Metronomic Capecitabine Effectively Blocks Leptomeningeal Carcinomatosis From Breast Cancer: A Case Report and Literature Review.

BACKGROUND Meningeal carcinomatosis is a rare complication in breast cancer patients. At present, there are no defined guidelines for its management. The efficacy of systemic treatment seems to depend on its ability to cross the blood-brain-barrier and its interaction with tumor vasculature. Metronomic chemotherapy is a known modality of drug administration able to inhibit tumor angiogenesis. CASE REPORT We present a case of symptomatic leptomeningeal carcinomatosis from breast cancer successfully treated with capecitabine. Based on the hypothesis that angiogenesis contributes to neoplastic meningitis, the patient was treated with a metronomic schedule that provided long-term clinical benefit with a very low toxicity profile. CONCLUSIONS To assess the real impact of metronomic chemotherapy in patients with meninges involvement, a phase II study will be starting soon in our institution. A review of the literature concerning the management of meningeal carcinomatosis is also presented

High-Up: A Remote Reservoir of Microbial Extremophiles in Central Andean Wetlands

The Central Andes region displays unexplored ecosystems of shallow lakes and salt flats at mean altitudes of 3700 m. Being isolated and hostile, these so-called “High-Altitude Andean Lakes” (HAAL) are pristine and have been exposed to little human influence. HAAL proved to be a rich source of microbes showing interesting adaptations to life in extreme settings (poly-extremophiles) such as alkalinity, high concentrations of arsenic and dissolved salts, intense dryness, large daily ambient thermal amplitude, and extreme solar radiation levels. This work reviews HAAL microbiodiversity, taking into account different microbial niches, such as plankton, benthos, microbial mats and microbialites. The modern stromatolites and other microbialites discovered recently at HAAL are highlighted, as they provide unique modern—though quite imperfect—analogs of environments proxy for an earlier time in Earth's history (volcanic setting and profuse hydrothermal activity, low atmospheric O2 pressure, thin ozone layer and high UV exposure). Likewise, we stress the importance of HAAL microbes as model poly-extremophiles in the study of the molecular mechanisms underlying their resistance ability against UV and toxic or deleterious chemicals using genome mining and functional genomics. In future research directions, it will be necessary to exploit the full potential of HAAL poly-extremophiles in terms of their biotechnological applications. Current projects heading this way have yielded detailed molecular information and functional proof on novel extremoenzymes: i.e., DNA repair enzymes and arsenic efflux pumps for which medical and bioremediation applications, respectively, are envisaged. But still, much effort is required to unravel novel functions for this and other molecules that dwell in a unique biological treasure despite its being hidden high up, in the remote Andes.Fil: Albarracín, Virginia Helena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Planta Piloto de Procesos Industriales Microbiologicos; ArgentinaFil: Kurth, Daniel German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Planta Piloto de Procesos Industriales Microbiologicos; ArgentinaFil: Ordoñez, Omar Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Planta Piloto de Procesos Industriales Microbiologicos; ArgentinaFil: Belfiore, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Planta Piloto de Procesos Industriales Microbiologicos; ArgentinaFil: Luccini, Eduardo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Química e Ingeniería-Rosario; ArgentinaFil: Salum, Graciela Marisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Piacentini, Ruben Dario Narciso. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Exactas, Ingeniería y Agrimensura; Argentina. Universidad Tecnológica Nacional. Facultad Regional Concepción del Uruguay; ArgentinaFil: Farias, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Planta Piloto de Procesos Industriales Microbiologicos; Argentin

Neoadjuvant treatments in triple-negative breast cancer patients: where we are now and where we are going

Abstract: Triple-negative breast cancer (TNBC) remains the poorest-prognosis breast cancer (BC) subtype. Gene expression profiling has identified at least six different triple-negative subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN tumors may justify the difficulty in treating this BC subtype. Several targeted agents have been investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic treatment is an effective option of care. The achievement of a pathological complete response represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitivity. In this review, we provide a brief description of the main predictive biomarkers for tumor response to systemic treatment. Moreover, we review the treatment strategies investigated for TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC patients may be treated on the basis of tumor molecular profile

Clinical Prognosticators in Patients Treated with CDK 4/6 Inhibitors for Hormone Receptors Positive Advanced Breast Cancer

Background: CDK4/6 inhibitors are the new standard of care in hormonal receptors positive (HR+) advanced breast cancer (ABC). Phase III trials demonstrated an improvement in survival outcomes in patients with combined endocrine approach compared to endocrine therapy (ET) alone. The aim of this retrospective study was to assess prognostic factors for clinical response to CDK4/6 inhibitors. Methods: All patients receiving CDK4/6 inhibitors from September 2016 to July 2019 were registered in a database. Data on tumor and patient\u2019s characteristics as well as concomitant medications were collected. Survival data were analyzed by Kaplan Meier curves and log rank test. Treatment toxicities were graded according to CTCAE v5. A drug-drug interactions analysis among CDK 4/6 inhibitors and co-administered medications was performed too. Results: 121 patients were included in the study: 49% of patients treated in 1st -line, 25% in 2nd -line and 26% in 3rd \u2013or further lines. 1st-line objective response rate (ORR) and clinical benefit rate (CBR) was 56% and 68%, compared to 40% and 50% in 2nd-line and 31% and 47% in heavily pre-treated patients, respectively. Median PFS according to line setting was: not reached in 1st-line, 17 months (95% CI 13-21) in 2nd-line and 7 months (95% CI 4-12) in 3rd or further lines. Negative prognostic factors in term of PFS were: previous chemotherapy for metastatic disease (p=0.0001), visceral metastatic sites (p=0.002) and endocrine sensitivity (p=0.001). No association among concomitant drugs administered and survival outcome was found. 94% of patients experienced neutropenia (G3-G4 60%) with 3% of febrile neutropenia. 71% of patients treated with Abemaciclib had diarrhea. Management of AE included 63% of treatment delay, 44% of 1st dose reduction and 15% of 2nd dose reduction, all due to neutropenia. No treatment discontinuation due to any toxicity was observed. Conclusion: Data on efficacy and safety profile of CDK 4/6 inhibitors administered outside the context of a clinical trial are consistent with those reported in Phase III trials. Previous chemotherapy for metastatic disease, visceral metastatic site as well as previous endocrine sensitivity negatively affect CDK 4/6 inhibitors efficacy. Concomitant medications did not affect survival outcome or safety profile

HIV-1 Nef enhances both membrane expression and virion incorporation of Env products. A model for the Nef-dependent increase of HIV-1 infectivity.

The expression of human immunodeficiency virus Nef increases the viral infectivity through mechanisms still not fully elucidated. Here we report that wild-type (wt) human immunodeficiency virus, type 1 (HIV-1), particles were neutralized by higher concentrations of either anti-Env glycoprotein (gp) 41 antibodies or recombinant soluble human CD4 compared with Δnef HIV-1. This appeared to be the result of a Nef-induced increase of virion incorporation of both gp41 (transmembrane (TM)) and surface gp120 Env products likely originating from enhanced steady-state levels of cell membrane-associated Env products. This, in turn, seemed to be the consequence of a reduced retention of the Env precursor. Most interesting, we found that both the Nef-directed increase of Env membrane expression and the Nef-induced enhancement of HIV-1 infectivity relied on the presence of the intracytoplasmic domain of TM, supporting the hypothesis of a functional correlation between these effects. Mutagenesis studies allowed us to establish that the two leucine residues at the TM C terminus, which are part of a sorting motif involved in the control of Env membrane expression, and the 181–210-residue Nef C-terminal region were critically involved in the Nef/Env functional interaction. In conclusion, we propose that Nef increases the infectivity of HIV-1 at least in part by enhancing the amounts of Env products incorporated into virus particles

Impact of anaemia on tumor response to neoadjuvant chemotherapy in breast cancer patients .

BACKGROUND - Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) in patients with breast cancer (BC) predicts long-term outcomes. Anaemia is one of the most common side effects of cytotoxic drugs. Biologically, anaemia induces adaptive responses due to the low intra-tumoral oxygen levels that may be responsible for increase chemotherapy resistance. In literature, data regarding this issue are lacking. AIM - To evaluate the influence of anaemia throughout treatment course on tumour shrinkage induced by NST. METHODS - Patients - 317 patients diagnosed with stage I-III BC treated with NST and with available blood tests were included. Patients and tumor characteristics and treatments information were collected. We focused on Haemoglobin (Hb) level (at baseline, at the end of NST, drop in Hb throughout treatment and duration of anaemia) and its correlation with pCR rate. Anaemia was defined as a drop of Hb under the local limit of normal in women (12 mg/dl). Statistical analysis - Categorical variables were analyzed using chi-square test or Fisher's exact test, continuous variables using t test. Univariate and multivariate analyses were fit to determinate the association between anaemia and pCR rate. A p-value < 0.05 was considered statistically significant; hazard ratio was estimated with 95% of confidence limits. RESULTS- No difference in Hb levels was observed stratifying patients according to nuclear grade, tumor stage, cancer subtypes and chemotherapy regimens. Median baseline Hb was 13.3 g/dl while median Hb level at the end of NST was 10 g/dl. 31 patients had pre-treatment anaemia. 60% of patients developed anaemia during NST period. In the subgroup of anaemic patients, who had a decrease in Hb ≥ 2 g/dl from baseline or anaemia longer than two months, a lower rate of pCR was observed (16% vs 29%, p=0.03 and 16% vs 25%, p=0.01, respectively). Patients with both these characteristics had the lowest rate of pCR (10%, p=0.01). CONCLUSIONS - Anaemia is a negative predictive factor for tumor response in women treated with NST for BC. This evidence suggests that anaemia should be improved in order to improve response to NST

Bone Marrow Foot Oedema in Adolescents: The Role of Vitamin D

BACKGROUND: Bone marrow oedema (BMO) in children/adolescents is a rare clinical condition without an etiologic cause. It is associated with typical increased signal intensity on T2-weighted magnetic resonance images (MRI) and an increase in bone turnover in which vitamin D plays a pivotal role. No treatment guidelines for these young patients are to date available. METHODS: We performed a retrospective study in a pediatric setting of 13 patients with diagnosis of primary BMO of the foot on the basis of clinical and radiological findings. Data collection included sex, age, patient history, symptoms at presentation, clinical examination, laboratory bone turnover markers, vitamin D levels, MRI, treatment, and outcome. RESULTS: Vitamin D deficiency or insufficiency was found in 76.9% of cases. All patients were treated with adequate vitamin D daily intake, a short course of analgesic therapy, physical therapy, avoiding detrimental feet and ankle immobilization. All fully recovered in 3-month lag period. CONCLUSIONS: Our data highlight that environmental factors, such as underestimated articular or bone microtraumatisms, as well as joint hyper mobility, in a bone turnover milieu of vitamin D deficiency could be the cause of this clinical conditions. Adequate vitamin D supplementation, associated with physical and analgesic therapy, is crucial in the management of BMO

Validation of the American Joint Committee on Cancer new prognostic stage groups for HER2-positive breast cancer patients treated with adjuvant chemotherapy and trastuzumab in the prospective ShortHER trial

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