The relationship between circulating 25-hydroxyvitamin D and survival in newly diagnosed advanced non-small-cell lung cancer

Abstract

Background

Serum 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D used for evaluating the vitamin D status of patients, has been associated with survival in a variety of cancers with conflicting evidence. We aimed to investigate this association in newly diagnosed advanced non-small-cell lung cancer (NSCLC) patients.

Methods

This was a consecutive cohort of 359 newly diagnosed stages III-IV NSCLC patients who underwent a baseline serum 25(OH)D evaluation prior to receiving any treatment at our institution between January 2008 and December 2010. We used the vitamin D categories of "deficient (<20 ng/ml)" and "not deficient (> = 20 ng/ml)". Cox regression was used to evaluate the prognostic significance of serum 25(OH)D after adjusting for relevant confounders.

Results

Mean age at diagnosis was 57.4 years. Of the 359 patients, 151 (42.1 %) were deficient in vitamin D at the time of diagnosis. The median survival in deficient and not deficient cohorts was 11.7 and 12.8 months respectively (p = 0.06). Season of diagnosis, performance status, smoking status and hospital location significantly predicted vitamin D status. On univariate Cox analysis, gender, stage of disease, hospital location, histologic subtype, subjective global assessment (SGA), performance status, smoking status, body mass index and serum albumin were significantly associated with survival (p <0.05 for all). On multivariate Cox analysis, six variables demonstrated statistically significant associations with survival: stage of disease, hospital location, histologic subtype, SGA, smoking status and serum albumin (p <0.05 for all). Serum vitamin D, which was borderline significant in univariate analysis, lost its significance in multivariate analysis.

Conclusions

We found season of diagnosis, performance status and smoking history to be predictive of vitamin D status. Consistent with previously published research in advanced NSCLC, we did not find any significant association between pre-treatment serum 25(OH)D and survival in our patients.

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Role of HLA-G and extracellular vesicles in renal cancer stem cell-induced inhibition of dendritic cell differentiation

Abstract

Background

Tumor immune-escape has been related to the ability of cancer cells to inhibit T cell activation and dendritic cell (DC) differentiation. We previously identified a tumor initiating population, expressing the mesenchymal marker CD105, which fulfills the criteria for definition as cancer stem cells (CD105⁺ CSCs) able to release extracellular vesicles (EVs) that favor tumor progression and metastases. The aim of the present study was to compare the ability of renal CSCs and derived EVs to modulate the behavior of monocyte-derived DCs with a non-tumor initiating renal cancer cell population (CD105^- TCs) and their EVs.

Methods

Maturation of monocyte-derived DCs was studied in presence of CD105⁺ CSCs and CD105^- TCs and their derived EVs. DC differentiation experiments were evaluated by cytofluorimetric analysis. T cell proliferation and ELISA assays were performed. Monocytes and T cells were purified from peripheral blood mononuclear cells obtained from healthy donors.

Results

The results obtained demonstrate that both CD105⁺ CSCs and CD105^- TCs impaired the differentiation process of DCs from monocytes. However, the immune-modulatory effect of CD105⁺ CSCs was significantly greater than that of CD105^- TCs. EVs derived from CD105⁺ CSCs and in less extent, those derived from CD105^- TCs retained the ability to impair monocyte maturation and T cell activation. The mechanism has been mainly related to the expression of HLA-G by tumor cells and to its release in a form associated to EVs. HLA-G blockade significantly reduced the inhibitory effect of EVs on DC differentiation.

Conclusions

In conclusion, the results of the present study indicate that renal cancer cells and in particular CSCs and derived EVs impair maturation of DCs and T cell immune response by a mechanism involving HLA-G.

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A case study on the potential angiogenic effect of human chorionic gonadotropin hormone in rapid progression and spontaneous regression of metastatic renal cell carcinoma during pregnancy and after surgical abortion

Abstract

Background

Treatment possibilities of metastatic renal cell carcinoma (mRCC) have recently changed dramatically prolonging the overall survival of the patients. This kind of development brings new challenges for the care of mRCC.

Case presentation

A 22 year-old female patient with translocation type mRCC, who previously had been treated for nearly 5 years, became pregnant during the treatment break period. Follow-up examinations revealed a dramatic clinical and radiological progression of mRCC in a few weeks therefore the pregnancy was terminated. A few days after surgical abortion, CT examination showed a significant spontaneous regression of the pulmonary metastases, and the volume of the largest manifestation decreased from ca. 30 to 3.5 cm³ in a week. To understand the possible mechanism of this spectacular regression, estrogen, progesterone and luteinizing hormone receptors (ER, PGR and LHR, respectively) immuno-histochemistry assays were performed on the original surgery samples. Immuno-histochemistry showed negative ER, PGR and positive LHR status suggesting the possible angiogenic effect of human chorionic gonadotropin hormone (hCG) in the background.

Conclusion

We hypothesize that pregnancy may play a causal role in the progression of mRCC via the excess amount of hCG, however, more data are necessary to validate the present notions and the predictive role of LHR overexpression.

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Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain

Abstract

Background

Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain.

Methods

Patient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgamma^null (NSG) mice. Human NK cells were isolated from peripheral blood mononucleated cells and expanded in vitro.

Results

Patient-derived GBM cells in the brains of NSG mice unexpectedly induced spontaneous lung metastasis although no metastasis was detected in BALB/c-nude mice. Based on the difference of the innate immunity between two mouse strains, NK cell activities of orthotopic GBM xenograft models based on BALB/c-nude mice were inhibited. NK cell inactivation induced spontaneous lung metastasis of GBM cells, which indicated that NK cells inhibit the systemic metastasis. In vitro cytotoxic activities of human NK cells against GBM cells indicated that cytotoxic activity of NK cells against GBM cells prevents systemic metastasis of GBM and that NK cells could be effective cell therapeutics against GBM. Accordingly, NK cells transplanted into orthotopic GBM xenograft models intravenously or intratumorally induced apoptosis of GBM cells in the brain and showed significant therapeutic effects.

Conclusions

Our results suggest that innate NK immunity is responsible for rare systemic metastasis of GBM and that sufficient supplementation of NK cells could be a promising immunotherapeutic strategy for GBM in the brain.

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TGFβ isoforms and receptors mRNA expression in breast tumours: prognostic value and clinical implications

Abstract

Background

Transforming growth factor beta (TGFβ) signalling is involved in both tumour suppression and tumour progression. The mRNA expression levels of the TGFβ isoforms and receptors in breast tumours may have prognostic value and clinical implications.

Methods

The mRNA levels of TGFB1, TGFB2, TGFB3, TGFBR1 and TGFBR2 were analysed in primary breast tumours and adjacent normal breast tissues, and the associations with tumour characteristics and patients' overall and relapse-free survival were evaluated, using the public gene expression microarray data from The Cancer Genome Atlas (n = 520) and the Gene Expression Omnibus (four datasets) and our quantitative real-time PCR validation data (n = 71).

Results

Significantly higher TGFB1 and TGFB3 mRNA levels and lower TGFBR2 mRNA levels were observed in primary tumours compared with their paired normal tissues. TGFB1 mRNA expression was seemly lower in triple-negative tumours and in tumours from lymph node-negative patients. TGFB3 mRNA expression was significantly lower in estrogen receptor-negative/progesterone receptor-negative/Basal-like/Grade 3 tumours. High TGFB2, TGFB3 and TGFBR2 mRNA levels in tumours were generally associated with better prognosis for patients, especially those diagnosed with lymph node-negative diseases. High TGFBR1 mRNA levels in tumours were associated with poorer clinical outcomes for patients diagnosed with small (diameter ≤2 cm) tumours.

Conclusions

The results indicate a reduced responsiveness of tumour cells to TGFβ, a preferential up-regulation of TGFB1 in malignant tumours and a preferential up-regulation of TGFB3 in premalignant tumours. The results may not only provide prognostic value for patients but also assist in classifying tumours according to their potential responses to TGFβ and selecting patients for TGFβ signalling pathway targeted therapies.

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Enormous, rapidly growing breast mass

Abstract

Background

Signs and symptoms of a rapidly enlarging breast mass are not only important for all clinicians to recognize and assess, but also are not uncommon occurrences. We describe a similar but unique case that developed into an enormous, 36 cm exophytic mass.

Case presentation

A 51-year-old woman with history of psychiatric conditions presented for signs and symptoms of sepsis. It was determined that the source was an enormous 36 cm mass originating from the breast/chest wall. After stabilizing the patient with antibiotics, she underwent successful resection. Surgical margins were positive, and histopathology demonstrated bland spindle cells with stromal overgrowth. Together with clinical and histopathological information, the patient was diagnosed with a phyllodes tumor.

Conclusion

Differential diagnosis of rapidly growing breast masses is discussed, which are not uncommon occurrences in clinical medicine. One etiology, phyllodes tumors, can grow into large, exophytic masses as described. Oncologic treatment is discussed, usually consisting of surgery with postoperative radiotherapy for high-risk features.

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Annual Medical Expenditure and Productivity Loss Among Colorectal, Female Breast, and Prostate Cancer Survivors in the United States

Background:

There are limited nationally representative estimates of the annual economic burden among survivors of the three most prevalent cancers (colorectal, female breast, and prostate) in both nonelderly and elderly populations in the United States.

Methods:

The 2008 to 2012 Medical Expenditure Panel Survey data were used to identify colorectal (n = 540), female breast (n = 1568), and prostate (n = 1170) cancer survivors and individuals without a cancer history (n = 109 423). Excess economic burden attributable to cancer included per-person excess annual medical expenditures and productivity losses (employment disability, missed work days, and days stayed in bed). All analyses were stratified by cancer site and age (nonelderly: 18–64 years vs elderly: ≥65 years). Multivariable analyses controlled for age, sex, race/ethnicity, marital status, education, number of comorbidities, and geographic region. All statistical tests were two-sided.

Results:

Compared with individuals without a cancer history, cancer survivors experienced annual excess medical expenditures (for the nonelderly population, colorectal: $8647, 95% confidence interval [CI] = $4932 to $13 974, P < .001; breast: $5119, 95% CI = $3439 to $7158, P < .001; prostate: $3586, 95% CI = $1792 to $6076, P < .001; for the elderly population, colorectal: $4913, 95% CI = $2768 to $7470, P < .001; breast: $2288, 95% CI = $814 to $3995, P = .002; prostate: $3524, 95% CI = $1539 to $5909, P < .001). Nonelderly colorectal and breast cancer survivors experienced statistically significant annual excess employment disability (13.6%, P < .001, and 4.8%, P = .001) and productivity loss at work (7.2 days, P < .001, and 3.3 days, P = .002) and at home (4.5 days, P < .001, and 3.3 days, P = .003). In contrast, elderly survivors of all three cancer sites had comparable productivity losses as those without a cancer history.

Conclusions:

Colorectal, breast, and prostate cancer survivors experienced statistically significantly higher economic burden compared with individuals without a cancer history; however, excess economic burden varies by cancer site and age. Targeted efforts will be important in reducing the economic burden of colorectal, breast, and prostate cancer.

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