Autologous tumor lysate-loaded dendritic cell vaccination in glioblastoma: What happened to the evidence?

In patients with glioblastoma, the "DCVax-L" trial reported a survival benefit with the addition of autologous tumor lysate-loaded denditric cell vaccination to the standard-of-care (SoC) in patients with glioblastoma. The trial presented as a phase 3 externally controlled trial is showing an improvement in overall survival (OS) in patients receiving the vaccine therapy as compared to externally controlled patients, both in the newly diagnosed setting (median OS = 19.3 months versus 16.5 months; HR = 0.80; 98% CI, 0.00-0.94; P = 0.002) and in the recurrent setting (median OS = 13.2 months versus 7.8 months; HR = 0.58; 98% CI, 0.00-0.76; P < 0.001). Interestingly, the original endpoint, progression-free survival (PFS), was not improved by the experimental therapy. While we praise efforts to improve outcomes in a population representing a true unmet need, the trial's design, methods and report raise several issues undermining the ability to derive meaningful conclusion. These limitations are mainly driven by multiple changes occurring years after the trial ended. External controls were used in a trial originally randomizing patients, the primary endpoint was modified (OS instead of PFS), a new study population (recurrent glioblastoma) was added, and unplanned analyses were conducted, among several other changes. Additionally, due to inclusion criteria, the external controls likely selected patients with less favorable outcome as compared with patients enrolled in the trial, potentially biasing the reported survival benefit. In the absence of data sharing, these shortcomings will not be clarified. Dendritic cell vaccination remains a promising approach for GBM. It is therefore disappointing that due to key methodological limitations, the DCVax-L trial ultimately failed to provide sound conclusions about the potential efficacy of such approach for patients with glioblastoma.

Next generation sequencing in adult patients with glioblastoma in Switzerland: a multi-centre decision analysis.

BACKGROUND: Glioblastoma is the most common malignant primary brain tumour in adults and driven by various genomic alterations. Next generation sequencing (NGS) provides timely information about the genetic landscape of tumours and might detect targetable mutations. To date, differences exist in the application and NGS assays used as it remains unclear to what extent these variants may affect clinical decision making. In this survey-based study, we investigated the use of NGS in adult patients with glioblastoma in Switzerland. METHODS: All eight primary care centres for Neuro-Oncology in Switzerland participated in this survey. The NGS assays used as well as the criteria for the application of NGS in newly diagnosed glioblastoma were investigated. Decision trees were analysed for consensus and discrepancies using the objective consensus methodology. RESULTS: Seven out of eight centres perform NGS in patients with newly diagnosed glioblastoma using custom made or commercially available assays. The criteria most relevant to decision making were age, suitability of standard treatment and fitness. NGS is most often used in fitter patients under the age of 60 years who are not suitable for standard therapy, while it is rarely performed in patients in poor general health. CONCLUSION: NGS is frequently applied in glioblastomas in adults in Neuro-Oncology centres in Switzerland despite seldom changing the course of treatment to date.

CHD3 dissociation on Pt(111): A comparison of the reaction dynamics based on the PBE functional and on a specific reaction parameter functional.

We present a comparison of ab initio molecular dynamics calculations for CHD3 dissociation on Pt(111) using the Perdew, Burke and Ernzerhof (PBE) functional and a specific reaction parameter (SRP) functional. Despite the two functionals predicting approximately the same activation barrier for the reaction, the calculations using the PBE functional consistently overestimate the experimentally determined dissociation probability, whereas the SRP functional reproduces the experimental values within a chemical accuracy (4.2 kJ/mol). We present evidence that suggests that this difference in reactivity can at least in part be attributed to the presence of a van der Waals well in the potential of the SRP functional which is absent from the PBE description. This leads to the CHD3 molecules being accelerated and spending less time near the surface for the trajectories run with the SRP functional, as well as more energy being transferred to the surface atoms. We suggest that both these factors reduce the reactivity observed in the SRP calculations compared to the PBE calculations.

Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes.

Despite moderate improvements in outcome of glioblastoma after first-line treatment with chemoradiation recent clinical trials failed to improve the prognosis of recurrent glioblastoma. In the absence of a standard of care we aimed to investigate institutional treatment strategies to identify similarities and differences in the pattern of care for recurrent glioblastoma. We investigated re-treatment criteria and therapeutic pathways for recurrent glioblastoma of eight neuro-oncology centres in Switzerland having an established multidisciplinary tumour-board conference. Decision algorithms, differences and consensus were analysed using the objective consensus methodology. A total of 16 different treatment recommendations were identified based on combinations of eight different decision criteria. The set of criteria implemented as well as the set of treatments offered was different in each centre. For specific situations, up to 6 different treatment recommendations were provided by the eight centres. The only wide-range consensus identified was to offer best supportive care to unfit patients. A majority recommendation was identified for non-operable large early recurrence with unmethylated MGMT promoter status in the fit patients: here bevacizumab was offered. In fit patients with late recurrent non-operable MGMT promoter methylated glioblastoma temozolomide was recommended by most. No other majority recommendations were present. In the absence of strong evidence we identified few consensus recommendations in the treatment of recurrent glioblastoma. This contrasts the limited availability of single drugs and treatment modalities. Clinical situations of greatest heterogeneity may be suitable to be addressed in clinical trials and second opinion referrals are likely to yield diverging recommendations.

[Relationship between clinical diagnosis and microbiological diagnosis of symptomatic vaginitis]. / Rapporti fra diagnosi clinica e diagnosi microbiologica delle vaginiti sintomatiche.

After comparing the referral diagnoses of women with vaginitis sen to our cervicovaginitis out-patient clinic at the Ospedale Fatebenefratelli e Oftalmico of Milan with the subsequent bacteriological diagnoses, the Authors emphasize that treatment for the different types of vaginitis must be prescribed only after accurate and thorough bacteriological examination in order to avoid inadequate treatment and unnecessary discomfort to the patients.

[Mycoplasmas and dysplasia of the uterine cervix]. / Micoplasmi e displasie della portio uterina.

The Authors report a case-list of 395 patients vaginal specimens who were never treated with chemo-antibiotic therapy. Cell dysplastic impairments were found in 213 cases. About these dysplastic alterations, 133 are of slight type, 53 intermediate type and 27 are in advanced phase. We can say, about the last 27 cases, that the concomitance of pH greater than 6.1 in 67% of the cases and the absence of Lactobacillus acidophilus in 81.4% of the cases is not casual. Furthermore, we can notice that vaginal pH suffers an increase in dysplastic patients with a smaller colonization with Lactobacillus acidophilus that, in dysplastic advanced phase is absent in 81.4% of the cases. It is also to remark a significant increase of cases Trichomonas-positive and Mycoplasmas-positive in dysplastic patients, as compared with normal women. The results of the case-list, even if preliminary, seem to be indicative for an evolution of the studies on the relationship between uterine cervix cells and Mycoplasmas and eventual possibility the Mycoplasmas can act as carriers of oncogenic viruses such as Herpes and Papova Virus.

An open study of human lymphoblastoid interferon and oral acyclovir in chronic hepatitis B virus infection.

Ten patients were entered into an open study of interferon (IFN) 'induction' and oral acyclovir (ACV) 'maintenance' therapy. They received 5 Mega units (Mu)/m2 IFN by intramuscular injection daily for 3 days, followed by 7.5 Mu/m2 IFN daily for 7 days. IFN therapy was then discontinued and a 6-week course of oral ACV at a dose of 800 mg 4 times daily commenced. At 6 months, 2 patients had become HBeAg-negative and 1 had developed anti-HBe. Elimination of HBeAg in these patients was accompanied by return of serum liver function tests to normal. There was a statistically significant inhibition of DNA polymerase levels after the 1st week of IFN therapy, which then slowly increased to pretreatment values over 8 weeks. There were no significant adverse effects of ACV therapy, while fever, 'flu-like illness', fatigue, anorexia, and leucopenia were the main side-effects observed during the course of IFN which necessitated dose reduction in 7 patients. Combination therapy appears to effectively inhibit viral replication, although the 'maintenance' effect of oral ACV is minimal. A more effective drug to combine with IFN is needed.

[Doppler echography and color Doppler echography in the assessment of the vascular functional aspects of medical nephropathies]. / Contributo dell'eco Doppler e dell'eco color Doppler nella valutazione degli aspetti funzionali vascolari delle nefropatie mediche.

This study was aimed at finding a Doppler parameter to distinguish, among medical nephropathies, the ones with glomerular from those with vascular or tubulointerstitial involvement. Therefore, 32 patients (20 men and 10 women, average age: 43 years, range: 10-77 years) with clinical and laboratory signs of medical renal disease were examined with color-Doppler US. The resistive index (RI, n.v. < 0.70), as calculated from the Doppler waveform signal was especially considered to assess eventual significant changes differentiating renal diseases according to the different kinds of involvement. RI values were compared with renal biopsy findings, creatininemia levels and clinical and laboratory variables as hematuria and proteinuria. Histology diagnosed 18 glomerulonephritis, 4 glomerulonephritis with interstitial involvement and 10 vascular and tubulointerstitial nephroses, with 1 tubular necrosis. Doppler US demonstrated a normal RI value in 17/18 patients with glomerulonephrosis (mean value: 0.59 +/- 0.05). In one case only, even though biopsy indicated the involvement of one glomerulus only (membranous GN II stage), RI was high--i.e., 0.79. In 4 patients with simultaneous glomerular and interstitial involvement, the mean RI value was 0.17 +/- 0.01. In the 10 cases of tubulointerstitial or vascular nephrosis, the RI was 0.83 +/- 0.07. As far as the correlation between creatininemia levels and RI is concerned, in 8 patients with high values (1.5-8 mg/dl), the mean RI was 0.72 +/- 0.08 and only a weak correlation was found between the RI and the renal failure degree as expressed by creatininemia levels. Therefore, the RI seems to be related more to the site of the disease in the renal field than to renal failure degree. Doppler US seems to be capable of characterizing medical nephrosis, distinguishing glomerular from vascular or tubulointerstitial involvement. In this application area, the combined use of Doppler and color-Doppler US allowed each examination to be performed in a relatively short time--i.e., 30 minutes on the average.

Treatment of chronic HBeAg-positive hepatitis with acyclovir. A controlled trial.

In a previous study a partial inhibition of viral replication was observed in HBeAg-positive patients after acyclovir (ACV) treatment. To assess those results and to evaluate different treatment regimens, a randomized controlled trial with ACV given at 45 mg/kg/day by continuous infusion (in 5 patients) or by intermittent 8-hourly infusion (in 6 patients) for 28 days versus placebo has been performed in 20 patients affected by chronic hepatitis positive for both HBsAg and HBeAg for at least 6 months. Patients were stratified for sex, presence of cirrhosis and homosexual activity. Modest inhibition of serum DNA polymerase activity was observed after intermittent ACV treatment but not with the continuous infusion. After a 8-12 months follow-up, 2 of 10 of the ACV-treated patients and 3 of the controls had become HBeAg-negative, with 1 and 2 seroconversions to anti-HBe in the treated and placebo group respectively. No adverse effects were observed in ACV-treated patients after continuous infusion, but 2 of 6 patients who received intermittent therapy had to stop treatment, because of abdominal colics and elevation of the serum creatinine. Our data confirm that ACV partially inhibits viral replication in HBeAg-positive patients but without significantly affecting the rate of seroconversion to anti-HBe.

[Treatment of Plummer's adenoma: correlation between ultrasonography-guided percutaneous injection of ethanol and autoimmunity]. / Trattamento dell'adenoma di Plummer: correlazione tra iniezione percutanea ecoguidata di etanolo e autoimmunità.

The authors investigated the value of percutaneous ethanol injection in the treatment of Plummer's adenoma. Ten patients were studied: they exhibited a single, hot and toxic nodule in the thyroid. Thyroid autoimmunization (TSAb; TMAb; TGAb) and function (T3; T4; TSH; FT3; FT4) were studied in all patients, before treatment and at 1 month and 3 months. Scintigraphy with 99Tc was performed at the same time intervals. In the euthyroid stage, alcoholization was preceded by US and cytology. Three-four ml of ethanol 95 degrees were injected once or twice a week, from a minimum of 3 to a maximum of 8 injections. Treatment was successful in 2 cases; partial success was obtained in 4 cases, and in 4 cases treatment failed. In all successful cases antibodies were negative and the nodules had hypoechoic echostructure, with a peripheral hypoechoic halo and no areas of internal colliquation. Thus, US-guided percutaneous alcoholization seems to be capable of correct indications in hypoechoic nodules not exhibiting areas of colliquative necrosis and with negative antibodies. However, the problem of the dose of alcohol to inject to treat the nodule thoroughly is still to be debated.