Venous thromboembolism and mortality in breast cancer: cohort study with systematic review and meta-analysis

Abstract

Background

Breast cancer patients are at an increased risk of venous thromboembolism (VTE). However, current evidence as to whether VTE increases the risk of mortality in breast cancer patients is conflicting. We present data from a large cohort of patients from the UK and pool these with previous data from a systematic review.

Methods

Using the Clinical Practice Research Datalink (CPRD) dataset, we identified a cohort of 13,202 breast cancer patients, of whom 611 were diagnosed with VTE between 1997 and 2006 and 12,591 did not develop VTE. Hazard ratios (HR) were used to compare mortality between the two groups. These were then pooled with existing data on this topic identified via a search of the MEDLINE and EMBASE databases (until January 2015) using a random-effects meta-analysis.

Results

Within the CPRD, VTE was associated with increased mortality when treated as a time-varying covariate (HR = 2.42; 95% CI, 2.13–2.75), however, when patients were permanently classed as having VTE based on presence of a VTE event within 6 months of cancer diagnosis, no increased risk was observed (HR = 1.22; 0.93–1.60). The pooled HR from seven studies using the second approach was 1.69 (1.12–2.55), with no effect seen when restricted to studies which adjusted for key covariates.

Conclusion

A large HR for VTE in the time-varying covariate analysis reflects the known short-term mortality following a VTE. When breast cancer patients are fortunate to survive the initial VTE, the influence on longer-term mortality is less certain.

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MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1

Abstract

Background

Melanoma is the most lethal type of skin cancer. Since chemoresistance is a significant barrier, identification of regulators affecting chemosensitivity is necessary in order to create new forms of intervention. Prohibitin 1 (PHB1) can act as anti-apoptotic or tumor suppressor molecule, depending on its subcellular localization. Our recent data shown that accumulation of PHB1 protects melanoma cells from chemotherapy-induced cell death. Lacking of post-transcriptional regulation of PHB1 could explain this accumulation. Interestingly, most of melanoma patients have down-regulation of microRNA-195. Here, we investigate the role of miR-195, its impact on PHB1 expression, and on chemosensitivity in melanoma cells.

Methods

TCGA-RNAseq data obtained from 341 melanoma patient samples as well as a panel of melanoma cell lines were used in an expression correlation analysis between PHB1 and predicted miRNAs. miR-195 impact on PHB1 mRNA and protein levels and relevance of this regulation were investigated in UACC-62 and SK-MEL-5 melanoma lines by RT-qPCR and western blot, luciferase reporter and genetic rescue experiments. Cell proliferation, cell-cycle analysis and caspase 3/7 assay were performed to investigate the potential action of miR-195 as chemosensitizer in melanoma cells treated with cisplatin and temozolomide.

Results

Analysis of the TCGA-RNAseq revealed a significant negative correlation (Pearson) between miR-195 and PHB1 expression. Moreover, RT-qPCR data showed that miR-195 is down-regulated while PHB1 is up-regulated in a collection of melanoma cells. We demonstrated that miR-195 regulates PHB1 directly by RT-qPCR and western blot in melanoma cells and luciferase assays. To establish PHB1 as a relevant target of miR-195, we conducted rescue experiments in which we showed that PHB1 transgenic expression could antagonize the suppressive effect miR-195 on the proliferation of melanoma cells. Finally, transfection experiments combined with drug treatments performed in the UACC-62 and SK-MEL-5 melanoma cells corroborated miR-195 as potential anti-proliferative agent, with potential impact in sensitization of melanoma cell death.

Conclusions

This study support the role of miR-195 as anti-proliferative miRNA via targeting of PHB1 in melanoma cells.

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miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple-negative breast cancer

Abstract

Background

Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy.

Methods

We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model.

Results

The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up-regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = −0.28, P = 3.88 × 10⁻³). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient.

Conclusions

Our data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.

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Thoracoscopic and hand assisted laparoscopic esophagectomy with radical lymph node dissection for esophageal squamous cell carcinoma in the left lateral decubitus position: a single center retrospective analysis of 654 patients

Abstract

Background

The rates of thoracoscopic esophagectomy performed in the prone and left lateral decubitus positions are similar in Japan. We retrospectively reviewed short- and long-term outcomes of thoracoscopic esophagectomy for esophageal cancer performed in the left lateral decubitus position.

Methods

Between 1996 and 2015, 654 patients with esophageal cancer underwent thoracoscopic esophagectomy in the left lateral decubitus position. Patients were divided into early (1996–2008) and late groups (2009–2015, with standardization of the procedure and formalized training), and their clinical outcomes reviewed.

Results

The completion rate of thoracoscopic esophagectomy was 99.5%, and the procedure was converted to thoracotomy in three patients, due to hemorrhage. The mean intrathoracic operative time, intrathoracic blood loss, and number of dissected mediastinal lymph nodes were 205.0 min, 127.3 mL, and 24.7, respectively. Postoperative complications included pneumonia (8.5%), anastomotic leakage (7.5%), and recurrent nerve paralysis (3.5%). Postoperative (30d) mortality was 4/654 (0.61%) due to anastomotic leak and pneumonia. The five year overall survival rate was 70%. A comparison of the 289 early- and 365 late-study period cases revealed significant differences in mean intrathoracic blood loss (174.0 vs. 94.2 mL), number of mediastinal lymph nodes dissected (20.0 vs. 28.4), hospital length of stay (33.4 vs. 20.0 days, p < 0.001), and postoperative anastomotic leakage (14% vs. 1.6%, p < 0.0001).

Conclusions

Standardization of the procedure for thoracoscopic esophagectomy in the left lateral decubitus position, with a standardized clinical pathway for perioperative care led to significant improvements in surgical outcomes.

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Contrast-enhanced ultrasound of small cell carcinoma in urinary bladder: a case report and review of literature

Abstract

Background

Small cell carcinoma of the urinary bladder (SCCB) is a relatively rare malignant bladder tumor, and few reports have investigated the microvasculature of SCCB imaged using contrast-enhanced ultrasound (CEUS).

Case presentation

A 63-year-old female was admitted to our hospital after experiencing painless gross hematuria for one week. The gray-scale ultrasound (US) demonstrated a 4.8 × 3.4 × 3.6-cm³ hypoechoic mass in the apex of the urinary bladder with a wide base and an irregular surface; the mass did not move with changes in body position. Color Doppler flow imaging (CDFI) showed rich blood flow in the mass. CEUS with low mechanical index (MI) of 0.06 confirmed a highly enhanced 5.0 × 3.3 × 3.8 cm³ mass within the bladder at the apex wall. The time-intensity curves (TICs) showed a wash-in time of 10 s, a time to peak (TTP) of 33 s, a signal intensity (SI) of 62.7% and a wash-out time > 60 s. Finally, the transurethral resection of the bladder tumor (TURBT) was performed, and the pathological examination proved the diagnosis of SCCB.

Conclusion

CEUS can provide valuable information related to the rich microvasculature of SCCB, which may be helpful in its diagnosis.

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Prognostic Awareness and Communication Preferences among Caregivers of Patients with Malignant Glioma

Abstract

Objective

Malignant glioma is a devastating neuro-oncologic disease with almost invariably poor prognosis, yet many families facing malignant glioma have poor prognostic awareness (PA), or the awareness of the patient's incurable disease and shortened life-expectancy. Accurate PA is associated with favorable medical outcomes at the end-of-life for patients and psychosocial outcomes for informal caregivers (ICs) through bereavement. To date, however, no study has specifically examined PA among MG ICs and the information they receive that shapes their awareness.

Methods

Thirty-two ICs of patients with malignant glioma completed a semi-structured assessment of their awareness of the incurability and life expectancy of their loved one's illness, and to understand their sources of prognostic information and preferences for communication of prognostic information.

Results

Twenty two (69%) ICs had full PA - awareness of the incurability of malignant glioma and accurate estimates of their loved ones' life expectancy. Twenty-three (72%) felt that prognostic information was extremely or very important to possess, and 16 (50%) desired more prognostic information. The majority of ICs received prognostic information from physicians and the Internet. Qualitative analyses revealed that many ICs had difficulty navigating medical encounters in which they concurrently wanted to elicit prognostic information from physicians and protect patients from such information.

Conclusions

Accurate and timely PA is necessary for ICs to serve as critical members of healthcare teams. Interventions are needed to foster ICs' skills in navigating prognostic communication with patients and healthcare providers and thereby improve their ability to advocate for their loved one's wishes.

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A Dyadic Analysis of Stress Processes in Latinas with Breast Cancer and Their Family Caregivers

Abstract

Objective

Breast cancer diagnosis and treatment negatively affect quality of life for survivors and their family caregivers. The stress process model has been useful for describing the cascade of social and psychological experiences that culminate in degraded quality of life for both survivors and their family caregivers. This study is designed to test theoretically specified predictors of negative psychosocial outcomes in a dyadic context.

Method

Participants were 230 dyads comprised of Latinas recently diagnosed with breast cancer and their primary family caregiver, who completed measures of socioeconomic status, stress, family conflict, depression, and anxiety. Data were analyzed following the actor-partner interdependence mediation model (APIMeM) in structural equation modeling.

Results

For both survivors and caregivers there were significant direct and indirect actor effects (through family conflict) of perceived stress on depression and anxiety. Several indirect partner effects were also evident in this sample. Specifically, caregivers' stress was predictive of survivors' depression and anxiety through survivors' increased perceptions of family conflict.

Conclusions

As predicted by the stress process model, stress and family conflict were predictive of psychological distress in breast cancer survivors and their family caregivers. Significant partner effects in the APIMeM suggest that there are some dyadic influences, particularly from caregivers' stress to survivors' perceptions of exacerbated family conflict. These findings show how strained family relationships can aggravate the well-being of cancer survivors and their family caregivers through this challenging experience.

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