Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

Robot-assisted retroperitoneal lymph node dissection (RA-RPLND) in the adolescent population.

BACKGROUND: Robot-assisted retroperitoneal lymph node dissection (RA-RPLND) has built on success and techniques of laparoscopic RPLND, with the added benefits of robotic technology. This paper demonstrates use of the da Vinci Xi® system for RA-RPLND in two adolescent patients. METHODS: Case #1: A 17-year-old male presented with a left testicular mass and elevated alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG). Pathology revealed a mixed non-seminomatous germ cell tumor (60% embryonal, 35% yolk sac, 5% choriocarcinoma, + lymphovascular invasion). Tumor marker normalized post-orchiectomy, and staging imaging was without evidence of metastatic disease. After discussion of options he opted to undergo RA-RPLND. Case #2: A 15-year-old male presented with a right para-testicular mass and negative tumor markers. He underwent inguinal exploration and excision of the paratesticular mass. Final pathology revealed an ectomesenchymoma with a spindle cell rhabdomyosarcoma component. Staging imaging was negative, and after discussion of options he underwent completion orchiectomy and RA-RPLND. RESULTS: The patient in Case #1 underwent a left modified-template nerve-sparing RA-RPLND. Sixteen lymph nodes were negative for tumor. The patient in Case #2 underwent complete bilateral nerve-sparing RA-RPLND. Forty-two lymph nodes were negative for tumor. Estimated blood loss was <50 cc for both cases, and console time averaged 262 min. CONCLUSION: This was a report of two cases of RA-RPLND in the adolescent population. RA-RPLND is technically feasible in this population, and further study of RA-RPLND is needed to determine long-term outcomes, as this technique is becoming more widely adopted.

Número de ganglios linfáticos metastásicos como determinante de los resultados de la prostatectomía radical de rescate en el cáncer de próstata de recidivante tras radioterapia / Number of metastatic lymph nodes as determinant of outcome after salvage radical prostatectomy for radiation-recurrent prostate cancer

Antecedentes: La presencia de metástasis en los ganglios linfáticos (MGL) en la prostatectomía radical de rescate (PRs) se asocia con un mal pronóstico. Los factores predictivos de resultados en este contexto siguen siendo indeterminados. El objetivo fue evaluar el papel del número de ganglios linfáticos positivos sobre el resultado de los pacientes con MGL después de PRs y para el cáncer de próstata de radiorrecurrente. Material y métodos: Se analizaron los datos de una cohorte consecutiva de 215 hombres tratados con PRr en una sola institución. Se utilizaron los modelos de regresión de riesgos proporcionales de Cox univariante para la recurrencia bioquímica (RBQ) y los resultados metastásicos, con el antígeno prostático específico, la puntuación de Gleason, la extensión extraprostática, la invasión de vesículas seminales, el tiempo entre la terapia de radiación y PRr y el número de ganglios positivos como factores predictivos. Resultados: De los 47 pacientes con MGL, 37 desarrollaron RBQ, 11 desarrollaron metástasis a distancia y 4 fallecieron, con una mediana de seguimiento de 2,3 años para los supervivientes. El riesgo de metástasis aumentó con mayores niveles preoperatorios de PSA (HR 1,19 por 1ng/ml; IC 95%: 1,06-1,34; p=0,003). Los factores predictivos restantes no alcanzaron niveles convencionales de significación. Sin embargo, la eliminación de 3 o más ganglios linfáticos positivos demostró una asociación positiva, como se esperaba, con enfermedad metastásica (HR 3,44; IC 95%: 0,91-13,05; p = 0,069) en comparación con uno o 2 ganglios positivos. Del mismo modo, la presencia de extensión extraprostática, invasión de vesículas seminales y grado de Gleason superior a 7 también demostraron una asociación positiva con un mayor riesgo de metástasis, con índices de riesgo de 3,97 (IC 95%: 0,50-31,4; p = 0,2); 3,72 (IC 95%: 0,80-17,26; p = 0,1) y 1,45 (IC 95%: 0,44-4,76; p = 0,5), respectivamente. Conclusiones: En los pacientes con MGL después de PRr para el cáncer de próstata radiorrecurrente, es probable que el riesgo de metástasis a distancia esté influido por el número de ganglios positivos (≥ 3), alto PSA preoperatorio, grado de Gleason y estadio patológico avanzado. Estos resultados son consistentes con los hallazgos del número de ganglios (de 1 a 2 frente a 3 o más ganglios positivos) como un indicador pronóstico después de la prostatectomía radical primaria y fortalecen la petición de una revisión de la estadificación ganglionar del cáncer de próstata

Background: Presence of lymph node metástasis (LNM) at salvage radical prostatectomy (sRP) is associated with poor outcome. Predictors of outcome in this context remain undetermined. ThE objective was to assess the role of number of positive lymph node on outcome of patients with LNM after sRP and for radio-recurrent prostate cancer. Material and methods: We analyzed data from a consecutive cohort of 215 men treated with sRP at a single institution. We used univariate Cox proportional hazard regression models for biochemical recurrence (BCR) and metastatic outcomes, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, time between radiation therapy and sRP, and number of positive nodes as predictors. Results: Of the 47 patients with LNM, 37 developed BCR, 11 developed distant metastasis and 4 died with a median follow-up of 2.3 years for survivors. The risk of metastases increased with higher pre-operative PSA levels (HR 1.19 per 1ng/ml; 95% CI: 1.06-1.34; P = .003). The remaining predictors did not reach conventional levels of significance. However, removal of 3 or more positive lymph nodes demonstrated a positive association, as expected, with metastatic disease (HR 3.44; 95% CI: 0.91-13.05; P = .069) compared to one or 2 positive nodes. Similarly, the presence of extraprostatic extension, seminal vesicle invasion and Gleason grade greater than 7 also demonstrated a positive association with higher risk of metástasis, with hazard ratios of 3.97 (95% CI: 0.50, 31.4; P = .2), 3.72 (95% CI: 0.80-17.26;P = .1), and 1.45 (95% CI: 0.44-4.76; P = .5), respectively. Conclusions: In patients with LNM after sRP for radio-recurrent prostate cancer, the risk of distant metástasis is likely to be influenced by the number of positive nodes (3 or more), high preoperative PSA, Gleason grade and advanced pathologic stage. These results are consistent with the findings of number of nodes (1 to 2 vs. 3 or more nodes positive) as a prognostic indicator after primary radical prostatectomy and strengthen the plea for a revision of the nodal staging for prostate cancer

Number of metastatic lymph nodes as determinant of outcome after salvage radical prostatectomy for radiation-recurrent prostate cancer. / Número de ganglios linfáticos metastásicos como determinante de los resultados de la prostatectomía radical de rescate en el cáncer de próstata de recidivante tras radioterapia.

BACKGROUND: Presence of lymph node metástasis (LNM) at salvage radical prostatectomy (sRP) is associated with poor outcome. Predictors of outcome in this context remain undetermined. ThE objective was to assess the role of number of positive lymph node on outcome of patients with LNM after sRP and for radio-recurrent prostate cancer. MATERIAL AND METHODS: We analyzed data from a consecutive cohort of 215 men treated with sRP at a single institution. We used univariate Cox proportional hazard regression models for biochemical recurrence (BCR) and metastatic outcomes, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, time between radiation therapy and sRP, and number of positive nodes as predictors. RESULTS: Of the 47 patients with LNM, 37 developed BCR, 11 developed distant metastasis and 4 died with a median follow-up of 2.3 years for survivors. The risk of metastases increased with higher pre-operative PSA levels (HR 1.19 per 1ng/ml; 95% CI: 1.06-1.34; P=.003). The remaining predictors did not reach conventional levels of significance. However, removal of 3 or more positive lymph nodes demonstrated a positive association, as expected, with metastatic disease (HR 3.44; 95% CI: 0.91-13.05; P=.069) compared to one or 2 positive nodes. Similarly, the presence of extraprostatic extension, seminal vesicle invasion and Gleason grade greater than 7 also demonstrated a positive association with higher risk of metástasis, with hazard ratios of 3.97 (95% CI: 0.50, 31.4; P=.2), 3.72 (95% CI: 0.80-17.26; P=.1), and 1.45 (95% CI: 0.44-4.76; P=.5), respectively. CONCLUSIONS: In patients with LNM after sRP for radio-recurrent prostate cancer, the risk of distant metástasis is likely to be influenced by the number of positive nodes (3 or more), high preoperative PSA, Gleason grade and advanced pathologic stage. These results are consistent with the findings of number of nodes (1 to 2 vs. 3 or more nodes positive) as a prognostic indicator after primary radical prostatectomy and strengthen the plea for a revision of the nodal staging for prostate cancer.

The ZntA-like NpunR4017 plays a key role in maintaining homeostatic levels of zinc in Nostoc punctiforme.

Analysis of cellular response to zinc exposure provides insights into how organisms maintain homeostatic levels of zinc that are essential, while avoiding potentially toxic cytosolic levels. Using the cyanobacterium Nostoc punctiforme as a model, qRT-PCR analyses established a profile of the changes in relative mRNA levels of the ZntA-like zinc efflux transporter NpunR4017 in response to extracellular zinc. In cells treated with 18 µM of zinc for 1 h, NpunR4017 mRNA levels increased by up to 1300 % above basal levels. The accumulation and retention of radiolabelled (65)Zn by NpunR4107-deficient and overexpressing strains were compared to wild-type levels. Disruption of NpunR4017 resulted in a significant increase in zinc accumulation up to 24 % greater than the wild type, while cells overexpressing NpunR4107 accumulated 22 % less than the wild type. Accumulation of (65)Zn in ZntA(-) Escherichia coli overexpressing NpunR4017 was reduced by up to 21 %, indicating the capacity for NpunR4017 to compensate for the loss of ZntA. These findings establish the newly identified NpunR4017 as a zinc efflux transporter and a key transporter for maintaining zinc homeostasis in N. punctiforme.

Investigating the subjective reports of rejection processes in the word frequency mirror effect.

We sought to systematically investigate how participants subjectively classify the basis of their recognition memory judgments for low and high word frequency items. We found that participants more often reported rejection processes related to the increased perceived memorability for unstudied low word frequency items (relative to high word frequency items), rather than classifying their decision on a lack of familiarity. Experiment 2 replicated this pattern and demonstrated context variability and word frequency independently influenced the subjective classifications for correct rejections. Results of Experiment 3 revealed that these differences are dependent upon having experience with both low and high frequency items. Overall, these data suggest participants' rejection of low frequency items is more strongly related to judgments of perceived memorability, but only when they are presented in the context of high frequency items. The results are discussed in relation to distinctiveness and expected memorability.

On the role of imagery in event-based prospective memory.

The role of imagery in encoding event-based prospective memories has yet to be fully clarified. Herein, it is argued that imagery augments a cue-to-context association that supports event-based prospective memory performance. By this account, imagery encoding not only improves prospective memory performance but also reduces interference to intention-related information that occurs outside of context. In the current study, when lure words occurred outside of the appropriate responding context, the use of imagery encoding strategies resulted in less interference when compared with a standard event-based intention condition. This difference was eliminated when participants were not given a specific context to associate their intention (i.e., lures occurred within the appropriate responding context). These results support a cue-to-context association account of how imagery operates in certain event-based prospective memory tasks.

An observation on the spontaneous noticing of prospective memory event-based cues.

In event-based prospective memory, current theories make differing predictions as to whether intention-related material can be spontaneously noticed (i.e., noticed without relying on preparatory attentional processes). In 2 experiments, participants formed an intention that was contextually associated to the final phase of the experiment, and lures that overlapped to differing degrees with the features of the intention-related cues were embedded in the initial phase. When participants were outside of the appropriate responding context (i.e., the initial phase), they exhibited slower latencies to lures that exactly matched the features of their intention compared with other types of lures and control words. In addition, on a final remember/know recognition test, participants reported having greater subjective recollection for the occurrence of the exact-match lures. These results suggest that exact-match lures were spontaneously noticed and differentially processed in the absence of any observable preparatory attentional processes. The findings have implications for the theoretical debate over whether preparatory attention must always be relied upon to notice intention-related material.

The reactivation of associated information affects source monitoring.

In this study, we examined a source-monitoring phenomenon that arises from reactivated related information from the study phase. Three experiments showed that source attributions for target events were influenced not only by the target item itself, but also by studied information about related items. In Experiment 1, source memory for target items that have a high forward association value to a single related study item (e.g., credit) were affected by the source of the associated information (e.g., card), so that memory performance was better when associated items were presented in the same source rather than a different source. A similar effect occurred with bidirectional associates (Exp. 2), as well as with synonymous pairs of words (Exp. 3). We argue that the source information of the reactivated material can be commingled with information about a candidate during a source judgment at retrieval and thereby can affect performance.

Implementation intentions about nonfocal event-based prospective memory tasks.

Implementation intentions are detailed and systematic plans that are developed during intention formation. We compared two different implementation intentions to standard event-based prospective memory instructions using three different kinds of intentions. Two of these intentions involved nonfocal cues whereas the remaining intention was about specific, focal cues. Implementation intentions dramatically increased detection performance for the nonfocal intentions. Because the exact cues could not be specified during intention formation, we argue that cue salience and that strengthening the cue to target action association are not very viable mechanisms to explain all instances of the beneficial consequences of forming implementation intentions.

Robotics in urologic surgery.

Robotic surgery is becoming rapidly integrated in urology. Nearly every open or laparoscopic procedure has been described with robotic assistance. While the da Vinci robot is recently applied to the upper urinary tract, it has become widely adopted for performing radical prostatectomy. Benefits of robotics include 3-D vision, blood-less field from pneumoperitoneum, and ease of intracorporeal suturing. Disadvantages include cost, lack of haptic feedback, surgical learning curve and longer operative times. Here, the authors describe the state of the art applications and outcomes of robotics in urologic surgery.

The valence of event-based prospective memory cues or the context in which they occur affects their detection.

Event-based prospective memory tasks entail detecting cues or reminders in our environment related to previously established intentions. If they are detected at an opportune time, then the intention can be fulfilled. In Experiments 1a-1c, we gave people 3 different nonfocal intentions (e.g., respond to words denoting animals) and discovered that negatively valenced cues delivered the intention to mind less frequently than positively valenced cues. In Experiment 2, this effect was extended to valenced and neutral sentential contexts with convergent results that cues embedded in negatively valenced sentences evoked remembering the intention less often than in positive contexts. In addition, both classes of valence caused the intention to be forgotten more often than a more neutral context. We propose that valence has the ability to usurp attentional resources that otherwise would have supported successful prospective memory performance.

Memory for intention-related material presented in a to-be-ignored channel.

Three experiments were conducted to investigate the fate of intention-related material processed in a to-be-ignored channel. Participants were given an intention to respond to cues in a visual-processing stream while simultaneously trying to ignore information being presented in an auditory stream. Subsequent to the ongoing activity, a surprise recognition test for information presented in the to-be-ignored auditory modality was administered. As compared with comparable neutral information, corrected recognition memory for intention-related material was significantly better, depending on the type of event-based prospective memory task. These results suggest that holding certain kinds of intentions can bias attentional processes in a manner consistent with a perceptual readiness for uptake of intention-related material.

Learning is impaired by activated intentions.

Two experiments examined the task interference that sometimes accrues from having an intention. In standard prospective memory tasks, latency is often slower to an ongoing task performed concurrently with having an intention than it is when no intention is given. If the locus of this slowing resulted from different attentional allocation policies in the two cases, we predicted that the process of learning a word list would be impaired if participants had an intention rather than if they did not. Four different event-based prospective memory tasks were used in Experiment 1 to demonstrate that worse free recall of a word list resulted when studied with a concurrent intention than with a control condition that had no intention. In that experiment, linking an intention to a distal context that was to occur after learning did not impair free recall. Two time-based tasks were used in Experiment 2 to demonstrate that possessing a time-based prospective memory also hinders learning, unless the intention is linked to a future context that is expected to occur after the study session. In the latter case, no impairment was obtained.

Molecular genetics and genomic analysis of scytonemin biosynthesis in Nostoc punctiforme ATCC 29133.

The indole-alkaloid scytonemin is the most common and widespread sunscreen among cyanobacteria. Previous research has focused on its nature, distribution, ecology, physiology, and biochemistry, but its molecular genetics have not been explored. In this study, a scytonemin-deficient mutant of the cyanobacterium Nostoc punctiforme ATCC 29133 was obtained by random transposon insertion into open reading frame NpR1273. The absence of scytonemin under conditions of induction by UV irradiation was the single phenotypic difference detected in a comparative analysis of the wild type and the mutant. A cause-effect relationship between the phenotype and the mutation in NpR1273 was demonstrated by constructing a second scytoneminless mutant through directed mutagenesis of that gene. The genomic region flanking the mutation revealed an 18-gene cluster (NpR1276 to NpR1259). Four putative genes in the cluster, NpR1274 to NpR1271, with no previously known functions, are likely to be involved in the assembly of scytonemin. Also in this cluster, there is a redundant set of genes coding for shikimic acid and aromatic amino acid biosynthesis enzymes, leading to the production of tryptophan and tyrosine, which are likely to be biosynthetic precursors of the sunscreen.

Metacognitive awareness of event-based prospective memory.

This study examined people's ability to predict and postdict their performance on an event-based prospective memory task. Using nonfocal cues, one group of participants predicted their success at finding animal words and a different group predicted their ability to find words with a particular syllable in it. The authors also administered a self-report questionnaire on everyday prospective and retrospective memory failures. Based on the different strategies adopted by the two groups and correlations among the dependent variables, the authors concluded that people do have a basic awareness of their prospective memory abilities, but that this awareness is far from accurate. The importance of metamemory concerning one's prospective memory is discussed in terms of how it influences the strategies that people might choose for actually completing their various everyday intentions.

Concreteness and item-to-list context associations in the free recall of items differing in context variability.

Context variability can be defined as the number of preexperimental contexts in which a given concept appears. Following M. Steyvers and K. J. Malmberg's (2003) work, the authors have shown that concepts that are experienced in fewer preexperimental contexts generally are better remembered in episodic memory tasks than concepts that are experienced in a greater number of preexperimental contexts. The purpose of this article is to demonstrate that low context variability confers its memorial advantage because of stronger item-to-list context associations as compared with high context variability. Three experiments that use environmental context changes from study to test demonstrate that the low context variability advantage is eliminated when item-to-list context associations are not available because of environmental changes at test. In addition, the low context variability advantage is eliminated when inward processing at study prevents the formation of item-to-list context associations.

Phenotypic spectrum of mutations in DAX-1 and SF-1.

SF-1 (steroidogenic factor-1) (NR5A1) and DAX-1 (dosage-sensitive sex-reversal, adrenal hypoplasia congenital, X chromosome) (NR0B1) are orphan nuclear receptors that are expressed in the adrenal gland, gonads, ventromedial hypothalamus (VMH), and pituitary gonadotrope cells. The function of these genes has been clarified by examining the consequences of naturally occurring mutations in humans, as well as targeted disruption of the genes in mice. Mutations in DAX1 cause adrenal hypoplasia congenita (AHC), an X-linked disorder characterized by adrenal insufficiency and failure to undergo puberty because of hypogonadotropic hypogonadism. Most DAX1 mutations introduce frameshifts and/or cause premature termination of the protein. Relatively few missense mutations have been described and all are located within the carboxy-terminal half of the protein. Transfection assays demonstrate that AHC-associated DAX1 mutations abrogate its ability to act as a transcriptional repressor of SF-1. Most boys affected with AHC present with adrenal insufficiency in early infancy, although a significant fraction present in later childhood or even as young adults. The degree of gonadotropin deficiency is also variable. With the exception of one mild missense DAX1 mutation, genotype-phenotype correlations have been elusive, suggesting an important role for modifier genes. Targeted mutagenesis of Dax1 (Ahch) in mice reveals an additional role in testis development and spermatogenesis. Similar abnormalities appear to be present in humans. Targeted mutagenesis of Sf1 (FtzF1) prevents gonadal and adrenal development, and causes male-to-female sex-reversal. A human XY individual with a heterozygous SF1 mutation presented with adrenal insufficiency and complete sex-reversal; this DNA-binding domain mutation prevents SF-1 stimulation of its target genes. In addition to their clinical relevance, studies of SF1 and DAX1 are proving useful for unraveling the genetic pathways that govern adrenal and gonadal development.

Blockage of the rete testis and efferent ductules by ectopic Sertoli and Leydig cells causes infertility in Dax1-deficient male mice.

DAX-1, an X-linked member of the orphan nuclear receptor superfamily of transcription factors, plays a key role in sex determination and gonadal differentiation. Dax1-deficient male mice are infertile and have small testes despite normal serum levels of T and gonadotropins. Examination of Dax1-deficient testes reveals dilated seminiferous tubules and abnormal parameters of sperm fertilizing capability consistent with a possible obstruction in the testis. To test this hypothesis, we performed a comprehensive evaluation of the male reproductive tract in Dax1-deficient mice. Light and electron microscopic examination revealed the rete testis is blocked by aberrantly located Sertoli cells, creating a tailback of necrosing sperm in the testis. Sertoli cells also obstruct the proximal and middle efferent ductules, and this is accompanied by an overgrowth of the efferent duct epithelium. Seminiferous tubules close to the rete testis contain ectopic Leydig cells, distinct from the hyperplastic Leydig cells present in the interstitial space. The peritubular tissue surrounding these tubules is frequently abnormal, containing relatively undifferentiated myoid cells and no basement membrane between the myoid cells and Sertoli cells. A third of aged (>1-yr-old) Dax1-deficient male mice develop sex cord-stromal tumors, derived from cells of the Sertoli/granulosa cell or Leydig cell lineages. Combined, these observations reveal abnormal differentiation and proliferation of Leydig cells and Sertoli cells in Dax1-deficient male mice, leading to obstruction of the rete testis and infertility.

Molecular and structural analysis of two novel StAR mutations in patients with lipoid congenital adrenal hyperplasia.

Mutations in the gene encoding steroidogenic acute regulatory protein (StAR) cause lipoid congenital adrenal hyperplasia. We report a novel homozygous splice site mutation (IVS1 + 2T --> G) in STAR in two sisters (46XY, 46XX) who presented with primary adrenal insufficiency at birth and a novel homozygous R182H missense mutation in the putative lipid transfer domain of StAR in a phenotypic female (46XY) with adrenal failure and a parotid tumor. These cases highlight the importance of StAR-dependent steroidogenesis during fetal development and early infancy and of the critical functional role of R182 in cholesterol transport.