Impact of venous tumour thrombus consistency (solid vs friable) on cancer-specific survival in patients with renal cell carcinoma

Background

To our knowledge, the impact of venous tumour thrombus (VTT) consistency in patients affected by renal cell carcinoma (RCC) has never been addressed.

Objective

To analyse the effect of VTT consistency on cancer-specific survival (CSS).

Design, setting, and participants

We retrospectively analysed 174 consecutive patients with RCC and renal vein or inferior vena cava (IVC) VTT who underwent surgical treatment between 1989 and 2007 at our institute.

Intervention

All patients underwent radical nephrectomy and thrombectomy.

Measurements

Pathologic specimens were reviewed by a single uropathologist. In addition to traditional pathologic features, the morphologic aspect of the tumour thrombus was evaluated to distinguish solid from friable patterns. The prognostic role of thrombus consistency (solid vs friable) on CSS was assessed by means of Cox regression models.

Results and limitations

The VTT was solid in 107 patients (61.5%) and friable in 67 patients (38.5%). The presence of a friable VTT increased the risk of having synchronous nodal or distant metastases, higher tumour grade, higher pathologic stage, and simultaneous perinephric fat invasion (all p < 0.05). The median follow-up was 24 mo. The median CSS was 33 mo; the median CSS was 8 mo in patients with a friable VTT and 55 mo in patients with a solid VTT (p < 0.001). On multivariable analyses, the presence of a friable VTT was an independent predictor of CSS (p = 0.02). The power of our conclusion may be somewhat limited by the relatively small study population and the retrospective nature of the study.

Conclusions

In patients with RCC and VTT, the presence of a friable thrombus is an independent predictor of CSS. If our finding is confirmed by further studies, the consistency of the tumour thrombus should be introduced into routine pathologic reports to provide better patient risk stratification.     

Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubicin

Exosomes released from cancer cells support metastasis and growth of recipient cells and increase their resistance to chemotherapy. Therapeutic targeting of exosomes is a promising area in cancer research. Our aim is to test the effect of the mast cell stabilizer ketotifen on exosomes release from cancer cells and how this can modify their response to doxorubicin. Exosomes release from three cancer cell lines (MCF7, HeLa and BT549) was assessed by scan electron microscope and exosomes quantification kit. Doxorubicin export within exosomes was monitored flurometrically and cellular sensitivity to doxorubicin ± ketotifen was measured by sulphorhodamine-B and colony formation assays. The three cell lines release different amounts of exosomes with the highest quantity released from BT549 followed by MCF7 and then HeLa. Ketotifen (10 µmol L^?1) reduced exosomes release in all three cell lines with different efficiency (HeLa>MCF7>BT549). Doxorubicin export via exosomes was highest in BT549, lower in HeLa and lowest in MCF7 cells. Pretreatment with ketotifen sensitized the cells to doxorubicin (HeLa>MCF7>BT549) with a sensitization factor of 27, 8 and 1.25 respectively. Increased sensitivity of cells to doxorubicin by ketotifen was proportional to its effect on exosomes release. Our data is the first report of ketotifen modulating exosomes release from cancer cells and opens the avenue for exosomes-targeting cancer therapy. The differential effects of ketotifen on doxorubicin exosomal export in the cell lines studied, suggests an opportunity of pharmacological enhancement of doxorubicin anti-tumor activity in some but not all cancer types.     

Synthesis and anti-bacterial activities of some novel pyrazolobenzothiazine-based chalcones and their pyrimidine derivatives

A novel series of fifteen pyrimidine derivatives was prepared from pyrazolobenzothiazine-based chalcones by refluxing with guanidine hydrochloride. The starting materials 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c][1,2]thiazin-2(4-H)yl)phenyl)ethanone (2) or 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c][1,2]thiazin-2(4-H)yl)benzaldehyde (3) were obtained by N-arylation of 3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine 5,5-dioxide (1) with 4-fluoroacetophenone or 4-fluorobenzaldehyde, respectively, using phase transfer catalyst, hexadecyl-tri-n-butylphsophonium bromide. The N-arylated product (2) or (3) was reacted in MeONa/MeOH with diversified aromatic aldehydes or ketones to furnish two series of new chalcones 4 and 5. Refluxing of 4 or 5 with guanidine hydrochloride in KOH_(aq) and H₂O₂/EtOH yielded the 2-(4-(2-amino-6-arylpyrimidin-4-yl)phenyl)3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine-5,5-dioxide (6). The structures of chalcones (4 or 5) and corresponding pyrimidines (6) were confirmed with spectral data and elemental analysis. Several chalcones as well as pyrimidines showed marked activity against E. coli and S. aureus.     

Multifocal malignant optic glioma of adulthood presenting as acute anterior optic neuropathy

We report a 63-year-old, previously healthy female patient with glioblastoma multiforme of the optic nerve and chiasm presenting as acute anterior optic neuropathy. She presented with a 3-week history of progressively increasing headaches, retrobulbar pain, rapidly progressive visual loss in the right eye and blurred vision in the left eye. Early clinical examination revealed right optic disc swelling and she was initially diagnosed with demyelinating optic neuritis. Her clinical course deteriorated with total visual loss in the right eye and progressive visual loss in the left eye despite treatment with intravenous (IV) methylprednisone and IV immunoglobulins. MRI revealed enhancement of the right optic nerve and optic chiasm, with multiple periventricular hyperintense foci. Six weeks later, the patient presented with left facial palsy and left hemiparesis. Follow-up MRI showed multiple enhancing lesions in addition to the previous lesions involving right lentiform and right thalamic nucleus, right cerebral peduncle, right temporal and parietal lobes. Although the optic nerve biopsy was inconclusive, the brain biopsy revealed glioblastoma multiforme. This report demonstrated that malignant glioma of adulthood may be multicentric and may mimic optic neuritis clinically, which might help explain the difficulties in diagnosis.     

Delay in Seeking Medical Help in Patients with New‐Onset Erectile Dysfunction Remained High Over and Despite the PDE5 Era—An Ecological Study

IntroductionIt is common knowledge among researchers that erectile dysfunction (ED) is an important sentinel marker of cardiovascular and overall men's health.AimDetermine whether the delay of time between ED onset and seeking medical help (DSH), considered as a proxy of awareness of the importance of ED for overall men's health, has shortened during the phosphodiesterase type 5 inhibitors (PDE5) era.MethodsComplete data from 619 patients seeking first medical help for new‐onset ED as their primary disorder between July 2000 and July 2010 were analyzed (i.e., DSH, ED severity as defined by the International Index of Erectile Function‐erectile function [IIEF‐EF] domain score, patient's awareness of any PDE5, and Charlson Comorbidity Index [CCI]). Analysis of variance tested DSH throughout the 10‐year time frame. Cox regression models tested the association between predictors and DSH.Main Outcome MeasuresAssess if DSH has shortened throughout PDE5 era. Evaluate potential predictors of DSH.ResultsOverall, mean DSH was 30.2 months (median 12.0; range 5–300 months). DSH shortened throughout the analyzed 10‐year period (F = 1.918; P = 0.047), with a significant drop only from year 2009 (DSH up to year 2008 vs. from year 2009: 31.0 months [12.0] vs. 7.5 months [6.0], respectively; P < 0.001). Age, CCI, educational status, and ED severity did not significantly change over time. As a whole, 560 patients (90.5%) were aware of PDE5 at the time of their first office visit. PDE5 awareness emerged as an univarible and multivariable predictor of a shortened DSH. Conversely, DSH was not clearly associated with age, CCI, educational status, or ED severity.ConclusionDelay in seeking medical help in new‐onset ED patients remained high over the PDE5 era, with a significant drop only from the year 2009. PDE5 awareness emerged as an independent predictor of shortening of this delay. Salonia A, Ferrari M, Saccà A, Pellucchi F, Castagna G, Clementi MC, Matloob R, Briganti A, Rigatti P, and Montorsi F. Delay in seeking medical help in patients with new‐onset erectile dysfunction remained high over and despite the PDE5 era—An ecological study. J Sex Med 2012;9:3239–3246.     

Should We Tailor the Clinical Management of Erectile Dysfunction According to Different Ages?

IntroductionThe impact of erectile dysfunction (ED) on patients’ sexual satisfaction and mood profile could differ across different ages.AimTo investigate the relationship between erectile function (EF), sexual satisfaction, and mood status among patients seeking medical help for ED.MethodsData from 765 patients presenting at a single center for ED were analyzed. Patients were categorized as young (≤50 years), middle-aged (>50 and ≤65 years), and old (>65 years) individuals and completed the International Index of Erectile Function (IIEF) and the Beck’s Inventory for Depression (BDI).Main Outcome MeasuresThe IIEF overall satisfaction and intercourse satisfaction domain scores and the BDI score were used to investigate sexual life satisfaction and depressive symptoms (defined as BDI > 11) across ages and according to ED severity. Linear and logistic regression analyses assessed the relationship between satisfaction scores and the risk of depressive symptoms with age and EF.ResultsMedian (interquartile range) age at first assessment for ED was 50 (38, 59) years. Compared with older men, young and middle-aged patients showed significantly higher IIEF-OS and IIEF– Intercourse Satisfaction scores for increasing IIEF-EF scores. Older men showed no difference in terms of satisfaction scores for mild ED and normal EF status. At linear regression analysis, both IIEF-EF and age were significantly associated with sexual satisfaction (all P < .0001). The interaction term between age and EF was also significant, suggesting that the older the patients, the higher the feeling of sexual satisfaction for the same EF status (P = .004). Overall, 25% of patients reported depressive symptoms. Logistic regression analysis showed a 40% risk of depressive symptoms for patients <45 years with severe ED compared to a risk <20% for a man >65 years of age with the same EF status.Clinical ImplicationsTreating older patients with mild ED may not lead to a further improvement in sexual satisfaction as compared with younger patients with the same ED severity. Younger ED patients suffer more from depressive symptoms compared with older men, regardless of ED severity, thus supporting the need for a comprehensive psychological counseling.Strength & LimitationsThe single-center design and the lack of the assessment of the impact of ED treatment are the main limits.ConclusionsThe clinical management of ED should be tailored according to different ages: younger patients deserve to be investigated and eventually treated for depressive symptoms. Older patients should be counseled for treatment when a sexual satisfaction improvement is expected.Capogrosso P, Ventimiglia E, Boeri L, et al. Should We Tailor the Clinical Management of Erectile Dysfunction According to Different Ages? J Sex Med 2019;16:999–1004.