The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to ...examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.
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•Tertiary lymphoid structures are sites of in situ B cell maturation toward plasma cells•IgG+ and IgA+ plasma cells disseminate into the tumor tissue along fibroblastic tracks•Tumor cells are labeled by locally produced IgG•Patients with IgG-labeled tumor cells have high response rate to ICI and prolonged PFS
Meylan et al. show that tertiary lymphoid structures found in tumors are sites of generation of fully mature B cell immunity. Plasma cells disseminate into tumor beds, producing antibodies that bind to tumor cells and initiate their apoptosis, providing a mechanism to support cancer immunotherapies that modulate the tumor microenvironment.
Summary Background Vascular-targeted photodynamic therapy, a novel tissue-preserving treatment for low-risk prostate cancer, has shown favourable safety and efficacy results in single-arm phase 1 and ...2 studies. We compared this treatment with the standard of care, active surveillance, in men with low-risk prostate cancer in a phase 3 trial. Methods This randomised controlled trial was done in 47 European university centres and community hospitals. Men with low-risk, localised prostate cancer (Gleason pattern 3) who had received no previous treatment were randomly assigned (1:1) to vascular-targeted photodynamic therapy (4 mg/kg padeliporfin intravenously over 10 min and optical fibres inserted into the prostate to cover the desired treatment zone and subsequent activation by laser light 753 nm with a fixed power of 150 mW/cm for 22 min 15 s) or active surveillance. Randomisation was done by a web-based allocation system stratified by centre with balanced blocks of two or four patients. Best practice for active surveillance at the time of study design was followed (ie, biopsy at 12-month intervals and prostate-specific antigen measurement and digital rectal examination at 3-month intervals). The co-primary endpoints were treatment failure (histological progression of cancer from low to moderate or high risk or death during 24 months' follow-up) and absence of definite cancer (absence of any histology result definitely positive for cancer at month 24). Analysis was by intention to treat. Treatment was open-label, but investigators assessing primary efficacy outcomes were masked to treatment allocation. This trial is registered with ClinicalTrials.gov , number NCT01310894. Findings Between March 8, 2011, and April 30, 2013, we randomly assigned 206 patients to vascular-targeted photodynamic therapy and 207 patients to active surveillance. Median follow-up was 24 months (IQR 24–25). The proportion of participants who had disease progression at month 24 was 58 (28%) of 206 in the vascular-targeted photodynamic therapy group compared with 120 (58%) of 207 in the active surveillance group (adjusted hazard ratio 0·34, 95% CI 0·24–0·46; p<0·0001). 101 (49%) men in the vascular-targeted photodynamic therapy group had a negative prostate biopsy result at 24 months post treatment compared with 28 (14%) men in the active surveillance group (adjusted risk ratio 3·67, 95% CI 2·53–5·33; p<0·0001). Vascular-targeted photodynamic therapy was well tolerated. The most common grade 3–4 adverse events were prostatitis (three 2% in the vascular-targeted photodynamic therapy group vs one <1% in the active surveillance group), acute urinary retention (three 2% vs one <1%) and erectile dysfunction (two 1% vs three 1%). The most common serious adverse event in the vascular-targeted photodynamic therapy group was retention of urine (15 patients; severe in three); this event resolved within 2 months in all patients. The most common serious adverse event in the active surveillance group was myocardial infarction (three patients). Interpretation Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy. Funding Steba Biotech.
Abstract Background In selected patients with unilateral, organ-confined prostate cancer (PCa), hemiablation of the affected lobe might be feasible to achieve acceptable cancer control with fewer ...complications. Objectives To assess the oncologic and functional outcomes of focal high-intensity focused ultrasound (HIFU) hemiablation in unilateral organ-confined PCa. Design, setting and patients Single-center prospective evaluation of HIFU hemiablation for unilateral organ-confined PCa was performed from July 2009 through December 2013. Intervention Cancer localization was done with transrectal ultrasound–guided biopsy and multiparametric magnetic resonance imaging followed by HIFU hemiablation. Outcome measurement and statistical analysis Oncologic outcomes were analyzed with control biopsies and prostate-specific antigen (PSA) measurement. Functional outcomes were assessed with validated questionnaires for genitourinary symptoms. Results and limitations Of 71 HIFU hemiablation patients, 67 completed the study protocol. The mean age was 70.2 yr (standard deviation: 6.8 yr), and median PSA was 6.1 ng/ml (interquartile range IQR: 1.6–15.5 ng/ml). Median maximum cancer-core length was 3 mm (IQR: 2–10 mm), and total cancer length was 6.5 mm (IQR: 2–24 mm). Gleason score was 6 (3 + 3) in 58 patients (86.6%) and 7 (3 + 4) in 9 patients (13.4%). Median follow-up was 12 mo (IQR: 6–50 mo), and at 12 mo, 56 of 67 patients had a negative control biopsy in the treated lobe. At 3 mo, all patients were continent, and potency was maintained in 11 of 21 preoperatively potent patients (confidence interval, 0.18–0.69). Complications included 8% Clavien–Dindo grade 2 and 2.8% grade 3 events. Conclusions Focal HIFU hemiablation appears to achieve acceptable oncologic outcomes with low morbidity and minimal functional changes. Longer follow-up will establish future considerations. Patient summary This study showed that high-intensity focused ultrasound hemiablation in selected patients with unilateral organ-confined prostate cancer can be used for satisfactory cancer control with minimal effect on genitourinary functions.
Abstract Background Focal therapy as a treatment option for localized prostate cancer (PCa) is an increasingly popular and rapidly evolving field. Objective To gather expert opinion on patient ...selection, interventions, and meaningful outcome measures for focal therapy in clinical practice and trial design. Design, setting, and participants Fifteen experts in focal therapy followed a modified two-stage RAND/University of California, Los Angeles (UCLA) Appropriateness Methodology process. All participants independently scored 246 statements prior to rescoring at a face-to-face meeting. The meeting occurred in June 2013 at the Royal Society of Medicine, London, supported by the Wellcome Trust and the UK Department of Health. Outcome measurements and statistical analysis Agreement, disagreement, or uncertainty were calculated as the median panel score. Consensus was derived from the interpercentile range adjusted for symmetry level. Results and limitations Of 246 statements, 154 (63%) reached consensus. Items of agreement included the following: patients with intermediate risk and patients with unifocal and multifocal PCa are eligible for focal treatment; magnetic resonance imaging–targeted or template-mapping biopsy should be used to plan treatment; planned treatment margins should be 5 mm from the known tumor; prostate volume or age should not be a primary determinant of eligibility; foci of indolent cancer can be left untreated when treating the dominant index lesion; histologic outcomes should be defined by targeted biopsy at 1 yr; residual disease in the treated area of ≤3 mm of Gleason 3 + 3 did not need further treatment; and focal retreatment rates of ≤20% should be considered clinically acceptable but subsequent whole-gland therapy deemed a failure of focal therapy. All statements are expert opinion and therefore constitute level 5 evidence and may not reflect wider clinical consensus. Conclusions The landscape of PCa treatment is rapidly evolving with new treatment technologies. This consensus meeting provides guidance to clinicians on current expert thinking in the field of focal therapy. Patient summary In this report we present expert opinion on patient selection, interventions, and meaningful outcomes for clinicians working in focal therapy for prostate cancer.
Abstract Background Focal therapy has been introduced for the treatment of localised prostate cancer (PCa). To provide the necessary data for consistent assessment, all focal therapy trials should be ...performed according to uniform, systematic pre- and post-treatment evaluation with well-defined end points and strict inclusion and exclusion criteria. Objective To obtain consensus on trial design for focal therapy in PCa. Design, setting, and participants A four-staged consensus project based on a modified Delphi process was conducted in which 48 experts in focal therapy of PCa participated. According to this formal consensus-building method, participants were asked to fill out an iterative sequence of questionnaires to collect data on trial design. Subsequently, a consensus meeting was held in which 13 panellists discussed acquired data, clarified the results, and defined the conclusions. Outcome measurements and statistical analysis A multidisciplinary board from oncologic centres worldwide reached consensus on patient selection, pretreatment assessment, evaluation of outcome, and follow-up. Results and limitations Inclusion criteria for candidates in focal therapy trials are patients with prostate-specific antigen <15 ng/ml, clinical stage T1c–T2a, Gleason score 3 + 3 or 3 + 4, life expectancy of >10 yr, and any prostate volume. The optimal biopsy strategy includes transrectal ultrasound-guided biopsies to be taken between 6 mo and 12 mo after treatment. The primary objective should be focal ablation of clinically significant disease with negative biopsies at 12 mo after treatment as the primary end point. Conclusions This consensus report provides a standard for designing a feasible focal therapy trial. Patient summary A variety of ablative technologies have been introduced and applied in a focal manner for the treatment of prostate cancer (PCa). In this consensus report, an international panel of experts in the field of PCa determined pre- and post-treatment work-up for focal therapy research.
Abstract Background Focal therapy (FT) for prostate cancer (PCa) seems to be part of a natural evolution in the quest to improve the management of early organ-confined disease. Objective To assess ...the morbidity of the initial experience of FT in a tertiary referral center for PCa management. Design, setting, and participants From 2009 to 2011, a total of 1213 patients with clinically localized PCa were treated at our institution. Of these patients, 547 were considered to have indolent disease according to the D’Amico criteria for low-risk disease plus unilateral disease with a maximum of three positive biopsies. A total of 106 patients underwent FT using high-intensity focused ultrasonography (HIFU), brachytherapy, cryotherapy, or vascular-targeted photodynamic therapy (VTP). Outcome measurements and statistical analysis Complications were prospectively recorded and graded according to the Clavien-Dindo scale. Data were prospectively collected and retrospectively analyzed. Results and limitations This study included 106 patients, median age 66.5 yr (interquartile range IQR): 61–73), who had a prostate hemiablation; 50 patients (47%) had cryotherapy, 23 patients (22%) had VTP, 21 patients (20%) received HIFU, and 12 patients (11%) had brachytherapy. The median prostate-specific antigen (PSA) level was 6.1 ng/ml (IQR: 5–8.1), all the patients had a biopsy Gleason score of 6, and the median prostate weight was 43 g (IQR: 33–55). The median International Prostate Symptom Score was 6 (IQR: 3–10), and the median International Index of Erectile Function score was 20 (IQR: 15–23). After treatment, the median PSA at 3, 6, and 12 mo was 3.1 2.9, and 2.7 ng/ml (IQR: 2–5.1, 1.1–4.7, and 1–4.4), respectively. Thirteen percent of the patients experienced treatment-related complications. There were 11 minor medical complications (10 grade 1 complications and 1 grade 2 complication), 2 grade 3 complications, and no grade 4 or higher complications. Conclusions FT for a highly selected population with PCa is feasible and had an acceptable morbidity with <2% major complications.
Take Home Message Personalizing focal ablation energy for prostate cancer on the basis of cancer location is a novel concept. We propose the use of high-intensity focused ultrasound, cryotherapy, and ...brachytherapy for posterior, anterior, and apical tumors, respectively, to improve the overall outcome. This concept needs to be verified in prospective studies.
Current guidelines allow active surveillance for intermediate-risk prostate cancer patients but do not provide comprehensive recommendations for selection. We performed a systematic review and ...meta-analysis of outcomes for active surveillance in intermediate- and low-risk groups.
We performed a systematic literature search of intermediate-risk localized prostate cancer patients undergoing active surveillance using 3 literature search engines (Medline, Web of Science, and Scopus) over the past 10 years. The primary outcome was the percentage of patients who remain under surveillance. Secondary outcomes included cancer-specific survival, overall survival, and metastasis-free survival. For articles including both low- and intermediate-risk patients undergoing active surveillance, comparisons between the two groups were made.
The proportion of patients who remained on active surveillance was comparable between the low- and intermediate-risk groups after 10 and 15 years’ follow-up (odds ratio OR, 0.97; 95% confidence interval CI, 0.83–1.14; and OR, 0.86; 95% CI, 0.65–1.13). Cancer-specific survival was worse in the intermediate-risk group after 10 years (OR, 0.47; 95% CI, 0.31–0.69) and 15 years (OR, 0.34; 95% CI, 0.2–0.58). The overall survival rate showed no statistical difference at 5 years’ follow-up (OR, 0.84; 95% CI, 0.45–1.57) but was worse in the intermediate-risk group after 10 years (OR, 0.43; 95% CI, 0.35–0.53). Metastases-free survival did not significantly differ after 5 years (OR, 0.55; 95% CI, 0.2–1.53) and was worse in the intermediate-risk group after 10 years (OR, 0.46; 95% CI, 0.28–0.77).
Active surveillance could be offered to patients with intermediate-risk prostate cancer. However, they should be informed of the need for regular monitoring and the possibility of discontinuation as a result of a higher rate of progression. Available data indicate that 5-year survival rates between intermediate- and low-risk patients do not differ; 10-year survival rates are worse. To assess the long-term effectiveness and safety of active surveillance, it is necessary to develop unified algorithms for patient selection and management, and to prospectively conduct studies with long-term surveillance.
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