Influence of localization of PSMA-positive oligo-metastases on efficacy of metastasis-directed external-beam radiotherapy-a multicenter retrospective study.

PURPOSE: Approximately 40-70% of biochemically persistent or recurrent prostate cancer (PCa) patients after radical prostatectomy (RPE) are oligo-metastatic in 68gallium-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET). Those lesions are frequently located outside the prostate bed, and therefore not cured by the current standards of care like external-beam radiotherapy (EBRT) of the prostatic fossa. This retrospective study analyzes the influence of oligo-metastases' site on outcome after metastasis-directed radiotherapy (MDR). METHODS: Retrospectively, 359 patients with PET-positive PCa recurrences after RPE were analyzed. Biochemical recurrence-free survival (BRFS) (prostate-specific antigen (PSA) < post-radiotherapy nadir + 0.2 ng/mL) was assessed using Kaplan-Meier survival and Cox regression analysis. RESULTS: All patients were initially clinically without distant metastases (cM0). Seventy-five patients had local recurrence within the prostatic fossa, 32 patients had pelvic nodal plus local recurrence, 117 patients had pelvic nodal recurrence, 51 patients had paraaortic lymph node metastases with/without locoregional recurrence, and 84 patients had bone or visceral metastases with/without locoregional recurrence. Median PSA before MDR was 1.2 ng/mL (range, 0.04-47.5). Additive androgen deprivation therapy (ADT) was given in 35% (125/359) of patients. Median PSA nadir after MDR was 0.23 ng/mL (range, < 0.03-18.30). After a median follow-up of 16 months (1-57), 239/351 (68%) patients had no biochemical recurrence. Patients with distant lymph node and/or distant metastases, the so-called oligo-body cohort, had an overall in-field control of 90/98 (91%) but at the same time, an ex-field progress of 44/96 (46%). In comparison, an ex-field progress was detected in 28/154 (18%) patients with local and/or pelvic nodal recurrence (oligo-pelvis group). Compared with the oligo-pelvis group, there was a significantly lower BRFS in oligo-body patients at the last follow-up. CONCLUSION: Overall, BRFS was dependent on patterns of metastatic disease. Thus, MDR of PSMA PET-positive oligo-metastases can be offered considering that about one-third of the patients progressed within a median follow-up of 16 months.

Complications of Ultrasound-Guided Renal Transplant Biopsies.

Renal transplant biopsies to diagnose transplant pathology are routinely performed using ultrasound guidance. Few large studies have assessed the rate and risk factors of major biopsy complications. This study is a single-center 5-year retrospective cohort analysis of 2514 biopsies. Major complications occurred in 47 of 2514 patients (1.9%) and included hospitalization, transfusion of blood products, operative exploration and interventional radiology procedures. The complication rate among "cause" biopsies was significantly higher than in "protocol" biopsies (2.7% vs. 0.33%, p < 0.001). Complications presented on postbiopsy days 0-14, with the majority diagnosed on the same day as the biopsy and manifested by hematocrit drop, although the presence of such delayed presentation of complications occurring >24 h after the biopsy on days 2-14 is previously unreported. Specific patient characteristics associated with increased risk of a complication were increased age and blood urea nitrogen, decreased platelet count, history of prior renal transplant, deceased donor transplant type and use of anticoagulant medications but not aspirin.

Volume-based quantitative FDG PET/CT metrics and their association with optimal debulking and progression-free survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery.

OBJECTIVE: Our aim was to evaluate the associations between quantitative (18)F-fluorodeoxyglucose positron-emission tomography (FDG-PET) uptake metrics, optimal debulking (OD) and progression-free survival (PFS) in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery. METHODS: Fifty-five patients with recurrent ovarian cancer underwent FDG-PET/CT within 90 days prior to surgery. Standardized uptake values (SUVmax), metabolically active tumour volumes (MTV), and total lesion glycolysis (TLG) were measured on PET. Exact logistic regression, Kaplan-Meier curves and the log-rank test were used to assess associations between imaging metrics, OD and PFS. RESULTS: MTV (p = 0.0025) and TLG (p = 0.0043) were associated with OD; however, there was no significant association between SUVmax and debulking status (p = 0.83). Patients with an MTV above 7.52 mL and/or a TLG above 35.94 g had significantly shorter PFS (p = 0.0191 for MTV and p = 0.0069 for TLG). SUVmax was not significantly related to PFS (p = 0.10). PFS estimates at 3.5 years after surgery were 0.42 for patients with an MTV ≤ 7.52 mL and 0.19 for patients with an MTV > 7.52 mL; 0.46 for patients with a TLG ≤ 35.94 g and 0.15 for patients with a TLG > 35.94 g. CONCLUSION: FDG-PET metrics that reflect metabolic tumour burden are associated with optimal secondary cytoreductive surgery and progression-free survival in patients with recurrent ovarian cancer. KEY POINTS: • Both TLG and MTV were associated with optimal tumour debulking. • There was no significant association between SUVmax and tumour debulking status. • Patients with higher MTV and/or TLG had significantly shorter PFS. • SUVmax was not significantly related to PFS.

Variability of average SUV from several hottest voxels is lower than that of SUVmax and SUVpeak.

OBJECTIVES: To assess variability of the average standard uptake value (SUV) computed by varying the number of hottest voxels within an (18)F-fluorodeoxyglucose ((18)F-FDG)-positive lesion. This SUV metric was compared with the maximal SUV (SUV(max): the hottest voxel) and peak SUV (SUV(peak): SUV(max) and its 26 neighbouring voxels). METHODS: Twelve lung cancer patients (20 lesions) were analysed using PET dynamic acquisition involving ten successive 2.5-min frames. In each frame and lesion, average SUV obtained from the N = 5, 10, 15, 20, 25 or 30 hottest voxels (SUV(max-N)), SUV(max) and SUV(peak) were assessed. The relative standard deviations (SDrs) from ten frames were calculated for each SUV metric and lesion, yielding the mean relative SD from 20 lesions for each SUV metric (SDr(N), SDr(max) and SDr(peak)), and hence relative measurement error and repeatability (MEr-R). RESULTS: For each N, SDr(N) was significantly lower than SDr(max) and SDr(peak). SDr(N) correlated strongly with N: 6.471 × N(-0.103) (r = 0.994; P < 0.01). MEr-R of SUV(max-30) was 8.94-12.63% (95% CL), versus 13.86-19.59% and 13.41-18.95% for SUV(max) and SUV(peak) respectively. CONCLUSIONS: Variability of SUV(max-N) is significantly lower than for SUV(max) and SUV(peak). Further prospective studies should be performed to determine the optimal total hottest volume, as voxel volume may depend on the PET system. KEY POINTS: • PET imaging provides functional parameters of (18) F-FDG-positive lesions, such as SUVmax and SUVpeak. • Averaging SUV from several hottest voxels (SUVmax-N) is a further SUV metric. • Variability of SUVmax-N is significantly lower than SUVmax and SUVpeak variability. • SUVmax-N should improve SUV accuracy for predicting outcome or assessing treatment response. • An optimal total hottest volume should be determined through further prospective studies.

Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial.

BACKGROUND: Thymic malignancies are rare intrathoracic tumors, which may be aggressive and difficult to treat. They represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of first-line platinum-based chemotherapy. They are frequently associated with autoimmune disorders that also impact oncological management. MATERIALS AND METHODS: NIVOTHYM is an international, multicenter, phase II, two-cohort, single-arm trial evaluating the activity and safety of nivolumab [240 mg intravenously (i.v.) q2 weeks] alone or with ipilimumab (1 mg /kg i.v. q6 weeks) in patients with advanced/relapsed type B3 thymoma or thymic carcinoma, after exposure to platinum-based chemotherapy. The primary endpoint is progression-free survival rate at 6 months (PFSR-6) based on RECIST 1.1 as per independent radiological review. RESULTS: From April 2018 to February 2020, 55 patients were enrolled in 15 centers from 5 countries. Ten patients (18%) had type B3 thymoma and 43 (78%) had thymic carcinoma. The majority were male (64%), and the median age was 58 years. Among the 49 eligible patients who started treatment, PFSR-6 by central review was 35% [95% confidence interval (CI) 22% to 50%]. The overall response rate and disease control rate were 12% (95% CI 5% to 25%) and 63% (95% CI 48% to 77%), respectively. Using the Kaplan-Meier method, median progression-free survival and overall survival by local assessment were 6.0 (95% CI 3.1-10.4) months and 21.3 (95% CI 11.6-not estimable) months, respectively. In the safety population of 54 patients, adverse events (AEs) of grade 1/2 were observed in 22 (41%) patients and grade 3/4 in 31 (57%) patients. Treatment-related AEs of grade 4 included one case of neutropenia, one case of immune-mediated transaminitis, and two cases of myocarditis. CONCLUSIONS: Nivolumab monotherapy demonstrated an acceptable safety profile and objective activity, although it has been insufficient to meet its primary objective. The second cohort of NIVOTHYM is currently ongoing to assess the combination of nivolumab plus ipilimumab.

Predictors of survival after haemorrhagic stroke in a multi-ethnic population: the South London Stroke Register (SLSR).

OBJECTIVES: To identify the predictors of long-term survival after haemorrhagic stroke. METHODS: Data were collected within the population-based South London Stroke Register covering a multiethnic source population of 271,817 inhabitants (2001) in South London. Death data were collected at post-stroke follow-up. The impact of patients' demographic and clinical characteristics, ethnic origin, pre-stroke risk factors and acute treatment on long-term survival were investigated. Survival methods included Kaplan-Meier curves and Cox's proportional hazards model. RESULTS: Between January 1995 and December 2004, a total of 566 patients with first-ever haemorrhagic stroke (395 primary intracerebral haemorrhage; 171 subarachnoid haemorrhage) were registered. Mean age was 62.3 years; 365 (64.5%) were white, 132 (23.3%) were black and 69 (12.2%) were other or unknown ethnic origin; there were 1340 person-years of follow-up. After multivariable adjustment, age (p<0.001) and having diabetes (hazard ratio (HR), 1.69; 95% CI 1.06-2.70) were associated with increased risk of death. Patients with severe stroke (Glasgow Coma Scale (GCS) <9) had an increased risk of death (HR 6.5; 95% CI 4.68 to 8.90) compared with those with mild stroke (GCS >12). Treatment on a stroke unit reduced the long-term risk of death (HR 0.70; 95% CI 0.50 to 0.98). Black patients had a reduced risk of death (HR 0.62; 95% CI 0.42 to 0.92) compared with white patients. CONCLUSIONS: Age, diabetes, stroke severity and stroke unit care influenced the long-term risk of death after haemorrhagic stroke. An independent survival advantage was observed in black patients. These factors can be utilised for clinical predictions but the cause of the observations in black patients remains unclear.

Bilateral segmental agenesis of the vertebrobasilar junction: developmental and angiographic anatomy.

BACKGROUND AND PURPOSE: Bilateral vertebrobasilar junction agenesis is an exceptional anatomic variation. This article explores the angiographic characteristics of this variant and its embryologic mechanisms. MATERIALS AND METHODS: Two observations of bilateral agenesis of the vertebrobasilar junction are reported. A case of atheromatous disease of the vertebrobasilar junction is shown to highlight characteristics distinguishing such a lesion from the reported variant. RESULTS: In the 2 reported cases, the distal segment of both vertebral arteries (VAs) and the proximal portion of the basilar artery (BA) were absent. In addition, distal connections of the BA with the posterior cerebral arteries (PCA) were also lacking. As a consequence, the remaining portion of the BA was isolated from its usual sources of blood supply, which was provided by a persistent carotid-basilar anastomosis. CONCLUSION: The developmental mechanism underlying bilateral agenesis of the vertebrobasilar junction likely involves the anterior radicular artery of C1. This branch of the proatlantal artery normally becomes the adult distal VA and the proximal BA. The lack of cranial connection of the BA with the PCA may be secondary to the proximal vertebrobasilar agenesis and the resulting paucity of antegrade flow within the BA. Alternatively, the absence of both the proximal and distal connections of the BA could be the result of a similar, yet unknown, developmental mechanism. From a clinical standpoint, this vascular anomaly was discovered incidentally in our 2 patients, a finding consistent with the assumed congenital nature of the variant.

Developmental anatomy of the distal vertebral artery in relationship to variants of the posterior and lateral spinal arterial systems.

BACKGROUND AND PURPOSE: A certain number of anatomic variants involving the distal vertebral artery (VA) are explained by variations in size and connection of the lateral spinal artery (LSA). This study examined the possible role of another branch of the VA, the posterior spinal artery (PSA), in the development of similar vascular variations. MATERIALS AND METHODS: Four types of variations in the distal VA, including the C1 and C2 origins of the posterior inferior cerebellar artery (PICA), the duplication of the distal VA, and the aberrant course of the distal VA, are illustrated by 9 angiographic observations. RESULTS: For each type of VA variant listed above, examples resulting from variations in size and connection of the LSA and PSA could be matched. CONCLUSION: Variation in size and connection of the PSA is at the origin of a set of anatomic variations of the distal VA similar, but not identical, to the vascular variants linked to the LSA.

Confirmation of communication between deep venous drainage and the vein of galen after treatment of a vein of Galen aneurysmal malformation in an infant presenting with severe pulmonary hypertension.

Vein of Galen aneurysmal malformations (VGAM) are characterized by multiple arteriovenous connections draining into a markedly enlarged median draining vein. This ectatic vein is not the vein of Galen, but its embryonic precursor, the median prosencephalic vein of Markowski. During normal development, the posterior portion of the median prosencephalic vein persists as the vein of Galen, while its anterior portion regresses in parallel with the formation of the internal cerebral veins (ICV). It has been traditionally thought that, in children with a VGAM, the deep venous system does not connect to and, a fortiori, does not drain into the ectatic median prosencephalic vein/vein of Galen. This report describes a case of successfully treated VGAM in which the drainage of an ICV into the vein of Galen was only demonstrated by follow-up MR imaging and venography. The potential implications of this finding for the management of VGAMs are discussed.

Limitations of informed consent for in utero gene transfer research: implications for investigators and institutional review boards.

Only 10 years after the first human gene transfer protocols were approved for adults and children, researchers have begun to consider gene transfer on the fetus. While preliminary animal research is ongoing, the enthusiasm and pace of research in this area suggest that human protocols for in utero gene transfer research may be seriously considered in the foreseeable future. Federal guidelines for fetal research rely on minimizing risk and informed consent to protect the "rights and welfare" of both the fetus and pregnant woman. However, in utero gene transfer research poses special challenges to informed consent. This research represents an innovative approach for very ill subjects and takes place in the prenatal setting. These features may converge to undermine the expectant parents' comprehension of, and voluntariness for participation in, research. In this case, informed consent may not be able to bear the weight of adequately protecting the fetus from undue research risks. To compensate for this limitation, and using the regulations for pediatric research as a guide, a greater emphasis should be placed on the benefit/harm assessment rather than informed consent. Selecting diseases/patients where good alternative treatments exist may maximize informed consent, yet this may be a trade-off that exposes the fetus to greater relative risks. On the other hand, selecting diseases/patients without good alternative treatments to prolong life may convey an overestimation of the potential benefits of these interventions, and although care should be taken to strive to improve understanding of these limitations, misunderstanding may persist. However, selecting diseases/patients with no good alternatives might make serious risks more tolerable, and this should take precedence over informed consent. The limitations of informed consent brought into focus by the special features of in utero gene transfer research may be relevant to a broader range of innovative investigations.

A mono phenylalanine-based motif (F790) and a leucine-dependent motif (LI760) mediate internalization of furin.

The eukaryotic endoprotease furin, a member of the subtilisin-related family of prohormone convertases, is synthesized and transported within the constitutive secretory pathway to the plasma membrane, from where it recycles to the trans-Golgi network (TGN). Previous studies showed that TGN-residence and recycling are mediated by the cytoplasmic tail. Two targeting determinants have been described so far, the acidic signal CPSDSEEDEG783 containing two casein kinase II (CKII) phosphorylation sites and the internalization signal YKGL765. Refined analyses of the cytoplasmic domain of furin, which was mutagenized and tagged to the influenza hemagglutinin and to the membrane cofactor protein (CD46) as reporter molecules reveal two additional internalization determinants, a leucine-isoleucine signal, LI760, and a mono phenylalanine-based motif at F790, which functions without any specific neighboring amino acid sequence. Both signals are capable of independently mediating internalization, as has been shown previously for the tyrosine-based signal. Thus, furin internalization is mediated by at least three independent endocytosis signals.

Urban cause-specific socioeconomic mortality differences. Which causes of death contribute most?

BACKGROUND: Cause-specific information on socioeconomic differences in health is necessary for a rational public health policy. At the local level, the Municipal Health Service studies these differences in order to support the authorities in policy making. METHODS: Mortality data of the under 65 age group in The Hague were analysed (1982-1991) at residential area level. RESULTS: Causes of death with a high socioeconomic gradient among males were: homicide, chronic liver disease, 'other' external causes of injury, diabetes, bronchitis, emphysema and asthma, and motor vehicle accidents; and among females: diabetes, ischaemic heart disease, 'other' diseases of the circulatory system, signs, symptoms and ill-defined conditions, malignant neoplasm of cervix, and 'other' diseases. Main contributors to the mortality differences between the highest and lowest socioeconomic quartiles among males were: ischaemic heart disease (17.3%), 'other' diseases of the circulatory system (10.2%), signs, symptoms and ill-defined conditions (9.0%), 'other' external causes of injury (8.6%), and chronic liver disease (7.2%); and among females: ischaemic heart disease (25.5%), 'other' diseases (20.1%), signs, symptoms and ill-defined conditions (18.6%), 'other' diseases of the circulatory system (11.0%), and diabetes (9.1%). Among females the contributions of malignant neoplasms of breast (-16.3%) and colon (-5.5%) and suicide (-4.3%) were negative. CONCLUSIONS: The diseases that are the main contributors to urban socioeconomic mortality differences can be influenced by public health policy.

Detection of tick-borne encephalitis virus by sample transfer, plaque assay and strand-specific reverse transcriptase polymerase chain reaction: what do we detect?

Experimental inoculation of mice provides a well characterized model for studying infection with tick-borne encephalitis virus (TBEV), a flavivirus pathogenic for humans. Conflicting data on the kinetics of viremia and the development of virus titers in the brain, however, were only recently shown to have resulted from the use of assay systems with different levels of sensitivity in the titration of TBEV, i.e. plaque assay or sample transfer into naive recipient mice. Theoretically, RT-PCR could extend further the detectability to antibody-neutralized virus and when undertaken strand-specifically discriminate active replication from the mere presence of TBEV. We have compared the conventional methods for detection of TBEV with a newly devised RT-PCR method. As expected, RT-PCR, in contrast to the infectivity assays, detected antibody-neutralized virus. Furthermore, the mere presence or active replication of the virus could be differentiated by strand-specific RT-PCR. Plaque assay and sample transfer, in contrast, both detected only infectious virus. However, whereas sample transfer provides higher sensitivity for detection of TBEV from solid organs, the plaque assay is less costly and considering animals welfare more convenient. Thus, the newly devised method may allow the resolution of unanswered questions, while both the traditional infectivity assays retain their benefits in certain situations.

Triterpenoid saponins from Becium grandiflorum var. obovatum.

Two new triterpenoid saponins, beciumecine 1 and 2, were isolated from the root bark of Becium grandiflorum var. obovatum and their structures established as 3-O-(beta-D-glucopyranosyl) terminolic acid 28-O-beta-D-apiofuranosyl(1-3)-[alpha-L-rhamnopyranosyl (1-3)-beta-D-xylopyranosyl(1-4)]-alpha-L-rhamnopyranosyl (1-2)-alpha-L-arabinopyranoside and 3-O-(beta-D-glucopyranosyl) 24-hydroxyterminolic acid 28-O-alpha-L-rhamnopyranosyl(1-3)-beta-D-xylopyranosyl(1-4)-alpha-L- rhamnopyranosyl(1-2)-alpha-L-arabinopyranoside, respectively.