deficiency. Mitochondrial diameter was slightly increased in patients' cells cultured in galactose or treated with 2'-deoxyglucose without evidence of mitochondrial fragmentation. Expression levels of the main proteins involved in mitochondrial dynamics, OPA1, MFN2, and DRP1, were slightly augmented in all patients' cells lines. The study of mitochondrial dynamics showed delayed recovery of the mitochondrial network after treatment with the uncoupler carbonyl cyanide m-chlorophenyl hydrazone (cccp) in patients with severe CI deficiency. Intracellular ROS levels were not increased neither in glucose nor galactose medium in patients' fibroblasts. CONCLUSION: Our main finding was that severe CI deficiency in patients harbouring mutations in the NDUFA1 and NDUFV1 genes is linked to a delayed mitochondrial network recovery after cccp treatment. However, the CI deficiency is neither associated with massive mitochondrial fragmentation nor with increased ROS levels. The different genetic backgrounds of patients with OXPHOS disorders would explain, at least partially, differences in the pathophysiological manifestations of CI deficiency.

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[Uncommon etiology of gastrointestinal bleeding: duodenal metastases from renal cell carcinoma]. / Causa poco habitual de hemorragia digestiva alta: metástasis duodenal de adenocarcinoma renal.

Because of its unpredictable behavior, renal cell carcinoma is one of the most controversial neoplasms. On the one hand, patients frequently show metastases at diagnosis because of its slight manifestations, while on the other, the neoplasm can remain stable after nephrectomy and can then metastasize many years later. When this happens, the metastases usually involve more than 2 organs. The most frequent sites of metastases are the lung and lymph nodes, followed by the bones and liver, while duodenal involvement is rare. Indeed, intestinal metastases are found in only 2% of autopsies and of these, renal cell carcinoma metastases account for 7.1%. We present a case of a solitary late recurrence presenting as upper gastrointestinal bleeding 19 years after nephrectomy for clear cell renal carcinoma.

Causa poco habitual de hemorragia digestiva alta: metástasis duodenal de adenocarcinoma renal / Uncommon etiology of gastrointestinal bleeding: duodenal metastases from renal cell carcinoma

El adenocarcinoma renal es una de las neoplasias más controvertidas debido a su comportamiento impredecible. En muchas ocasiones los pacientes presentan enfermedad metastásica en el momento del diagnóstico dada su escasa expresividad clínica, y en otras, tras una nefrectomía, el tumor puede permanecer estable y metastatizar años después. Cuando la enfermedad metastásica ocurre, suele ser múltiple y los lugares afectados con mayor frecuencia son el pulmón, los ganglios, el hueso y el hígado, mientras que la afectación intestinal es inusual. De hecho, la afectación intestinal como zona de implantación de metástasis es infrecuente y representa sólo el 2% de las autopsias. De este pequeño porcentaje, el 7,1% corresponde a metástasis de adenocarcinoma renal. Presentamos un caso de metástasis única duodenal que se manifestó como hemorragia digestiva alta al cabo de 19 años de una nefrectomía por carcinoma renal de células claras

Because of its unpredictable behavior, renal cell carcinomais one of the most controversial neoplasms. On the one hand, patients frequently show metastases at diagnosis because of its slight manifestations, while on the other, the neoplasm can remain stable after nephrectomy and can then metastasize many years later. When this happens, the metastases usually involve more than 2 organs. The most frequent sites of metastases are the lung and lymph nodes, followed by the bones and liver, while duodenal involvement is rare. Indeed, Intestinal metastases are found in only 2% of autopsies and of these, renal cell carcinoma metastases account for 7.1%. We present a case of a solitary late recurrence presenting as upper gastrointestinal bleeding 19 years after nephrectomy for clear cell renal carcinoma

[Wilson's disease with severe neurological manifestations: response to trientine plus zinc therapy]. / Enfermedad de Wilson con afectación neurológica grave: respuesta al tratamiento combinado con trientina y acetato de cinc.

In patients with Wilson's disease and neurological manifestations, treatment with D-penicillamine can cause worsening of neurological symptoms, usually in the first few weeks of treatment. Because the neurological damage can be severe and irreversible, the use of D-penicillamine is controversial, and several authors believe that it should be avoided. Studies of the use of ammonium tetrathiomolybdate as an alternative chelating agent for the initial treatment of neurologic Wilson's disease are still in the experimental phase. Published experience on the simultaneous use of trientine, another chelating agent, and zinc, which blocks intestinal absorption of copper, is promising but limited. We present the case of a 17 year-old boy with severe neurologic Wilson's disease that had first presented six years previously. The patient showed a complete recovery after six months of treatment with a combination of trientine and zinc acetate.