The spinophilin (Spn, PPP1R9B) gene is located at 17q21.33, a region frequently associated with microsatellite instability and loss of heterozygosity, especially in breast tumors. Spn is a regulatory ...subunit of phosphatase1a (PP1), which targets the catalytic subunit to distinct subcellular locations. Spn downregulation reduces PPP1CA activity against the retinoblastoma protein, pRb, thereby maintaining higher levels of phosphorylated pRb. This effect contributes to an increase in the tumorigenic properties of cells in certain contexts. Here, we explored the mechanism of how Spn downregulation contributes to the malignant phenotype and poor prognosis in breast tumors and found an increase in the stemness phenotype. Analysis of human breast tumors showed that Spn mRNA and protein are reduced or lost in 15% of carcinomas, correlating with a worse prognosis, a more aggressive tumor phenotype and triple-negative tumors, whereas luminal tumors showed high Spn levels. Downregulation of Spn by shRNA increased the stemness properties along with the expression of stem-related genes (Sox2, KLF4, Nanog and OCT4), whereas ectopic overexpression of Spn cDNA reduced these properties. Breast tumor stem cells appeared to have low levels of Spn mRNA, and Spn loss correlated with increased stem-like cell appearance in breast tumors as indicated by an increase in CD44+/CD24- cells. A reduction of the levels of PPP1CA mimicked the cancer stem-like cell phenotype of Spn downregulation, suggesting that the mechanism of Spn involves PP1a. These increased cancer stem cell-like properties with reduced Spn might account for the malignant phenotype observed in Spn-loss tumors and may contribute to a worse patient prognosis.
Purpose
Chronic inflammation contributes to cancer development via multiple mechanisms. We hypothesized that cardiovascular diseases (CVD) are also an independent risk factor for survival in ...non-small cell lung cancer (NSCLC).
Materials and methods
Prospective multicenter data from 345 consecutive NSCLC patients treated from January 2013 to January 2017 were assessed. Median follow-up for all patients was 13 months (range 3–60 months). There were 109 patients with baseline heart disease (HD 32%), 149 with arterial hypertension (43%), 85 with diabetes mellitus (25%), 129 with hyperlipidemia (37%) and 45 with venous thromboembolism events (VTE 13%). A total of 289 patients (84%) were treated with platinum-based chemotherapy (CT), 300 patients (87%) received thoracic radiation therapy (RT; median radiation dose: 60 Gy range 12–70); and 50 (15%) patients underwent surgery.
Results
Our cohort consisted of 305 men (88%) and 40 (12%) women, with a median age of 67 years (range 31–88 years). Seventy percent had a Karnofsky performance status (KPS) ≥ 80. Multivariate analyses showed a lower OS and higher risk of distant metastasis in patients with advanced stages (
p
= 0.05 and
p
< 0.001, respectively) and HD (HR 1.43,
p
= 0.019; and HR 1.49,
p
= 0.025, respectively). Additionally, patients with VTE had lower local control (HR 1.84,
p
= 0.025), disease-free survival (HR 1.64,
p
= 0.020) and distant metastasis-free survival (HR 1.73,
p
= 0.025).
Conclusions
HD and VTE are associated with a higher risk of mortality and distant metastasis in NSCLC patients. Chronic inflammation associated with CVDs could be an additional pathophysiologic factor in the development of distant metastasis.
Unprovoked venous thromboembolism (VTE) may be the first manifestation of an underlying cancer. We aimed to assess the period prevalence of occult cancer detection stratified by VTE location (deep ...vein thrombosis DVT, pulmonary embolism PE or both) and the anatomical relationship between occult cancer and VTE.
Post-hoc analysis of a systematic review and individual patient data meta-analysis of adults with unprovoked VTE with at least 12 months of follow-up. Cancer types were grouped according to thoracic, abdomino-pelvic, or other locations.
A total of 2300 patients were eligible including 1218 with DVT only (53%), 719 with PE only (31%), and 363 with both PE and DVT (16%). The pooled 12-month period prevalence of cancer in DVT only, PE only, and DVT + PE was 5.6% (95% CI, 4.4 to 7.2), 4.3% (95% CI, 2.7 to 6.9), and 5.6% (95% CI, 1.7 to 15.5), respectively. Most occult cancers were located in the abdomen (68.4%). The proportion of patients with an abdomino-pelvic cancer was not different in patients with DVT + PE (81%; 95% CI, 54 to 96) than in those with DVT (68%; 95% CI, 57 to 78) or PE alone (65%; 95% CI, 48 to 79).
The 12-month prevalence of occult cancer was similar in patients with DVT only, PE only, or both. Most cancers were located in the abdomen, and there was no relationship between VTE type and cancer location.
•The relationship between sites of VTE and occult cancer is unclear.•The 12-month prevalence of occult cancer was similar in DVT only, PE only, or both.•There were no relationship between unprovoked VTE and occult cancer locations.•Two thirds of cancers diagnosed after unprovoked VTE were located in the abdomen.
Summary
The expression of activation‐induced cytidine deaminase, B‐aggressive lymphoma, cyclin D1 and serine/threonine kinase 15 genes, among others, is increased in B cells from patients with ...chronic hepatitis C virus (HCV) infection. It is unknown whether the level of expression of these genes in B cells is increased in patients with hepatitis C who have achieved a sustained virological response (SVR) but who have persistent, detectable HCV RNA, so‐called occult infection. Eighty‐three patients who achieved and SVR, 27 with detectable HCV and 56 without detectable HCV RNA, 28 chronic hepatitis C patients and 32 healthy controls were studied. RNA was extracted from B cells, and gene expression levels were measured by RT‐PCR. Patients with chronic HCV and those who achieved an SVR (with and without persistent low‐level HCV RNA) showed a statistically significant higher expression compared to healthy controls, of activation‐induced cytidine deaminase (P = 0.004, P < 0.001 and P = 0.002, respectively), B‐aggressive lymphoma (P < 0.001, P = 0.001 and P = 0.006) and cyclin D1 (P = 0.026, P = 0.001; P = 0.038). For activation‐induced cytidine deaminase patients with an SVR and ‘occult infection’ had a statistically significantly higher expression level than patients with and SVR without ‘occult infection’ (P = 0.014). The higher expression levels found for activation‐induced cytidine deaminase, together with other genes indicates that these B lymphomagenesis‐related genes are upregulated following HCV therapy and this is more marked when HCV can be detected in PBMCs.
Purpose
Lung cancer (LC) has a significant impact on patients’ health-related quality of life (HRQoL). We investigate the correlations between pre-radiation therapy HRQoL and survival.
Materials and ...methods
A prospective, intention-to-treat, multicentre study of 437 patients with LC recruited at the radiation oncology departments of three different institutions was conducted between 2012 and 2016. QoL was assessed using the EORTC-QLQ-C30 (v3.0) and EORTC-QLQ-LC13 questionnaires. Global health status (GHS), physical (PF), role functioning (RF), emotional (EF), cognitive (CF), and social functioning (SF) as well as symptoms scores were evaluated in univariate and multivariate analyses.
Results
The cohort consisted of 376 men (86%) and 61 women, with a median age of 66 years (range 31–88). Histology was: 72% (
n
= 315) non-small cell lung cancer and 28% small cell lung cancer. The most common stage was III (80%) and the median follow-up for alive patients was 30 months (range 7–76). Multivariate analysis showed that RF was associated with a lower risk of mortality (HR: 0.693;
p
= 0.008) and recurrence (HR: 0.737;
p
= 0.040). Additionally, lower scores on EF and PF were associated with higher mortality (HR: 0.696;
p
= 0.003 and HR: 0.765;
p
= 0.044, respectively). Appetite loss, constipation, and dysphagia were associated with a higher risk of mortality (HR: 1.985;
p
< 0.001, HR: 1.373;
p
= 0.036, and HR: 1.659;
p
= 0.002, respectively), while appetite loss was the only symptom associated with a higher risk of recurrence (HR: 1.525;
p
= 0.014).
Conclusions
Pre-radiation therapy scores on RF, EF, and PF and symptoms like appetite loss, dysphagia, and constipation were associated with the risk of mortality. This information could be added to other prognostic factors to guide our treatment decisions.
The Granada group in BNCT research is currently performing studies on: nuclear and radiobiological data for BNCT, new boron compounds and a new design for a neutron source for BNCT and other ...applications, including the production of medical radioisotopes. All these activities are described in this report.
•Basic research activities at two international facilities: CERN and ILL are shown.•Obtention of accurate nuclear and radiobiological data for reducing uncertainties in treatment planning is pursued.•The conceptual design of a facility for BNCT and isotope production is described.
Background
Cancer-specific survival for patients with clinical stage I (CSI) germ cell testicular cancer (GCTC) is outstanding after inguinal orchidectomy regardless the treatment utilized. This ...study evaluated whether active surveillance (AS) of such patients yielded similar health outcomes to other therapeutic strategies such as adjuvant chemotherapy, radiotherapy or primary retroperitoneal lymphadenectomy as described in the literature.
Patients and methods
Patients with CSI GCTC were screened between January 2012 and December 2016. Patients had previously undergone inguinal orchidectomy as the primary treatment and chosen AS as their preferred management strategy after receiving information about all available strategies.
Results
Out of 91 patients screened, 82 patients selected AS as their preferred management strategy. Relapse rate in the overall population was 20% (95% CI 12–30) and median time to relapse was 11.5 months (range 1.0–35.0). In patients with seminomatous tumors, relapse rate decreased to 13% and median time to relapse was 13 months; whereas in patients with non-seminomatous tumors, relapse rate was 33% (IA) or 29% (IB) and median time to relapse was 12 months in stage IA and 4.5 months in stage IB patients. All relapses were rescued with three or four cycles of chemotherapy and two also required a retroperitoneal lymphadenectomy. All patients are currently alive and free of disease.
Conclusions
The clinical outcomes of patients with CSI GCTC managed by AS in this series were excellent. This strategy limited the administration of active treatments specifically to the minority of patients who relapsed without compromising performance.
It is unknown whether hepatitis C virus (HCV)‐specific cellular immune responses can develop in seronegative sexual partners of chronically HCV‐infected patients and whether they have occult ...infection. Thirty‐one heterosexual partners of patients with chronic HCV were studied, fifteen of them with HCV transmission risks. Ten healthy individuals and 17 anti‐HCV seropositive patients, without viremia, were used as controls. Virus‐specific CD4+ and CD8+ T‐cell responses were measured by flow cytometry against six HCV peptides, situated within the nonstructural (NS) proteins NS3, NS4 and NS5, through intracellular detection of gamma interferon (IFN‐γ) or interleukin 4 (IL‐4) production and CD69 expression. Sexual partners had a higher production of IFN‐γ and IL‐4 by CD4+ cells against NS3‐p124 (P = 0.003), NS5b‐p257 (P = 0.005) and NS5b‐p294 (P = 0.012), and CD8+ cells against NS3‐p124 (P = 0.002), NS4b‐p177 (P = 0.001) and NS3‐p294 (P = 0.004) as compared with healthy controls. We observed elevated IFN‐γ production by CD4+ T cells against NS5b‐p257 (P = 0.042) and NS5b‐p294 (P = 0.009) in the sexual partners with HCV transmission risks (sexual, professional and familial altogether) than in those without risks. RNA was extracted from peripheral blood mononuclear cells (PBMC), and detection of HCV‐RNA positive and replicative (negative) strands was performed by strand‐specific real‐time PCR. In four sexual partners, the presence of positive and negative HCV‐ RNA strands in PBMC was confirmed. Hence, we found an HCV‐specific cellular immune response as well as occult HCV infection in seronegative and aviremic sexual partners of chronically HCV‐infected patients.
Background The benefits of a diagnostic workup for occult cancer in patients with VTE are controversial. Our aim was to provide and validate a risk score for occult cancer in patients with VTE. ...Methods We designed a nested case-control study in a cohort of patients with VTE included in the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry from 2001 to 2014. Cases included cancer detected beyond the first 30 days and up to 24 months after VTE. Control subjects were defined as patients with VTE with no cancer in the same period. Results Of 5,863 eligible patients, 444 (7.6%; 95% CI, 6.8%-8.2%) were diagnosed with occult cancer. On multivariable analysis, variables selected were male sex, age > 70 years, chronic lung disease, anemia, elevated platelet count, prior VTE, and recent surgery. We built a risk score assigning points to each variable. Internal validity was confirmed using bootstrap analysis. The proportion of patients with cancer who scored ≤ 2 points was 5.8% (241 of 4,150) and that proportion in those who scored ≥ 3 points was 12% (203 of 1,713). We also identified scores divided by sex and age subgroups. Conclusions This is the first risk score that has identified patients with VTE who are at increased risk for occult cancer. Our score needs to be externally validated.
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