Interstitial lung disease in patients enrolled in early-phase clinical trials: the ILDE study.

BACKGROUND: Interstitial lung disease (ILD) encompasses a heterogeneous group of disorders sharing pathophysiological inflammatory mechanisms, leading to parenchymal distortions. The prevalence of ILD with new cancer drugs is underreported: the identification of potential determinants is priority. MATERIALS AND METHODS: ILDE is a retrospective study aimed at describing the clinical course and potential determinants of ILD in patients receiving experimental treatments. RESULTS: We identified 226 eligible patients, of whom 5.3% (n = 12) had ILD. In five patients, the diagnosis was radiological, while seven patients had initial cough, dyspnea, fatigue or fever. ILD was graded as grade 1 (G1) in four, G2 in five and G3 in three patients. The first occurrence of ILD resolved completely in 50% of patients (n = 6/12). No patient had fatal ILD. Eight patients (66.7%) resumed the treatment after the first episode of ILD, while four patients (33.3%) had to discontinue the therapy. Five out of six patients had resolved the first ILD episode and then resumed treatment, experiencing a second ILD episode (n = 5/6; 83.3%). The second ILD event was G1 in three patients and G2 in two patients, resulting in three patients who eventually discontinued the treatment (n = 3/5; 60%). Correlation analysis showed a higher risk of ILD in older patients (P = 0.051), those who had received previous chest radiation therapy (P = 0.047) or those receiving antibody-drug conjugates (P = 0.006). In a survival analysis adjusted for immortal time bias, ILD was not independently prognostic (hazard ratio 0.50, 95% confidence interval 0.23-1.09, P = 0.082). CONCLUSIONS: In ILDE, patients experiencing ILD had generally good outcomes, and many could resume the cancer treatments. Implementing best practices to prompt diagnosis and management of ILD is critical to treat a potentially severe adverse effect of new drugs, while not affecting patients' outcomes. Research efforts to identify risk factors is warranted, to implement risk-based monitoring schedules and develop ad hoc strategies to improve the cure rates of ILD.

Unfavorable carcinoma of unknown primary with a gastrointestinal profile: a retrospective study.

BACKGROUND: Carcinoma of unknown primary (CUP) with a gastrointestinal profile is categorized by the European Society of Medical Oncology (ESMO) guidelines into favorable and unfavorable subsets. Favorable CUPs benefit from site-specific chemotherapy (CT), while the optimal treatment for unfavorable CUPs is still undefined. MATERIALS AND METHODS: We conducted a single-center retrospective study to describe outcomes of patients with CUP with a gastrointestinal profile referred to our center from January 2000 to August 2023. Favorable CUPs were defined as CK7-/CK20+/CDX2+ by immunohistochemistry, according to the ESMO definition; all other cases were considered unfavorable. The main endpoint was the progression-free survival (PFS) of first-line CT for advanced disease in all patients and in the unfavorable group. RESULTS: A total of 56 patients were included, of whom 46 (82%) had unfavorable CUPs. After a median follow-up of 43.9 months, the median overall survival (mOS) was 11.8 months [95% confidence interval (CI) 8.3-15.3 months]. At univariate analysis, the presence of peritoneal metastases and residual tumor after primary surgery were associated with a shorter OS. The median PFS (mPFS) was 6.1 months (95% CI 3.6-8.7 months). In the unfavorable CUP subgroup, the mOS was 12.6 months (95% CI 8.7-16.5 months), the mPFS was 6.1 months (95% CI 3.5-8.9 months) and none of the CT regimens used showed to portend better PFS. The most relevant altered genes included: KRAS (9/29; 31%), BRAF (1/26; 4%), NRAS (1/25; 4%), TP53 (9/23; 39%). CONCLUSIONS: CUPs with a gastrointestinal profile are characterized by poor prognosis and the absence of biomarker for treatment personalization. No CT regimen was superior in terms of PFS in patients with unfavorable CUPs.

Age, Blasts, Performance Status and Lenalidomide Therapy Influence the Outcome of Myelodysplastic Syndrome With Isolated Del(5q): A Study of 58 South American Patients.

BACKGROUND: Myelodysplastic Syndrome (MDS) with isolated deletion 5q is associated with a low risk to leukemic evolution and long overall survival (OS); it comprises 3%-4.5% of MDS cases in Latin America classified according to the World Health Organization 2008. This study aims to describe clinical, laboratory and the outcome of patients according to the newest World Health Organization 2016 proposal. METHODS: We retrospectively reviewed patients from four Brazilian (BR) and four Argentinean (AR) centers diagnosed between 1999 and 2019. RESULTS: The 58 patients (16-AR and 42-BR) presented a median age of 67 (IQR 61-75) years old, women predominance (70.7%) and transfusion dependency (62.5%) at diagnosis. Median hemoglobin level was 8.1g/dL, 27.5% and 44.4% presented thrombocytosis and neutropenia, respectively. Bone marrow (BM) was predominantly hypercellular (43.1%) with 66% showing dysplasia >1 lineage and 37.9% with >2% of blasts. Deletion 5q was mostly isolated (79.3%) and a variety of abnormalities were observed in remaining cases. Most patients were treated with erythropoietin-stimulating agents (ESA), 18 with lenalidomide and 15 with thalidomide. Median follow-up was 7.6 years, with a median OS of 3.5 years and an 8-years leukemic evolution rate of 18.4%. Multivariate analysis showed that age >75 years (HR 2.19), ECOG ≥2 (HR 5.76), BM blasts >2% (HR 2.92) and lenalidomide treatment (HR 0.25) independently influenced the OS. CONCLUSION: Older age, worse performance status and higher percentage of blasts, that can be easily assessed, were associated to a worse prognosis. Also, our results corroborate the protective influence of lenalidomide in terms of OS in this South American series.

ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research.

Aberrant activation of RET is a critical driver of growth and proliferation in diverse solid tumours. Multikinase inhibitors (MKIs) showing anti-RET activities have been tested in RET-altered tumours with variable results. The low target specificity with consequent increase in side-effects and off-target toxicities resulting in dose reduction and drug discontinuation are some of the major issues with MKIs. To overcome these issues, new selective RET inhibitors such as pralsetinib (BLU-667) and selpercatinib (LOXO-292) have been developed in clinical trials, with selpercatinib recently approved by the Food and Drug Administration (FDA). The results of these trials showed marked and durable antitumour activity and manageable toxicity profiles in patients with RET-altered tumours. The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to review the available methods for the detection of RET gene alterations, their potential applications and strategies for the implementation of a rational approach for the detection of RET fusion genes and mutations in human malignancies. We present here recommendations for the routine clinical detection of targetable RET rearrangements and mutations.

Occurrence of gastric ulcers and serum gastrin levels in jumping horses / Ocorrência de úlceras gástricas e níveis séricos de gastrina em cavalos de hipismo

The aim of this study was to determine the occurrence of EGUS and to quantify serum gastrin levels in jumping horses during competition season and interseason period. Forty jumping horses, competing at high level were randomly allocated into two groups, the Training Group: twenty jumping horses undergoing intense training and participating in competitions, and the Rest Group: twenty jumping horses in the interseason (resting period). The gastroscopic examinations and blood samples of the horses in the training group were performed 1-2 days following the competition while in the horses of the rest group, following 4 weeks of rest. The serum gastrin levels were measured at two different times: pre-feeding and two hours after feeding the horses (postprandial) by ELISA kit. Gastric lesion score data were compared by the Mann-Whitney U test (α= 0.05) and the mean gastrin values were compared between the groups and between the two moments by the paired tet tests, respectively (α= 0, 05). Squamous gastric ulcers were detected in 42.5% of all jumping horses examined independent of the period, competition season or interseason. Serum gastrin levels were significantly higher in the Training Group with no difference between pre-feeding and postprandial values.(AU)

O objetivo deste estudo foi determinar a ocorrência de EGUS e quantificar os níveis séricos de gastrina em cavalos de hipismo durante a época de competições e o período de férias. Quarenta cavalos de hipismo de alta performance foram aleatoriamente distribuídos em dois grupos, grupo treinamento: vinte cavalos de hipismo submetidos a treinamento intenso e participando de competições, e grupo descanso: vinte cavalos de hipismo em férias (período de descanso). As avaliações gastroscópicas e as coletas de sangue dos cavalos em treinamento foram realizadas um ou dois dias após as competições, enquanto nos cavalos do grupo descanso foram realizadas após quatro semanas de repouso. Os níveis séricos de gastrina foram mensurados por kit de ELISA, em dois momentos: antes da alimentação e duas horas após. Os dados de escore das lesões gástricas foram comparados pela prova U de Mann-Whitney (α= 0,05) e os valores médios de gastrina foram comparados entre os grupos e entre os dois momentos pelos testes t e t pareado, respectivamente (α= 0,05). Foram encontradas úlceras gástricas em 42,5% de todos os cavalos examinados, independentemente do período de competições ou repouso. Os níveis séricos de gastrina foram significativamente maiores no grupo treinamento, sem diferença entre os períodos pré e pós-alimentação.(AU)

Mammary botryomycosis: two concomitant cases in mares: case report / Botriomicose mamária: dois casos concomitantes em éguas: relato de caso

Mammary disorders in mares are rare and usually only one animal per paddock is affected. In this report, two mares with 7 and 9 years old, were concomitantly diagnosis of chronic pyogranulomatous mastitis, associated with the Splendore-Hoeppli reaction, indicative of botryomycosis a rare, chronic suppurative disease with microabscess formation, characterized by in vivo formation of eosinophilic materials around microorganisms or biologically inert material. Various bacteria can cause botryomycosis in horses, and the most frequently isolated one is Staphylococcussp., particularly S. aureus. This report confirms the role of Staphylococcus sp.; however, specifically S. hyicus and S. cohnii that prior to the current report, had not been associated with cases of botryomycosis.(AU)

Enfermidades mamárias em éguas são raras e, normalmente, apenas um animal é afetado. Neste relato, duas éguas, de sete e nove anos, foram diagnosticadas concomitantemente com mastite crônica piogranulomatosa, associada com reação de Splendore - Hoeppli, indicativa de botriomicose, uma doença crônica supurativa rara, com formação de microabscessos caracterizados pela presença de material eosinofílico em torno dos microrganismos ou de material biologicamente inerte. Várias bactérias podem causar botriomicose em cavalos, sendo Staphylococcus sp., particularmente S. aureus, as mais frequentemente isoladas. Este relato confirma o papel do Staphylococcus sp, no entanto este é o primeiro relato em que S. hyicus e S. cohnii foram identificados em lesões relacionadas à botriomicose.(AU)

Transforming growth factor-ß1 functional polymorphisms in myeloablative sibling hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) with sibling donors (s.d.) is a life-saving intervention for patients with hematological malignancies. Numerous genetic factors have a role in transplant outcome. Several functional polymorphisms have been identified in TGF-ß1 gene, such as single-nucleotide polymorphism (SNP) at +29C>T within exon 1. Two hundred and forty five patient/donor pairs who underwent a s.d. HSCT in our centers were genotyped for this SNP. In the myeloablative cohort, +29CC donors were associated with an increase in severe chronic GvHD (32% vs 16%, hazard ratio (HR) 9.0, P=0.02). Regarding survival outcomes, +29CC patients developed higher non relapse mortality (NRM) (1-5 years CC 28-32% vs TC/TT 7-10%; HR 5.1, P=0.01). Recipients of +29TT donors experienced a higher relapse rate (1-5 years TT 37-51% vs TC 19-25% vs CC 13%-19%; HR 2.4, P=0.01) with a decreased overall survival (OS) (1-5 years TT 69-50% vs TC/CC 77-69%; HR 1.9, P=0.05). Similar to previous myeloablative unrelated donors HSCT results, we confirmed that +29CC patients had higher NRM. In addition we found that +29TT donors might be associated with a higher relapse rate and lower OS. These results should be confirmed in larger series. Identification of these SNPs will allow personalizing transplant conditioning and immunosuppressant regimens, as well as assisting in the choice of the most appropriate donor.

Acetylcholine polarizes dendritic cells toward a Th2-promoting profile.

BACKGROUND: A growing body of research shows a reciprocal regulation between the neural and immune systems. Acetylcholine (ACh) is the most important parasympathetic neurotransmitter, and increasing evidence indicates that it is able to modulate the immune response. Interestingly, in recent years, it has become clear that immune cells express a non-neuronal cholinergic system, which is stimulated in the course of inflammatory processes. We have previously shown that dendritic cells (DC) express muscarinic receptors, as well as the enzymes responsible for the synthesis and degradation of ACh. Here, we analyzed whether ACh could also modulate the functional profile of DC. METHODS: Dendritic cells were obtained from monocytes cultured for 5 days with GM-CSF+IL-4 or isolated from peripheral blood (CD1c+ DC). The phenotype of DC was evaluated by flow cytometry, the production of cytokines was analyzed by ELISA or intracellular staining and flow cytometry, and the expression of muscarinic and nicotinic receptors was evaluated by flow cytometry or qRT-PCR. RESULTS: Treatment of DC with ACh stimulated the expression of the Th2-promoter OX40L, the production of the Th2-chemokines MDC (macrophage-derived chemokine/CCL22) and TARC (thymus and activation-regulated chemokine/CCL17), and the synthesis of IL-4, IL-5, and IL-13 by T cells, in the course of the mixed lymphocyte reaction (MLR). Moreover, we found that the stimulation of OX40L, HLA-DR, and CD83 expressions in DC induced by the Th2-promoting cytokine TSLP, as well as the production of IL-13, IL-4, and IL-5 by T cells in the course of the MLR, was further enhanced when DC were treated with TSLP plus ACh, instead of TSLP or ACh alone. CONCLUSIONS: Our observations suggest that ACh polarizes DC toward a Th2-promoting profile.

Capecitabine with/without mitomycin C: results of a randomized phase II trial of second-line therapy in advanced biliary tract adenocarcinoma.

PURPOSE: Advanced biliary tract adenocarcinoma (BTA) is a rare tumor with a poor prognosis. Since no standard salvage chemotherapy regimen exists, we explored the activity of capecitabine alone or combined with mitomycin C. METHODS: Patients aged 18-75 years and with KPS >50, with pathological diagnosis of BTA stratified based on site and stage of disease, were randomized to receive capecitabine 2000 mg/m(2) day 1-14 alone (ARM A) or in combination with mitomycin C 6 mg/m(2) day 1 (ARM B) as second-line therapy. Cycles were repeated in both arms every 3 weeks. Tumor assessment was performed every 2 months. The primary endpoint was the probability of being progression free at 6 months (PFS-6) from treatment start. According to the Fleming design, the study aimed to enroll 26 pts per arm. An exploratory endpoint was to assess thymidylate synthase (TS) and thymidine phosphorylase (TP) expression, as biomarkers predictive for clinical outcomes of capecitabine treatment. RESULTS: Between October 2011 and 2013, 57 metastatic pts were enrolled: ARM A/B 28/29. Accordingly, 55 (26/29) pts were assessable for the primary endpoint: 2 (8%) ARM A and 3 (10%) ARM B pts were PFS-6. Main G3-4 toxicities were: hand-foot syndrome and transaminitis in 4/0%, and thrombocytopenia, diarrhea and fatigue in 0/3% of pts. No statistically significant correlation was found between TS or TP expression and pts' outcome. CONCLUSIONS: Since capecitabine yielded a disappointing outcome and the addition of mitomycin C did not improve the results, new therapeutic strategies need to be explored to improve survival in this disease setting.

Renal Stenting for Kidney Salvage in the Management of Renal Artery Atherosclerotic Stenosis.

We studied the usefulness of preoperative resistance index to select patients who will benefit most from renal stenting. Sixty-two patients underwent renal stenting. All had chronic renal insufficiency with serum creatinine values ranging from 1.5 to 2.5 mg/dL and blood urea nitrogen between 80 and 107 mg/dL. All treated renal artery stenosis were >70%. Reduction in blood pressure in the early stages was observed in 39 (62.9%) patients; 31 (79.4%) patients returned to preoperative values within 12 months. A progressive reduction in creatinine values and blood urea nitrogen was reached in 43 (69.4%) patients, 12 (19.4%) patients remained unchanged, and the remaining 7 (11.2%) patients worsened. The best improvement in renal function was obtained in patients with a resistance index of ≤0.75 A preoperative resistance index up to 0.75 could be used as an indicator to predict which candidates will have improved renal function after stenting.

Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.

BACKGROUND: The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model. METHODS: Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models. RESULTS: The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215-0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370-0.891), progression-free survival after first-line CT ≥ 6 months (P=0.027; HR, 0.633; 95% CI 0.422-0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392-0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001). CONCLUSIONS: Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.

Breast metastases from oligodendroglioma: an unusual extraneural spread in two young women and a review of the literature.

BACKGROUND: Extraneural dissemination of oligodendroglioma is rare. Cases of breast metastases have never been described in the literature. CASE REPORTS: We report the first two cases of young women with initial diagnosis of anaplastic oligodendroglioma who experienced mammary gland metastases and a review of the literature. RESULTS: Immunohistochemical analysis performed on material from both primary and metastatic sites did not allow to draw any conclusion on possible etiopathogenetic hypothesis. A review of literature yielded 35 cases of extracranial metastatic oligodendroglioma from 1989 to 2012. CONCLUSION: Though rare, extracranial dissemination from oligodendroglioma may occur not only in long surviving heavily pre-treated patients. The review of literature and these two cases suggest that spread is primarily to bone and then from bone to other organs through hematogenous route mostly due to leptomeningeal or dura mater invasion. Chemotherapy regimens similar to those commonly used for non metastatic oligodendroglioma are recommended for patients with good performance status.

Novel variant Ph translocation t(9;22;11)(q34;q11.2;p15)inv(9)(p13q34) in chronic myeloid leukemia involving a one-step mechanism.

Chronic myeloid leukemia (CML) is a clonal malignant disorder of a pluripotent hematopoietic stem cell characterized by the presence of a Philadelphia (Ph) chromosome. Less than 10% of patients present variant Ph chromosomes involving 1 or more additional chromosomes, other than chromosomes 9 and 22, with uncertain prognosis. There are mainly 1- or 2-step mechanisms proposed to explain the genesis of variant Ph chromosomes depending on whether the involved chromosomes are simultaneously broken and rejoined or if a standard t(9;22) occurs first. By combined standard cytogenetic and FISH analysis we detected a novel variant Ph translocation among chromosomes 9, 11 and 22 in a patient with CML without progression to an accelerated phase of the disease after 7 years, with the derivative chromosome 9 also having an acquired pericentric inversion. This novel case illustrates the use of FISH in metaphase to confirm a new rearrangement not previously described in variant Ph formation and that the present karyotype could have originated by a 1-step mechanism with 4 simultaneous breakages without deletion of ABL1.

Will antiangiogenic agents be a future for mesothelioma therapy?

BACKGROUND: Malignant mesothelioma (MM) is an aggressive disease that is diagnosed mostly in locally advanced or metastatic stage. In this condition chemotherapy with the combination cisplatin and pemetrexed or ralitrexed represents the standard treatment as supported by a phase III study. However, chemotherapy has very limited effect on the improvement of survival of patients and very few of the MM patients survive more than 2 years. A better understanding of molecular mechanisms and pathways involved in angiogenesis in MM is the basis for the development of new drugs targeted against these pathways responsible for the proliferation and survival of tumor cells. OBJECTIVE: This review discusses the role of angiogenic factors in tumourigenesis with a particular focus on MM and it summarizes the results of clinical trials on the drugs targeting angiogenic pathways in MM. METHODS: We have used original research articles, abstracts and oral presentations from ASCO (American Society of Clinical Oncology) and the website of clinical trials http://www.ClinicalTrials.gov. RESULTS/CONCLUSIONS: This review summarizes the results of antiangiogenic agents under evaluation in clinical trials. A better understanding of the angiogenic pathways activated in MM will hopefully provide new therapeutic options for these patients in the future.

Serum vascular endothelial growth factor (VEGF) levels correlate with tumor VEGF and p53 overexpression in endocrine positive primary breast cancer.

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, associated with unfavorable clinical characteristics in breast cancer. The aim of this study was to evaluate different angiogenic markers in endocrine-positive breast cancer patients. The authors analyzed serum and tumor samples from 71 patients with endocrine-positive operable primary breast cancer to determine the expression and the possible relationship between circulating serum VEGF levels, tumor VEGF expression, microvessel density (MVD), and other immunohistochemical parameters. Basal VEGF serum levels were significantly higher in breast cancer patients than in healthy controls. A significant correlation was observed between basal VEGF serum concentrations, microvessel density (p = 0.01) and p53 status (p = 0.004). Intratumoral VEGF expression was significantly associated with neoplastic embolization (p = 0.041) and circulating VEGF levels (p = 0.047). The results confirm that in primary endocrine-positive breast cancer serum VEGF levels are elevated and show a positive relationship with tumor VEGF and p53 overexpression.

Solução concentrada de albumina eqüina na fluidoterapia em eqüinos com desidratação leve a moderada / Equine concentrated albumin solution in the fluid therapy in horses with slight to moderate dehydration

Avaliou-se o efeito da solução concentrada de albumina eqüina diluída a 5 por cento em solução fisiológica (SF) durante fluidoterapia em eqüinos, após indução de desidratação leve a moderada, utilizando-se cinco eqüinos adultos, sem alterações clínicas. Cada animal passou por dois protocolos de fluidoterapia: apenas com SF (metade sob pressão e metade em fluxo contínuo - grupo-controle); com solução de albumina eqüina e SF (apenas em fluxo contínuo - grupo experimental). Avaliaram-se peso, exame físico geral, hematócrito, osmolalidade plasmática, gasometria, proteína total, albumina, uréia, creatinina, Na, K, débito cardíaco e pressão arterial, e calcularam-se pressão oncótica e volume plasmático. Após a aplicação de metade da SF sob pressão nos animais do grupo-controle, as alterações no hematócrito, na proteína total, na albumina, na pressão arterial e na pressão oncótica foram semelhantes às encontradas nos do grupo experimental após aplicação apenas da solução de albumina. Conclui-se que a solução de albumina eqüina é de fácil preparação e aplicação, não demonstra efeitos deletérios na dose e velocidade utilizadas e é passível de ser utilizada como colóide na fluidoterapia na espécie eqüina.

The effect of the equine concentrated albumin solution diluted to 5 percent in physiologic saline solution (PSS) during fluid therapy in horses after induced slight to moderate dehydration was evaluated in five adult horses with no clinical alterations. Each animal was submitted to two fluid therapy protocols; with only PSS (half of the total volume under pressure and half in continuous flow - control-group), or with equine albumin solution and PSS (only in continuous flow - treated-group). Body weight; general physical examination, packed cell volume (PCV); plasmatic osmometry; gasometry, total protein, albumin, urea, creatinin, Na, and K, cardiac output; and arterial pressure; and calculation of the oncotic pressure and plasmatic volume were evaluated. After the administration of the first half of PSS under pressure in control group, it was observed that alterations in PCV, total protein, albumin, arterial pressure, and oncotic pressure were similar to those found in experimental group after the administration of the albumin solution. It was concluded that the equine albumin solution is easily prepared and administered, with no deleterial effects in the employed dose and speed, and it is suitable for use as a colloid in fluid therapy in equine species.