Influence of melatonin on the proliferation of hepatoma cells in the Syrian hamster: In vivo and in vitro study

A study was carried out to determine the possible influence of melatonin on the proliferation of Kirkman-Robbins hepatoma cells in Syrian hamsters, both in vivo and in vitro. A highly significant inhibition of the proliferation of transplanted hepatoma cells was observed in vivo following melatonin administration (proliferation index 10.3 +/- 1.5; mean +/- SD) in comparison with controls (proliferation index 23.3 +/- 2.2), whereas in vitro melatonin (at concentrations of 10(-5)-10(-11) M) was ineffective. These results indicate that inhibitory effect of melatonin on transplantable hepatoma cells in vivo may be indirect.     

Sulodexide inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures

Sulodexide (SDX) is a mixed drug containing low‐molecular‐weight heparin sulfate and dermatan sulfate. It exerts mild anticoagulant action but can also affect leukocytes, macrophages, and cell–cell adhesion and may interact with growth factors although its direct influence on endothelial cells is not well described. Clinically, SDX is used for the treatment of cardiovascular diseases, where it exerts anti‐inflammatory and endothelial protective effects. The aim of this study was to determine the influence of SDX on tubule formation and angiogenesis‐related proteins’ mRNA expression in endothelial cell line C166 and mouse proepicardial explants. C166 cells and explants were stimulated with a proangiogenic cocktail containing bFGF/VEGF‐A₁₂₀/VEGF‐A₁₆₄ enriched with SDX. After stimulation, the number and morphology of tubules stained with anti‐CD31 antibody were examined under confocal microscope and expression of mRNA for VEGF‐A, VEGF‐B, VEGF‐C, bFGF, IGF‐1, Dll4, and Notch1 was measured with real‐time PCR. In C166 cell line, there was no difference in tubule formation and mRNA expression, but in proepicardial explants, we observed reduction in tubule number and in mRNA level for DLL4 and Notch1 after SDX administration. In conclusion, SDX indirectly inhibits angiogenesis in mouse proepicardial explant cultures but has no direct effect on the C166 endothelial cell line.     

Defining biochemical recurrence after radical prostatectomy and timing of early salvage radiotherapy

Background

The optimal prostate-specific antigen (PSA) level after radical prostatectomy (RP) for defining biochemical recurrence and initiating salvage radiation therapy (SRT) is still debatable. Whereas adjuvant or extremely early SRT irrespective of PSA progression might be overtreatment for some patients, SRT at PSA >0.2?ng/ml might be undertreatment for others. The current study addresses the optimal timing of radiation therapy after RP.

Patients and methods

Cohort 1 comprised 293 men with PSA 0.1–0.19?ng/ml after RP. Cohort 2 comprised 198 men with SRT. PSA progression and metastases were assessed in cohort 1. In cohort 2, we compared freedom from progression according to pre-SRT PSA (0.03–0.19 vs. 0.2–0.499?ng/ml). Multivariable Cox regression analyses predicted progression after SRT.

Results

In cohort 1, 281 (95.9%) men had further PSA progression ≥0.2?ng/ml and 27 (9.2%) men developed metastases within a median follow-up of 74.3 months. In cohort 2, we recorded improved freedom from progression according to lower pre-SRT PSA (0.03–0.19 vs. 0.2–0.499?ng/ml: 69 vs. 53%; log-rank p = 0.051). Patients with higher pre-SRT PSA ≥0.2?ng/ml were at a higher risk of progression after SRT (hazard ratio: 1.8; p < 0.05).

Conclusion

The vast majority of patients with PSA ≥0.1?ng/ml after RP will progress to PSA ≥0.2?ng/ml. Additionally, early administration of SRT at post-RP PSA level <0.2?ng/ml might improve freedom from progression. Consequently, we suggest a PSA threshold of 0.1?ng/ml to define biochemical recurrence after RP.

     

Selective regain of egfr gene copies in CD44+/CD24-/low breast cancer cellular model MDA-MB-468

Background

The objective of this retrospective study is to investigate laryngeal preservation and long-term treatment results in hypopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) combined with chemotherapy.

Methods

Twenty-seven patients with hypopharyngeal carcinoma (stage II-IV) were enrolled and underwent concurrent chemoradiotherapy. The chemotherapy regimens were monthly cisplatin and 5-fluorouracil for six patients and weekly cisplatin for 19 patients. All patients were treated with IMRT with simultaneous integrated boost technique. Acute and late toxicities were recorded based on CTCAE 3.0 (Common Terminology Criteria for Adverse Events).

Results

The median follow-up time for survivors was 53.0 months (range 36-82 months). The initial complete response rate was 85.2%, with a laryngeal preservation rate of 63.0%. The 5-year functional laryngeal, local-regional control, disease-free and overall survival rates were 59.7%, 63.3%, 51.0% and 34.8%, respectively. The most common greater than or equal to grade 3 acute and late effects were dysphagia (63.0%, 17 of 27 patients) and laryngeal stricture (18.5%, 5 of 27 patients), respectively. Patients belonging to the high risk group showed significantly higher risk of tracheostomy compared to the low risk group (p = 0.014).

Conclusions

After long-term follow-up, our results confirmed that patients with hypopharyngeal carcinoma treated with IMRT concurrent with platinum-based chemotherapy attain high functional laryngeal and local-regional control survival rates. However, the late effect of laryngeal stricture remains a problem, particularly for high risk group patients.     

3D conformal radiotherapy is not associated with the long-term cardiac mortality in breast cancer patients: a retrospective cohort study in Germany (PASSOS-Heart Study)

Purpose

In breast cancer patients treated in the 1970s and 1980s, radiation therapy (RT) for left-sided tumors has been associated with an elevated risk of cardiac mortality. In recent years, improved RT techniques have reduced radiation exposure of the heart and major coronary vessels, but some exposure remains unavoidable. In a retrospective cohort study, we investigated the long-term cardiac mortality risk of breast cancer survivors treated with modern RT in Germany.

Methods

A total of 11,982 women were included who were treated for breast cancer between 1998 and 2008. A systematic mortality follow-up was conducted until December 2012. The effect of breast cancer laterality on cardiac mortality and on overall mortality was investigated as a surrogate measure of exposure. Using Cox regression, we analyzed survival time as the primary outcome measure, taking potential confounding factors into account.

Results

We found no evidence for an effect of tumor laterality on mortality in irradiated patients (N = 9058). For cardiac mortality, the hazard ratio was 0.94 (95% CI 0.64–1.38) for left-sided versus right-sided tumors. For all causes of death, the hazard ratio was 0.95 (95% CI 0.85–1.05). A diagnosis of cardiac illness prior to breast cancer treatment increased both cardiac mortality risk and overall mortality risk.

Conclusions

Contemporary RT seems not to be associated with an increased risk of cardiac mortality or overall mortality for left-sided breast cancer relative to right-sided RT. However, an extended follow-up period and exact dosimetry might be necessary to confirm this observation.

     

Self-reported long-term cardiac morbidity in breast cancer patients: a retrospective cohort study in Germany (PASSOS Heart Study)

Purpose

Improved survival after locoregional breast cancer has increased the concern about late adverse effects after therapy. In particular, radiotherapy was identified as a risk factor for major cardiac events in women treated until the 1990s. While modern radiotherapy with computerized planning based on 3D-imaging can help spare organs at risk, heart exposure may remain substantial. In a retrospective cohort study of women treated for locoregional breast cancer, we investigated whether current radiotherapy is associated with an elevated long-term cardiac morbidity risk.

Methods

The study included 11,982 women diagnosed with breast cancer in Germany in 1998–2008. After an individual mortality follow-up, 9338 questionnaires on cardiac events before or after therapy and on associated risk factors were sent out in 2014. Based on 4434 questionnaires from women with radiotherapy, we used Cox regression to analyze the association between self-reported cardiac morbidity and breast cancer laterality as a surrogate measure of radiation exposure.

Results

After a median follow-up of 8.3 years, there was no significant association of tumor laterality with cardiac morbidity in irradiated patients (458 events, hazard ratio for left-sided vs. right-sided tumors 1.07, 95% CI 0.89–1.29). Significant risk factors for any cardiac event included age at diagnosis, chemotherapy, hypertension, hypercholesteremia, and chronic kidney disease.

Conclusions

For contemporary radiotherapy, we found no evidence for a significantly elevated cardiac morbidity risk in left-sided versus right-sided breast cancer. Possible reasons for failing to confirm earlier reports on increased risk include shorter follow-up, application of newer radiotherapy techniques, and improved health monitoring.

     

Sequential DNA flow cytometry in metastatic malignant melanoma

Sequential flow cytometry was performed on 73 metastatic malignant melanomas, derived from 804 primary tumors. Tumor thickness was confirmed an excellent prognostic parameter in primary melanoma, but did not allow reliable predictions in metastatic disease. Also, aneuploidy and genetic heterogeneity, both common in metastatic melanoma, were equally distributed among patients differing in survival time. However, a remarkable acceleration was observed in the generation of abnormal cell lines in patients dying early of metastatic disease.     

Acute lymphoblastic leukemia in adult first manifested as severe aplastic anemia--role of molecular analysis in correct diagnosis

Aplastic anemia (AA) may sometimes precede the diagnosis of acute lymphoblastic leukemia (ALL) in children. Such presentation of ALL is externally rare in adults and until now only few such cases have been reported. We present a 40-year-old male with ALL common type, which developed 14 months after the diagnosis of severe AA, successfully treated with corticosteroids. ALL was treated with standard induction chemotherapy but remission has not been achieved. The patient died 6 weeks after the diagnosis of ALL because of central nervous system bleeding. The pattern of IgH gene rearrangement analyzed with PCR method in bone marrow from the period of AA diagnosis and in peripheral blood mononuclear cells from ALL diagnosis showed two different monoclonal IgH configurations as the results of biallelic monoclonal rearrangement of IgH genes. The observed bands in both specimens were identical and indicated that leukemic cells originated from B-cell progenitor were also present in the bone marrow when AA was diagnosed. We suggest that molecular analysis of monoclonality in patients with AA may be important for proper selection of the rare cases of ALL first presenting as marrow aplasia.     

Accuracy of transvaginal sonography,sonohysterography and hysteroscopy in diagnosis of intrauterine pathology

OBJECTIVES: Sonohysterography (SHG) is a relatively new technique in evaluation of intrauterine disorders. We compared the diagnostic accuracy of this method with that of transvaginal sonography(TVS) and diagnostic hysteroscopy (DH) in diagnosis of intracavitary abnormalities in women with abnormal uterine bleeding, inconclusive endometrial view at TVS and thickened endometrium. METHODS: In prospective study, pre- and postmenopausal women underwent TVS, SHG, and DH. The findings at TVS and SHG were compared with hysteroscopic and histologic findings (obtained from operative hysteroscopy, hysterectomy and d&c). Sensitivity, specificity, positive and negative predictive values were calculated for focally growing lesions. RESULTS: 150 patients were included in the study. There was very good agreement between SHG and DH in the diagnosis of focally growing lesions. SHG was more sufficient in detecting intracavitary abnormalities than TVS. Problems with distention of the uterine cavity were due to cervical stenosis and endometrial carcinoma. CONCLUSION: SHG is more accurate in the diagnosis of intracavitary abnormalities than is TVS. SHG is almost as good as DH at detecting focally growing lesions in the uterine cavity.