Redefining bladder neck dose in low-dose-rate prostate brachytherapy-Can we improve urinary toxicity without impacting disease control?

BACKGROUND: We sought to assess the impact of bladder neck dose (BND) on patient reported urinary toxicity, and feasibility of relative urethral sparing technique in prostate brachytherapy (PB). METHODS AND MATERIALS: We retrospectively identified bladder neck as a point dose on post-implant CT scans in patients treated with 131Cs PB. Urinary symptoms were assessed through EPIC questionnaires. Patient cohorts were identified based on mean BND as a percentage of prescription dose with toxicity assessment at each time point. RESULTS: In our cohort of 542 patients, BND was associated with clinically significant acute urinary symptoms and chronic symptoms, as patients receiving >70% of the prescription dose had significantly worse overall EPIC scores than patients receiving ≤70% of prescription dose. There was no difference in bDFS between patients receiving BND ≤70% (96% bDFS) and >70% (94% bDFS) at a median follow up of 57 months. CONCLUSIONS: BND has a significant impact on both acute and chronic urinary symptoms, with reduced symptoms reported with BND <70% of prescription dose. With a median follow up of 4.7 years, excellent bDFS has thus far been achieved with relative urethral and bladder neck sparing. Utilizing this constraint should improve urinary symptoms without impacting disease control.

Cs-131 prostate brachytherapy boost and effect of hydrogel rectal spacer on long-term patient-reported rectal bleeding and bowel quality of life.

PURPOSE: This study evaluates long-term patient-reported bowel quality of life (QOL), rectal bleeding, and bleeding bother in patients with prostate cancer treated with external beam radiation therapy (EBRT) and Cesium-131 LDR brachytherapy (LDR-BT) boost with and without hydrogel rectal spacer. METHODS AND MATERIALS: This is a retrospective analysis of prostate cancer patients treated between 2007 and 2022 with 45 Gy EBRT followed by 85 Gy Cs-131 LDR-BT boost with or without hydrogel rectal spacer. Expanded Prostate Cancer Index Composite (EPIC) QOL questionnaires pre-treatment and at each follow-up were collected. Patient-reported rectal bleeding occurring more than "rarely" and bother from rectal bleeding occurring more than a "very small problem" were deemed clinically significant. Fisher's exact test was used to test the association of rectal spacer use and the incidence of clinically significant rectal bleeding and bleeding bother. Paired samples t-test was used to analyze mean bowel scores at each time point. RESULTS: Three hundred and forty-one patients were included in the analysis. The rectal spacer was used in 108 patients. Overall median follow-up was 48 months (IQR, 24-72), with a median follow-up of 24 months (IQR, 12-37.5) for the hydrogel group and 60 months (IQR, 36-84) for the non-hydrogel group. EPIC questionnaire response rates at median follow-up were 33% and 37% for the hydrogel and non-hydrogel groups, respectively. A clinically significant decrease in mean bowel domain scores was seen in the bowel bother domain at 6 and 12 months for patients who did not receive a rectal spacer. At the last follow-up of 60 months, the prevalence of clinically significant rectal bleeding and bleeding bother were 2.2% and 2.2%, respectively. The cumulative incidence of clinically significant long-term rectal bleeding was 2.8% and 18.9% in the hydrogel group and non-hydrogel group, respectively (Fisher's exact test, p < 0.0001). The cumulative incidence of clinically significant long-term bowel bother was 4.6% and 19.7% in the hydrogel group and non-hydrogel group, respectively (Fisher's exact test, p < 0.001). CONCLUSIONS: Use of hydrogel rectal spacer with EBRT and Cs-131 LDR-BT boost was significantly associated with a lower incidence of patient-reported rectal bleeding and bother from rectal bleeding, and better long-term bowel QOL. Cumulative incidence was 2.8% (hydrogel group) versus 18.9% (non-hydrogel group) and 4.6% (hydrogel group) versus 19.7% (non-hydrogel group) for clinically significant long-term rectal bleeding and long-term bleeding bother, respectively.

Effect of short-term corticosteroid usage on acute urinary toxicity following Cs-131 prostate brachytherapy.

PURPOSE: To evaluate short-term patient reported urinary quality of life scores in patients with prostate cancer treated at our institution with and without perioperative prednisone following Cesium-131 (131Cs) prostate LDR brachytherapy. METHODS AND MATERIALS: We started routinely using a perioperative 7-day course of prednisone at a dose of 5 mg per day, beginning 1 day prior to 131Cs prostate LDR brachytherapy from 2013 with goal of improving acute urinary symptomatology. One hundred consecutive patients treated with prednisone were selected, with comparison to 100 consecutive patients who were not treated with prednisone. We analyzed for differences in mean change with standard deviation (SD) in EPIC and AUA scores at 0.5-1 month and 3 months with or without prednisone by Mann-Whitney U Test. Binary logistic regression was performed to assess for impact of prednisone on postoperative urinary catheter use. RESULTS: Pretreatment EPIC and AUA scores were available in 197 patients. Less reduction in EPIC US score was noted at 0.5-1.0 month in the group who received prednisone with mean change of -22.9 (SD 15.4) when compared to the group who did not receive prednisone with mean change of -31.7 (SD 19.3), p < 0.01, with significance lost at 3 months. There was no significant difference in acute urinary retention requiring postoperative urinary catheter placement with perioperative prednisone (OR 1.13, p = 0.71). CONCLUSIONS: A short course of perioperative low-dose prednisone was associated with less severe worsening in urinary symptoms by the EPIC questionnaire at the 0.5-1.0-month timepoint suggesting some improvement in acute urinary quality of life, although differences did not remain statistically significant at 3 months.

Treatment of intermediate-risk prostate cancer with Cs-131: Long-term results from a single institution.

PURPOSE: To evaluate our institutional outcomes utilizing Cs-131 prostate brachytherapy (PB) for the intermediate-risk (IR) group of prostate cancer patients. METHODS AND MATERIALS: We reviewed a prospectively collected database of men treated with Cs-131 PB between 2006 and 2019. Patients with less than 24-months follow-up were excluded. Patients were classified as IR if they had one of the following factors: Gleason Score 7, prostate specific antigen >10 but <20 ng/mL, or T2b-c on clinical exam. We defined unfavorable-IR (UIR) as having either Grade Group 3, >1 IR factors, or ≥50% positive core biopsies. The Kaplan-Meier method was used to estimate actuarial event-time probabilities for biochemical freedom from disease (BFD). RESULTS: A total of 335 patients with a median follow-up of 70.1 months (IQR 48.3-106.3 months) were identified. Androgen deprivation therapy (ADT) was used in 7.2% of patients. Favorable-IR (FIR) patients were commonly treated with PB alone (91.8%). FIR patients who underwent PB alone had a 5-year BFD of 98.1%. UIR patients were commonly treated with external beam radiotherapy plus PB (61.2%). These patients had 5-year BFD of 91.1%. The 5-year BFD for UIR patients treated without ADT was 90.9%, whereas it was 95.0% among UIR patients treated with ADT (log-rank p = 0.83). CONCLUSIONS: FIR patients have excellent outcomes when treated with PB alone. External beam radiotherapy plus PB is a reasonable treatment approach for UIR patients. Future studies may elucidate which IR patients would benefit from treatment intensification.

Hypofractionated Prostate Radiation Therapy: Adoption and Dosimetric Adherence Through Clinical Pathways in an Integrated Oncology Network.

PURPOSE: Updates to consensus guidelines in October 2018 recommending moderately hypofractionated external beam radiotherapy (mHF-EBRT) in prostate cancer lagged several years after publication of evidence supporting its efficacy. In January 2018, we amended our prostate cancer clinical pathway (CP) to facilitate adoption of mHF-EBRT. Herein, we analyze patterns of care and changes in mHF-EBRT use after the CP modification. METHODS: Our prostate CP was amended in January 2018 to make mHF-EBRT the recommended treatment for patients with low- and intermediate-risk prostate cancer pursuing curative EBRT monotherapy. Normal-tissue dose constraints accompanied the CP modification to guide planning. Use of mHF-EBRT from 2015 to 2017 was compared with use in 2018 after the CP modification, using the Cochran-Armitage test for trend. Predictors of mHF-EBRT use and adherence to dose constraints were analyzed with binary logistic regression. RESULTS: In 560 patients treated with EBRT monotherapy, mHF-EBRT use increased from 3.7% in 2015-2017 to 85.6% in 2018 (P < .001), whereas conventionally fractionated EBRT (CF-EBRT) use decreased from 96.3% to 14.4% (P < .001). Consultation year of 2018 (odds ratio [OR], 214.6; 95% CI, 94.5 to 484.6; P < .001), treatment at an academic facility (OR, 4.5; 95% CI, 1.8 to 11.3; P = 0.001), and having a smaller prostate (OR, 0.99; 95% CI, 0.97 to 1.00; P = .028) predicted for mHF-EBRT use. At least five of six recommended bladder and rectal dose constraints were met in 89.4% of patients. CONCLUSION: Modification of our prostate cancer CP, in concert with institutional policies to monitor and audit CP compliance, facilitated rapid adoption of mHF-EBRT in our large, integrated cancer center with good adherence to dosimetric constraints.

Acute patient-reported bowel quality of life and rectal bleeding with the combination of prostate external beam radiation, low-dose-rate brachytherapy boost, and SpaceOAR.

PURPOSE: This study evaluates acute patient-reported bowel quality of life (QOL) and rectal bleeding in prostate cancer patients treated with combination external beam radiation (EBRT), low-dose-rate brachytherapy (LDR-BT), and SpaceOAR. MATERIALS AND METHODS: A retrospective review of prostate cancer patients treated with EBRT (45 Gy), cesium-131 LDR-BT (85 Gy), and SpaceOAR was conducted. Patient-reported acute (≤3 months after LDR-BT) bowel QOL and rectal bleeding was analyzed from Expanded Prostate Cancer Index Composite (EPIC) questionnaires. Five-point changes in mean bowel QOL scores were considered clinically significant. Clinically significant rectal bleeding was bleeding occurring more than "rarely" ("about half the time," "usually," or "always"), and clinically significant bleeding bother was considering bleeding a "small, moderate, or big problem." Outcomes were analyzed using descriptive statistics and paired t-tests. RESULTS: 69 patients were identified. Bowel summary, function, and bother scores clinically and significantly decreased 2 weeks after LDR-BT (79.9 ± 15.6, 80.5 ± 15.4, and 79.4 ± 18.1, respectively) compared with pre-EBRT scores (92.3 ± 9.1, 93.3 ± 9.0, and 92.6 ± 11.9, respectively) and pre-LDR-BT scores (91.1 ± 11.0, 91.6 ± 9.8, and 90.6 ± 13.3, respectively), but returned to clinical and statistical baseline pre-EBRT values at 3 months (88.7 ± 12.4, 88.8 ± 11.1, and 88.7 ± 14.5, respectively). The 3-month cumulative incidence of clinically significant rectal bleeding and bleeding bother was 4.35% and 2.90%, respectively. CONCLUSIONS: With combination EBRT, LDR-BT, and SpaceOAR, bowel QOL returned to the baseline 3 months after LDR-BT. Clinically significant rectal bleeding was <5%. Further followup will confirm if low acute rectal toxicity translates to reduced late toxicity.

Cesium-131 prostate brachytherapy: A single institutional long-term experience.

AIMS: To report on the PSA outcomes in men undergoing prostate seed implant (PSI) with Cesium-131 at a single institution. MATERIALS AND METHODS: All patients who underwent prostate brachytherapy with Cesium-131 (131Cs) at our institution and had the potential for at least 24 months of follow up were included in this study. Results are reported for the by NCCN risk group (low, low/high-intermediate, and high), as well as by treatment received (monotherapy, combination external beam radiation + PSI, or trimodal therapy with androgen deprivation). The Phoenix definition (absolute nadir plus 2 ng/mL) was used to define biochemical freedom from disease (BFD). RESULTS: Eight hundred and six men have undergone prostate brachytherapy with Cesium-131 at our institution, and 669 men were included in analysis. Median follow up was 60.0 months (range: 0-144 months). According to NCCN risk categories, 29.9% were low-, 55.6% intermediate-, and 14.5% high-risk. Using the Phoenix criteria, 5/10-year BFD was 97.1/95.3% for patients in the low-risk category, 94.0/90.1% for patients in the intermediate-risk category, and 86.2/56.6% for patients in the high-risk category. PSA ≤0.2 ng/dL at 4 years was predictive of 10 year biochemical control: 96.3% vs 70.4%, p < 0.001. CONCLUSIONS: The present study demonstrates that prostate brachytherapy with 131Cs achieves excellent long-term biochemical control.

Declining brachytherapy utilization for high-risk prostate cancer-Can clinical pathways reverse the trend?

PURPOSE: Although external beam radiation therapy (EBRT) plus a brachytherapy boost (BB) offers a 20% improvement in biochemical progression-free survival compared with dose-escalated EBRT alone for men with intermediate and high-risk prostate cancer, population studies show a concerning decline in BB utilization. METHODS: We modified our clinical pathway (CP) in January 2016 to indicate EBRT with BB as first-choice modality for high-risk prostate cancer, based on preliminary findings of Androgen Suppression Combined with Elective Nodal and Dose-Escalated Radiation Therapy. A retrospective review was performed on 659 patients with high-risk prostate cancer treated with definitive intent EBRT ± BB within a network of 19 sites between December 2011 and July 2017. χ2 test was used to determine changes in practice pattern before vs. after CP modification. RESULTS: Before CP modification, 25.2% of patients were planned for BB, compared with 45.4% afterward (p < 0.001). Among 23 nonbrachytherapist physicians, utilization of BB increased from 3.4% to 14.8% (p < 0.001) after CP modification. Among nine brachytherapists, utilization increased from 46.4% to 55.6% (p = 0.120). Among patients treated by a nonbrachytherapist who did not receive BB, the reason was physician preference in 59.7%, patient preference in 19.9%, and other in 20.4%. CONCLUSION: Based on recent evidence suggesting improved biochemical progression-free survival with use of BB for high-risk prostate cancer, we modified our CP, after which we observed increased use of a BB across a network, especially among physicians who do not perform brachytherapy. However, physician preference remains the most significant factor in the nonutilization of BB. New mechanisms are needed to overcome this barrier.

Species-specific escape of Plasmodium sporozoites from oocysts of avian, rodent, and human malarial parasites.

BACKGROUND: Malaria is transmitted when an infected mosquito delivers Plasmodium sporozoites into a vertebrate host. There are many species of Plasmodium and, in general, the infection is host-specific. For example, Plasmodium gallinaceum is an avian parasite, while Plasmodium berghei infects mice. These two parasites have been extensively used as experimental models of malaria transmission. Plasmodium falciparum and Plasmodium vivax are the most important agents of human malaria, a life-threatening disease of global importance. To complete their life cycle, Plasmodium parasites must traverse the mosquito midgut and form an oocyst that will divide continuously. Mature oocysts release thousands of sporozoites into the mosquito haemolymph that must reach the salivary gland to infect a new vertebrate host. The current understanding of the biology of oocyst formation and sporozoite release is mostly based on experimental infections with P. berghei, and the conclusions are generalized to other Plasmodium species that infect humans without further morphological analyses. RESULTS: Here, it is described the microanatomy of sporozoite escape from oocysts of four Plasmodium species: the two laboratory models, P. gallinaceum and P. berghei, and the two main species that cause malaria in humans, P. vivax and P. falciparum. It was found that sporozoites have species-specific mechanisms of escape from the oocyst. The two model species of Plasmodium had a common mechanism, in which the oocyst wall breaks down before sporozoites emerge. In contrast, P. vivax and P. falciparum sporozoites show a dynamic escape mechanism from the oocyst via polarized propulsion. CONCLUSIONS: This study demonstrated that Plasmodium species do not share a common mechanism of sporozoite escape, as previously thought, but show complex and species-specific mechanisms. In addition, the knowledge of this phenomenon in human Plasmodium can facilitate transmission-blocking studies and not those ones only based on the murine and avian models.

The Plasmodium bottleneck: malaria parasite losses in the mosquito vector.

Nearly one million people are killed every year by the malaria parasite Plasmodium. Although the disease-causing forms of the parasite exist only in the human blood, mosquitoes of the genus Anopheles are the obligate vector for transmission. Here, we review the parasite life cycle in the vector and highlight the human and mosquito contributions that limit malaria parasite development in the mosquito host. We address parasite killing in its mosquito host and bottlenecks in parasite numbers that might guide intervention strategies to prevent transmission.

The Plasmodium bottleneck: malaria parasite losses in the mosquito vector

Nearly one million people are killed every year by the malaria parasite Plasmodium. Although the disease-causing forms of the parasite exist only in the human blood, mosquitoes of the genus Anopheles are the obligate vector for transmission. Here, we review the parasite life cycle in the vector and highlight the human and mosquito contributions that limit malaria parasite development in the mosquito host. We address parasite killing in its mosquito host and bottlenecks in parasite numbers that might guide intervention strategies to prevent transmission.

Importance of animal/human health interface in potential Public Health Emergencies of International Concern in the Americas / Importancia de la interfaz entre la salud humana y la sanidad animal en las posibles emergencias de salud pública de importancia internacional en la Región de las Américas

This study analyzed the importance of zoonoses and communicable diseases common to man and animals as potential Public Health Emergencies of International Concern to build an evidence base for future efforts to reduce risk of infection at the animal/human health interface. The events recorded in the World Health Organization (WHO) Event Management System (EMS) database for the Americas during the 18 months since the implementation of the 2005 revised version of WHO's International Health Regulations (15 June 2007-31 December 2008) were the main source for this analysis. Of the 110 events recorded by the EMS for the Americas during the study period, 86 were classified as communicable diseases-77 (70.0 percent) "within the animal/human health interface," 9 (8.2 percent) "not common to man and animals," 16 (14.5 percent) "syndromes with unknown etiologies," and 8 (7.3 percent) "product-related/ other." Of the 77 events within the animal/human health interface, 48 were "substantiated" (the presence of hazard was confirmed and/or human cases occurred clearly in excess of normal expectancy). These results confirm previous research and underscore the importance of the animal/human health interface as well as inter-sectoral collaboration.

En este estudio se analizó la importancia de las zoonosis y las enfermedades transmisibles comunes a los seres humanos y los animales como posibles emergencias de salud pública de importancia internacional, a fin de sentar una base científica para las actividades futuras destinadas a reducir el riesgo de infección en la interfaz entre animales y seres humanos. La fuente principal para este análisis fueron los eventos registrados en la base de datos del Sistema de Gestión de Eventos de la Organización Mundial de la Salud (OMS) para las Américas durante los 18 meses que transcurrieron (15 de junio del 2007 al 31 de diciembre del 2008) desde la puesta en marcha del Reglamento Sanitario Internacional de la OMS (versión revisada en el 2005). De los 110 eventos registrados por el Sistema de Gestión de Eventos para las Américas durante el período de estudio, 86 se clasificaron como enfermedades transmisibles -77 (70,0 por ciento) como "dentro de la interfaz entre animales y seres humanos" y 9 (8,2 por ciento) como "no comunes a seres humanos y animales"-, 16 (14,5 por ciento) como "síndromes de etiología desconocida", y 8 (7,3 por ciento) como "relacionados con productos/otros". De los 77 eventos comprendidos dentro de la interfaz entre animales y seres humanos, se fundamentaron 48 (se confirmó la presencia del riesgo u ocurrieron casos en seres humanos que claramente superaron los casos esperados). Estos resultados confirman las investigaciones anteriores y destacan la importancia de la interfaz entre la salud humana y la sanidad animal, así como la importancia de la colaboración intersectorial.