Clinical interest in the human intestinal microbiota has increased considerably. However, an overview of clinical studies investigating the link between the human intestinal microbiota and systemic ...cancer therapy is lacking. This systematic review summarizes all clinical studies describing the association between baseline intestinal microbiota and systemic cancer therapy outcome as well as therapy-related changes in intestinal microbiota composition. A systematic literature search was performed and provided 23 articles. There were strong indications for a close association between the intestinal microbiota and outcome of immunotherapy. Furthermore, the development of chemotherapy-induced infectious complications seemed to be associated with the baseline microbiota profile. Both chemotherapy and immunotherapy induced drastic changes in gut microbiota composition with possible consequences for treatment efficacy. Evidence in the field of hormonal therapy was very limited. Large heterogeneity concerning study design, study population, and methods used for analysis limited comparability and generalization of results. For the future, longitudinal studies investigating the predictive ability of baseline intestinal microbiota concerning treatment outcome and complications as well as the potential use of microbiota-modulating strategies in cancer patients are required. More knowledge in this field is likely to be of clinical benefit since modulation of the microbiota might support cancer therapy in the future.
Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of ...targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies.
In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival.
A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group.
Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. (Funded by Assistance Publique-Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033 .).
Background
Intermittent claudication (IC) is the classic symptomatic form of peripheral arterial disease affecting an estimated 4.5% of the general population aged 40 years and older. Patients with ...IC experience limitations in their ambulatory function resulting in functional disability and impaired quality of life (QoL). Endovascular revascularisation has been proposed as an effective treatment for patients with IC and is increasingly performed.
Objectives
The main objective of this systematic review is to summarise the (added) effects of endovascular revascularisation on functional performance and QoL in the management of IC.
Search methods
For this review the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (February 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1). The CIS also searched trials registries for details of ongoing and unpublished studies.
Selection criteria
Randomised controlled trials (RCTs) comparing endovascular revascularisation (± conservative therapy consisting of supervised exercise or pharmacotherapy) versus no therapy (except advice to exercise) or versus conservative therapy (i.e. supervised exercise or pharmacotherapy) for IC.
Data collection and analysis
Two review authors independently selected studies, extracted data, and assessed the methodological quality of studies. Given large variation in the intensity of treadmill protocols to assess walking distances and use of different instruments to assess QoL, we used standardised mean difference (SMD) as treatment effect for continuous outcome measures to allow standardisation of results and calculated the pooled SMD as treatment effect size in meta‐analyses. We interpreted pooled SMDs using rules of thumb (< 0.40 = small, 0.40 to 0.70 = moderate, > 0.70 = large effect) according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated the pooled treatment effect size for dichotomous outcome measures as odds ratio (OR).
Main results
We identified ten RCTs (1087 participants) assessing the value of endovascular revascularisation in the management of IC. These RCTs compared endovascular revascularisation versus no specific treatment for IC or conservative therapy or a combination therapy of endovascular revascularisation plus conservative therapy versus conservative therapy alone. In the included studies, conservative treatment consisted of supervised exercise or pharmacotherapy with cilostazol 100 mg twice daily. The quality of the evidence ranged from low to high and was downgraded mainly owing to substantial heterogeneity and small sample size.
Comparing endovascular revascularisation versus no specific treatment for IC (except advice to exercise) showed a moderate effect on maximum walking distance (MWD) (SMD 0.70, 95% confidence interval (CI) 0.31 to 1.08; 3 studies; 125 participants; moderate‐quality evidence) and a large effect on pain‐free walking distance (PFWD) (SMD 1.29, 95% CI 0.90 to 1.68; 3 studies; 125 participants; moderate‐quality evidence) in favour of endovascular revascularisation. Long‐term follow‐up in two studies (103 participants) showed no clear differences between groups for MWD (SMD 0.67, 95% CI ‐0.30 to 1.63; low‐quality evidence) and PFWD (SMD 0.69, 95% CI ‐0.45 to 1.82; low‐quality evidence). The number of secondary invasive interventions (OR 0.81, 95% CI 0.12 to 5.28; 2 studies; 118 participants; moderate‐quality evidence) was also not different between groups. One study reported no differences in disease‐specific QoL after two years.
Data from five studies (n = 345) comparing endovascular revascularisation versus supervised exercise showed no clear differences between groups for MWD (SMD ‐0.42, 95% CI ‐0.87 to 0.04; moderate‐quality evidence) and PFWD (SMD ‐0.05, 95% CI ‐0.38 to 0.29; moderate‐quality evidence). Similarliy, long‐term follow‐up in three studies (184 participants) revealed no differences between groups for MWD (SMD ‐0.02, 95% CI ‐0.36 to 0.32; moderate‐quality evidence) and PFWD (SMD 0.11, 95% CI ‐0.26 to 0.48; moderate‐quality evidence). In addition, high‐quality evidence showed no difference between groups in the number of secondary invasive interventions (OR 1.40, 95% CI 0.70 to 2.80; 4 studies; 395 participants) and in disease‐specific QoL (SMD 0.18, 95% CI ‐0.04 to 0.41; 3 studies; 301 participants).
Comparing endovascular revascularisation plus supervised exercise versus supervised exercise alone showed no clear differences between groups for MWD (SMD 0.26, 95% CI ‐0.13 to 0.64; 3 studies; 432 participants; moderate‐quality evidence) and PFWD (SMD 0.33, 95% CI ‐0.26 to 0.93; 2 studies; 305 participants; moderate‐quality evidence). Long‐term follow‐up in one study (106 participants) revealed a large effect on MWD (SMD 1.18, 95% CI 0.65 to 1.70; low‐quality evidence) in favour of the combination therapy. Reports indicate that disease‐specific QoL was comparable between groups (SMD 0.25, 95% CI ‐0.05 to 0.56; 2 studies; 330 participants; moderate‐quality evidence) and that the number of secondary invasive interventions (OR 0.27, 95% CI 0.13 to 0.55; 3 studies; 457 participants; high‐quality evidence) was lower following combination therapy.
Two studies comparing endovascular revascularisation plus pharmacotherapy (cilostazol) versus pharmacotherapy alone provided data showing a small effect on MWD (SMD 0.38, 95% CI 0.08 to 0.68; 186 participants; high‐quality evidence), a moderate effect on PFWD (SMD 0.63, 95% CI 0.33 to 0.94; 186 participants; high‐quality evidence), and a moderate effect on disease‐specific QoL (SMD 0.59, 95% CI 0.27 to 0.91; 170 participants; high‐quality evidence) in favour of combination therapy. Long‐term follow‐up in one study (47 participants) revealed a moderate effect on MWD (SMD 0.72, 95% CI 0.09 to 1.36; P = 0.02) in favour of combination therapy and no clear differences in PFWD between groups (SMD 0.54, 95% CI ‐0.08 to 1.17; P = 0.09). The number of secondary invasive interventions was comparable between groups (OR 1.83, 95% CI 0.49 to 6.83; 199 participants; high‐quality evidence).
Authors' conclusions
In the management of patients with IC, endovascular revascularisation does not provide significant benefits compared with supervised exercise alone in terms of improvement in functional performance or QoL. Although the number of studies is small and clinical heterogeneity underlines the need for more homogenous and larger studies, evidence suggests that a synergetic effect may occur when endovascular revascularisation is combined with a conservative therapy of supervised exercise or pharmacotherapy with cilostazol: the combination therapy seems to result in greater improvements in functional performance and in QoL scores than are seen with conservative therapy alone.
Stem Cells in the Treatment of Disease Blau, Helen M; Daley, George Q
The New England journal of medicine,
05/2019, Letnik:
380, Številka:
18
Journal Article
In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease ...progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.
We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.
A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.
Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
Inactivation of cancer stem cells (CSCs) is of utmost importance for tumor cure after radiotherapy. An increasing body of evidence complies with a higher radioresistance of CSCs compared to the mass ...of tumor cells, supporting the use of CSC related biomarkers for prediction of radiotherapy outcome. Treatment individualization strategies for patient groups with vastly different risk of recurrence will most likely require application of more than one biomarker. Specifically, inclusion of established biomarkers like tumor size for primary radio(chemo)therapy or human papilloma virus (HPV) infection status in head and neck squamous cell carcinoma seems to be of very high relevance. The high heterogeneity of CSC subclones along with changes of the functional behavior of individual tumors under treatment underlines the importance of the selection of the optimal timepoint(s) of biomarker evaluation, but also provides a potential therapeutic target for combined treatment approaches with irradiation.
Display omitted
Acute pancreatitis is one of the most common GI conditions requiring acute hospitalisation and has a rising incidence. In recent years, important insights on the management of acute pancreatitis have ...been obtained through numerous randomised controlled trials. Based on this evidence, the treatment of acute pancreatitis has gradually developed towards a tailored, multidisciplinary effort, with distinctive roles for gastroenterologists, radiologists and surgeons. This review summarises how to diagnose, classify and manage patients with acute pancreatitis, emphasising the evidence obtained through randomised controlled trials.
T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with ...advanced CD19(+) B-cell malignancies.
We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells.
Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL.
This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.
Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and ...uncertainty about its effectiveness remains.
We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days.
We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval CI, 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%.
In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).
The new 2016 WHO brain tumor classification defines different diffuse gliomas primarily according to the presence or absence of IDH mutations ( IDH-mt) and combined 1p/19q loss. Today, the diagnosis ...of anaplastic oligodendroglioma requires the presence of both IDH-mt and 1p/19q co-deletion, whereas anaplastic astrocytoma is divided into IDH wild-type ( IDH-wt) and IDH-mt tumors. IDH-mt tumors have a more favorable prognosis, and tumors with low-grade histology especially tend evolve slowly. IDH-wt tumors are not a homogeneous entity and warrant further molecular testing because some have glioblastoma-like molecular features with poor clinical outcome. Treatment consists of a resection that should be as extensive as safely possible, radiotherapy, and chemotherapy. Trials of patients with newly diagnosed grade II or III glioma have shown survival benefit from adding chemotherapy to radiotherapy compared with initial treatment using radiotherapy alone. Both temozolomide and the combination of procarbazine, lomustine, and vincristine provide survival benefit. In contrast, trials that compare single modality treatment of chemotherapy alone with radiotherapy alone did not observe survival differences. Currently, for patients with grade II or III gliomas who require postsurgical treatment, the preferred treatment consists of a combination of radiotherapy and chemotherapy. Low-grade gliomas with favorable characteristics are slow-growing tumors. When deciding on the timing of postsurgical treatment with radiotherapy and chemotherapy, both clinical and molecular factors should be taken into account, but a more conservative approach can be considered initially in some of these patients. The factor that best predicts benefit of chemotherapy in grade II and III glioma remains to be established.