Effectiveness and Safety of Intrathecal Drug Delivery Systems for the Management of Cancer Pain: A Systematic Review and Meta-Analysis.

OBJECTIVES: Intrathecal drug delivery systems (IDDS) and spinal cord stimulation (SCS) have been proposed and assessed for the management of cancer pain; however, such treatments remain underused. We conducted a systematic review to evaluate the effectiveness and safety of IDDS and SCS for cancer pain. MATERIALS AND METHODS: Electronic databases MEDLINE, CENTRAL, EMBASE, and WikiStim were searched from 1988 to March 2021. Randomized controlled trials and observational studies of adults with pain related to cancer or its treatment who received an implantable IDDS or SCS were eligible for inclusion. The primary outcome of the review was change in pain intensity from baseline to the last available follow-up, measured using a visual analog scale or numerical rating scale. The protocol for this review is registered on PROSPERO (CRD42021240717). RESULTS: A total of 22 studies (24 reports) included a total of 3043 participants who received either IDDS or SCS for cancer pain. Eight studies reporting data for 405 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction at the latest posttreatment follow-up time compared with baseline (mean difference [MD], -3.31; 95% CI, -4.18 to -2.45; p < 0.001). Six studies reporting data for 325 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction up to one month after treatment compared with baseline (MD, -3.53; 95% CI, -4.06 to -3.00; p < 0.001). A meta-analysis including studies of participants with either an IDDS or an SCS device showed similar results. Improvements in other outcomes following implantation of IDDS also were observed. Postdural puncture headache was the most reported complication, whereas urinary retention, nausea, and vomiting were commonly reported side effects. CONCLUSION: Our findings suggest that IDDS is effective in reducing pain intensity for patients with cancer pain when compared with pretreatment.

A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants.

BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children.

BACKGROUND: An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries. METHODS: From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories. RESULTS: In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64). CONCLUSIONS: The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).

Compliance with fluoride custom trays in irradiated head and neck cancer patients.

PURPOSE: The purpose of this study is to assess compliance with fluoride gel custom trays in irradiated head and neck cancer patients. METHODS AND MATERIALS: One hundred fifty-five consecutive patients on remission following radiation therapy of head and neck cancers were assessed retrospectively for dental care practices prior to radiation and prospectively for long-term compliance with custom trays from November 2009 to January 2010. A five-item questionnaire was filled in by patients in the waiting room, and a 15-item questionnaire by the physician in charge during the corresponding follow-up visit. RESULTS: Ten percent of patients were edentulous at inclusion. Among dentate patients, 17% had total extractions. With a mean follow-up of 24 months, 19% of patients used custom trays for over a year. Primary stage, age, and tobacco consumption were correlated with compliance with custom trays. More than half of dentate patients developed carious lesions, and 8% had stage 1-3 osteoradionecrosis of the whole population of edentulous and dentate patients. CONCLUSION: Compliance with custom trays was poor in this series. Specific postirradiation dental care follow-up visits and education have demonstrated their utility in the era of 2D irradiation. We currently advocate an 18-month compliance with custom trays in IMRT patients on the basis of the Parsport trial, after which we assess the quality of salivary recovery before recommending prolonged use or interruption. Data with innovative irradiation techniques are however required.

The immune microenvironment of uterine adenosarcomas.

BACKGROUND: Uterine adenosarcoma (UA) is an extremely rare sarcoma subtype. There has been limited evaluation of the immune microenvironment in these tumors. The objective of this study is to examine and describe the immune infiltrate and PD-1/PD-L1 expression in UA and to correlate these changes in the tumor micro-environment with the overall survival status or the disease-free survival status (DFSS), respectively. METHODS: Patients (pts) treated at our center from 1982 to 2014 with UA were identified. Fifteen cases had tumor paraffin-embedded blocks available. Immunohistochemistry studies for CD3, CD8, FOXP3, CD163, PD-1 and PD-L1 (clone 22C3) were performed. Image analysis was used to assess the density (cells/mm2), except in PD-L1, where the percentage of membranous staining on tumor cells was noted. RESULTS: Immune infiltrate analysis median (range) density in cells/mm2 varied broadly: CD3 178 (15-802); CD8 117 (11-661); FoxP3 4.8 (0.2-82); CD163 791 (264-1861); and PD1 5 (1-65). 3 cases had rare (1%) PD-L1 tumor membranous labeling. The reports yielded that ten pts were alive, and 5 were dead. Pts who were alive had significant higher CD3 and CD8 median densities in tumors than those who were dead (p = 0.040). There was no correlation between DFSS and CD3 or CD8 median densities. Patients who had no local recurrence had significantly higher CD3 and CD8 median densities in tumors than those who had local recurrence (p = 0.040). CONCLUSIONS: In conclusion, this is the first report characterizing the presence of immune infiltrate and PD-1/PD-L1 expression in UA. CD3+ CD8+ T-cells density may be prognostic. The immune-responsiveness of UA needs to be further investigated in a larger study.

[Radiation-induced nephropathy]. / Néphropathie post-radique.

BACKGROUND: The kidneys are dose-limiting organs when total body irradiation or irradiation of the digestive tract is planned. The incidence of radiation-induced toxicity is probably underestimated due to its latency and confounding factors like chemotherapy. MATERIAL AND METHODS: A search of the literature for radiation induced renal toxicity was performed. RESULTS: Most toxicities occur around 18 months. Renal mobility is significant in terms of dosimetric consequences, in particular in the young child. In case of total body irradiation, the dose responsible for a 5% risk of toxicities is around 16 Gy in 2 Gy fractions over 2 weeks. For partial renal irradiation, the volume receiving 20 Gy should be below 32% of the total renal volume. Compensatory mechanisms remain possible in areas receiving 12 Gy or less in 1 Gy fractions. When nephrotoxic chemotherapy, these tolerance doses must be lowered. Treatment of radiation-induced nephropathy may include ACE inhibitors. DISCUSSION/CONCLUSION: Prospective assessment of dose-volume histograms and consideration of renal mobility in treatment plans along with improving radiation techniques should help to improve treatment plans including the kidneys.

Genetic rearrangements on the Chlorovirus genome that switch between hyaluronan synthesis and chitin synthesis.

Chlorella viruses or chloroviruses form polysaccharide fibers on the cell wall of host Chlorella cells after infection. Such polysaccharides are either hyaluronan synthesized by virus-encoded hyaluronan synthase (HAS) or chitin synthesized by viral chitin synthase (CHS). Some chloroviruses synthesize both hyaluronan (HA) and chitin simultaneously. To understand the relationship between "HA-synthesizing" and "chitin-synthesizing" viruses, we characterized the CVK2 genomic regions, one flanking chs and the other corresponding to PBCV-1 has and found that on CVK2 DNA, a single ORF (PBCV-1 A330R) was replaced with a 5 kbp region containing chs, ugdh2 (the second gene for UDP-glucose dehydrogenase) and two other ORFs, and that has was replaced with another chs gene. In some chloroviruses, ugdh was lost. These results suggest that chlorovirus types changed from "has viruses" to "chs viruses" or from "chs viruses" to "has viruses" by exchanging the genes.