Search

Context: Identifying malignant tissue and leaving adjacent structures undisturbed constitute an ongoing challenge in prostate cancer (PCa) surgery. Image and radioguided surgical technologies targeting the prostate-specific membrane antigen (PSMA) receptor may facilitate identification and removal of diseased tissue. Objective: To perform a systematic review of the clinical studies on PSMA-targeted surgery. Evidence acquisition: The MEDLINE (OvidSP), Embase.com, and Cochrane Library databases were searched. Identified reports were critically appraised according to the Idea, Development, Exploration, Assessment, Long-term framework criteria. The risk of bias (RoB) was assessed as per the Risk Of Bias In Non-randomized Studies—of Interventions tool. The strengths and limitations of the techniques and corresponding oncological outcomes were extracted as areas of interest. Data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Evidence synthesis: In total, 29 reports were selected, including eight prospective studies, 12 retrospective analyses, and nine case reports, all with a high or an unclear RoB. In 72.4% of studies, PSMA targeting was achieved via radioguided surgery (RGS), predominantly using 99mTc-PSMA-I&S (66.7%). Hybrid approaches that complement RGS with optical guidance are emerging. The majority of studies retrieved were pilot studies with a short follow-up. In 13 reports, salvage lymph node surgery was discussed (44.8%). In 12 more recent reports (41.4%), PSMA targeting was studied in primary PCa surgery (50.0% lymph nodes and 50.0% surgical margins), and four studied both primary and salvage surgery (13.8%). Overall, specificity was higher than sensitivity (median 98.9% and 84.8%, respectively). Oncological outcomes were discussed only in reports on the use of 99mTc-PSMA-I&S in salvage surgery (median follow-up of 17.2 mo). A decline in prostate-specific antigen level of >90% ranged from 22.0% to 100.0%, and biochemical recurrence ranged from 50.0% to 61.8% of patients. Conclusions: In PSMA-targeted surgery, most studies address salvage PSMA-RGS using 99mTc-PSMA-I&S. Available evidence suggests that the specificity of intraoperative PSMA targeting is higher than the sensitivity. The studies that included follow-up did not yet objectify a clear oncological benefit. Lacking solid outcome data, PSMA-targeted surgery remains investigational. Patient summary: In this paper, we review recent advances in prostate–specific membrane antigen (PSMA)-targeted surgery, which is used to help identify and remove prostate cancer. We found good evidence to suggest that PSMA targeting helps identify prostate cancer during surgery. The oncological benefits have yet to be investigated further.

Background: Transperineal focal laser ablation (TPLA) treatment for prostate cancer (PCa) is an experimental focal ablative therapy modality with low morbidity. However, a dosimetry model for TPLA is lacking. Objective: To determine (1) the three-dimensional (3D) histologically defined ablation zone of single- and multifiber TPLA treatment for PCa correlated with magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) and (2) a reliable imaging modality of ablation zone volumetry. Design, setting, and participants: This was a prospective, multicenter, and interventional phase I/II pilot study with an ablate-and-resect design. TPLA was performed in 12 patients with localized prostate cancer divided over four treatment regimens to evaluate potential variation in outcomes. Intervention: TPLA was performed approximately 4 wk prior to robot-assisted radical prostatectomy (RARP) in a daycare setting using local anesthesia. Outcome measurements and statistical analysis: Four weeks after TPLA, ablation zone volumetry was determined on prostate MRI and CEUS by delineation and segmentation into 3D models and correlated with whole-mount RARP histology using the Pearson correlation index. Results and limitations: Twelve office-based TPLA procedures were performed successfully under continuous transrectal ultrasound guidance using local perineal anesthesia. No serious adverse events occurred. A qualitative analysis showed a clear demarcation of the ablation zone on T2-weighted MRI, dynamic contrast-enhanced MRI, and CEUS. On pathological evaluation, no remnant cancer was observed within the ablation zone. Ablation zone volumetry on CEUS and T2-weighted MRI compared with histology had a Pearson correlation index of r = 0.94 (95% confidence interval [CI] 0.74–0.99, p

Objective: To describe the initiation, integration, and costs of reduced-cost infertility services within the maternal health department of a public hospital in a low-income country. Design: Retrospective review of the clinical and laboratory components of patients undergoing in vitro fertilization (IVF) treatment in Rwanda from 2018 to 2020. Setting: Academic tertiary referral hospital in Rwanda. Patients: Patients seeking infertility services beyond the primary gynecological options. Interventions: The national government furnished facilities and personnel, and the Rwanda Infertility Initiative, an international nongovernmental organization, provided training, equipment, and materials. The incidence of retrieval, fertilization, embryo cleavage, transfer, and conception (observed until ultrasound verification of intrauterine pregnancy with fetal heartbeat) were analyzed. Cost calculations used the government-issued tariff specifying insurers' payments and patients' copayments with projected delivery rates using early literature. Main Outcome Measures: Assessment of functional clinical and laboratory infertility services and costs. Results: A total of 207 IVF cycles were initiated, 60 of which led to transfer of ≥1 high-grade embryo and 5 to ongoing pregnancies. The projected average cost per cycle was 1,521 USD. Using optimistic and conservative assumptions, the estimated costs per delivery for women

Recent advances in diploid F1 hybrid potato breeding rely on the production of inbred lines using the S-locus inhibitor (Sli) gene. As a result of this method, female parent lines are self-fertile and require emasculation before hybrid seed production. The resulting F1 hybrids are self-fertile as well and produce many undesirable berries in the field. Utilization of cytoplasmic male sterility would eliminate the need for emasculation, resulting in more efficient hybrid seed production and male sterile F1 hybrids. We observed plants that completely lacked anthers in an F2 population derived from an interspecific cross between diploid S. tuberosum and S. microdontum. We studied the antherless trait to determine its suitability for use in hybrid potato breeding. We mapped the causal locus to the short arm of Chromosome 6, developed KASP markers for the antherless (al) locus and introduced it into lines with T and A cytoplasm. We found that antherless type male sterility is not expressed in T and A cytoplasm, proving that it is a form of CMS. We hybridized male sterile al/al plants with P cytoplasm with pollen from al/al plants with T and A cytoplasm and we show that the resulting hybrids set significantly fewer berries in the field. Here, we show that the antherless CMS system can be readily deployed in diploid F1 hybrid potato breeding to improve hybridization efficiency and reduce berry set in the field.

BackgroundResponsible digital care refers to any intentional systematic effort designed to increase the likelihood of a digital care technology developed through ethical decision-making, being socially responsible and aligned with the values and well-being of those impacted by it. ObjectiveWe aimed to present examples of action opportunities for (1) designing “technology”; (2) shaping the “context” of use; and (3) adjusting the behavior of “users” to guide responsible digital care for people with intellectual disabilities. MethodsThree cases were considered: (1) design of a web application to support the preparation of meals for groups of people with intellectual disabilities, (2) implementation of an app to help people with intellectual disabilities regulate their stress independently, and (3) implementation of a social robot to stimulate interaction and physical activity among people with intellectual disabilities. Overall, 26 stakeholders participated in 3 multistakeholder workshops (case 1: 10/26, 38%; case 2: 10/26, 38%; case 3: 6/26, 23%) based on the “guidance ethics approach.” We identified stakeholders’ values based on bottom-up exploration of experienced and expected effects of using the technology, and we formulated action opportunities for these values in the specific context of use. Qualitative data were analyzed thematically. ResultsOverall, 232 effects, 33 values, and 156 action opportunities were collected. General and case-specific themes were identified. Important stakeholder values included quality of care, autonomy, efficiency, health, enjoyment, reliability, and privacy. Both positive and negative effects could underlie stakeholders’ values and influence the development of action opportunities. Action opportunities comprised the following: (1) technology: development of the technology (eg, user experience and customization), technology input (eg, recipes for meals, intervention options for reducing stress, and activities), and technology output (eg, storage and use of data); (2) context: guidelines, training and support, policy or agreements, and adjusting the physical environment in which the technology is used; and (3) users: integrating the technology into daily care practice, by diminishing (eg, “letting go” to increase the autonomy of people with intellectual disabilities), retaining (eg, face-to-face contact), and adding (eg, evaluation moments) certain behaviors of care professionals. ConclusionsThis is the first study to provide insight into responsible digital care for people with intellectual disabilities by means of bottom-up exploration of action opportunities to take account of stakeholders’ values in designing technology, shaping the context of use, and adjusting the behavior of users. Although part of the findings may be generalized, case-specific insights and a complementary top-down approach (eg, predefined ethical frameworks) are essential. The findings represent a part of an ethical discourse that requires follow-up to meet the dynamism of stakeholders’ values and further develop and implement action opportunities to achieve socially desirable, ethically acceptable, and sustainable digital care that improves the lives of people with intellectual disabilities.

Compared with reduced-intensity conditioning (RIC), myeloablative conditioning (MAC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, disease-specific risk factors in AML/MDS can further inform when MAC and RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the Disease Risk Index (DRI) in 4387 adults (age 40 to 65 years) to identify the impact of conditioning intensity. In the low/intermediate-risk DRI cohort, RIC was associated with lower nonrelapse mortality (NRM) (hazard ratio [HR], .74; 95% confidence interval [CI], .62 to .88; P < .001) but significantly greater relapse risk (HR, 1.54; 95% CI, 1.35 to 1.76; P < .001) and thus inferior disease-free survival (DFS) (HR, 1.19; 95% CI, 1.07 to 1.33; P = .001). In the high/very high-risk DRI cohort, RIC was associated with marginally lower NRM (HR, .83; 95% CI, .68 to 1.00; P = .051) and significantly higher relapse risk (HR, 1.23; 95% CI, 1.08 to 1.41; P = .002), leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for patients with AML/MDS with low/intermediate-risk DRI, but with a similar benefit as RIC in high/very high-risk DRI. Novel MAC regimens with less toxicity could benefit all patients, but more potent antineoplastic approaches are needed for the high/very-high risk DRI group.

Although hematopoietic cell transplantation from an HLA-matched unrelated donor is potentially curative for hematologic malignancies, survival is lower for African Americans compared with Caucasians. Because only approximately 20% of African Americans will have an HLA-matched unrelated donor, many of these patients undergo HLA-haploidentical relative or umbilical cord blood transplantation. In this study, we analyzed outcomes after HLA-haploidentical related donor (n = 249) and umbilical cord blood (n = 118) transplantations in African American patients with hematologic malignancy between 2008 and 2016. The predominant disease was acute myelogenous leukemia for recipients of both types of donor grafts. The incidences of grade II-IV and III-IV acute graft-versus-host disease were higher after umbilical cord blood transplantation compared with HLA-haploidentical relative transplantation (56% and 29%, respectively, versus 33% and 11%, respectively; P < .0001). The 2-year incidence of transplantation-related mortality adjusted for age and conditioning regimen intensity was higher after umbilical cord blood transplantation compared with HLA-haploidentical related donor transplantation (31% versus 18%; P = .008); however, there were no between-group differences in the 2-year adjusted incidence of relapse (30% versus 34%; P = .51), overall survival (54% versus 57%; P = .66), or disease-free survival (43% versus 47%; P = .46). Our findings show that the use of HLA-haploidentical and umbilical cord blood transplants expands the access to transplantation with comparable leukemia-free and overall survival for African Americans with hematologic malignancies.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (P=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (P=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.

Background: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined. Objective: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa. Design, setting, and participants: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting. Outcome measurements and statistical analysis: Consensus was reached if ≥75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method. Results and limitations: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hereditary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveillance was considered appropriate, except in case of the patient being a BRCA2 germline pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as follows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline. Conclusions: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa. Patient summary: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.

Background: Accurate identification of men who harbor nodal metastases is necessary to select patients who most likely benefit from whole pelvis radiotherapy (WPRT). Limited sensitivity of diagnostic imaging approaches for the detection of nodal micrometastases has led to the exploration of the sentinel lymph node biopsy (SLNB). Objective: To evaluate whether SLNB can be used as a tool to select pathologically node-positive patients who likely benefit from WPRT. Design, setting, and participants: We included 528 clinically node-negative primary prostate cancer (PCa) patients with an estimated nodal risk of >5% treated between 2007 and 2018. Intervention: A total of 267 patients were directly treated with prostate-only radiotherapy (PORT; non-SLNB group), while 261 patients underwent SLNB to remove lymph nodes directly draining from the primary tumor prior to radiotherapy (SLNB group); pN0 patients were treated with PORT, while pN1 patients were offered WPRT. Outcome measurements and statistical analysis: Biochemical recurrence–free survival (BCRFS) and radiological recurrence-free survival (RRFS) were compared using propensity score weighted (PSW) Cox proportional hazard models. Results and limitations: The median follow-up was 71 mo. Occult nodal metastases were found in 97 (37%) SLNB patients (median metastasis size: 2 mm). Adjusted 7-yr BCRFS rates were 81% (95% confidence interval [CI] 77–86%) in the SLNB group and 49% (95% CI 43–56%) in the non-SLNB group. The corresponding adjusted 7-yr RRFS rates were 83% (95% CI 78–87%) and 52% (95% CI 46–59%), respectively. In the PSW multivariable Cox regression analysis, SLNB was associated with improved BCRFS (hazard ratio [HR] 0.38, 95% CI 0.25–0.59, p < 0.001) and RRFS (HR 0.44, 95% CI 0.28–0.69, p < 0.001). Limitations include the bias inherent to the study’s retrospective nature. Conclusions: SLNB-based selection of pN1 PCa patients for WPRT was associated with significantly improved BCRFS and RRFS compared with (conventional) imaging-based PORT. Patient summary: Sentinel node biopsy can be used to select patients who will benefit from the addition of pelvis radiotherapy. This strategy results in a longer duration of prostate-specific antigen control and a lower risk of radiological recurrence.