Selecting Patients with Favorable Risk, Grade Group 2 Prostate Cancer for Active Surveillance-Does Magnetic Resonance Imaging Have a Role?

PURPOSE: The National Comprehensive Cancer Network® recommends that selected men with grade group 2 prostate cancer be considered for active surveillance. However, selecting which patients with grade group 2 disease can be safely managed by active surveillance remains controversial. The aim of this study was to evaluate the association of multiparametric magnetic resonance imaging with adverse pathology in the radical prostatectomy specimen of men with favorable risk grade group 2 prostate cancer, which could help select patients for active surveillance. MATERIALS AND METHODS: We retrospectively analyzed a cohort of patients with favorable grade group 2 disease who underwent radical prostatectomy between 2010 and 2019. Preoperative multiparametric magnetic resonance imaging was scored as negative (no identifiable lesion), positive (identifiable lesion) or equivocal. We defined a multivariable logistic regression model with multiparametric magnetic resonance imaging score as the predictor and adverse pathology (up staging to T3a/b disease, upgrading to ≥grade group 3 or lymph node invasion) as the outcome, adjusting for preoperative prostate specific antigen, biopsy Gleason grade, clinical stage, and number of negative and positive prostate biopsy cores. Secondary outcomes of biochemical recurrence, grade group upgrading alone and the added value of incorporating multiparametric magnetic resonance imaging data into the nomogram were also investigated. RESULTS: We identified 1,117 patients with favorable risk grade group 2 disease who underwent radical prostatectomy. Positive multiparametric magnetic resonance imaging was associated with higher rates of adverse pathology (OR 2.55, 95% CI 1.75-3.40, p <0.0001) and upgrading (OR 3.89, 95% CI 2.00-7.56, p <0.0001). However, as our study included only grade group 2 patients who underwent radical prostatectomy, our cohort may represent a higher risk group than grade group 2 patients as a whole. Adding multiparametric magnetic resonance imaging results to a standard prediction model led to higher net benefit on decision curve analysis. An identifiable lesion on multiparametric magnetic resonance imaging was associated with an increased risk of aggressive pathological features in the radical prostatectomy specimen of patients with favorable risk grade group 2 prostate cancer who were potential active surveillance candidates. This information could be used to inform biopsy strategy, counsel patients on treatment options and guide strategies for those on active surveillance. CONCLUSIONS: Combining multiple magnetic resonance imaging modalities (multiparametric magnetic resonance imaging) provides a more accurate prediction of the risk presented by prostate cancer than current prediction methods. In this study, positive magnetic resonance imaging results approximately doubled the chances that a patient with favorable risk prostate cancer would be found to have adverse pathology when their prostate was removed. Thus, multiparametric magnetic resonance imaging could help select patients with favorable risk cancer who may be good candidates for active surveillance, and help guide biopsy and surveillance strategies for such patients.

The emerging global community.

Human society may be viewed as an evolving system. From time to time, there occurs the equivalent of a phase shift, or more appropriately, a 'cultural discontinuity'. In each case, such a discontinuity is preceded by, and caused by the emergence of a constellation of new technologies. During and following such a discontinuity previously existing cultural institutions become modified, or abolished all together, while new ones arise. The paper considers the impact of the Industrial and the Electronic revolutions on absolute monarchy, slavery, the State, war, and the emergence of an integrated global community.

Information as a basic property of the universe.

A theory is proposed which considers information to be a basic property of the universe the way matter and energy are. Operationally--just as energy is defined in terms of its capacity to perform work--so is information defined in terms of its capacity to organize a system. Pure energy can perform no 'useful' (entropy reducing) work without a concomitant input of information. Conversely, all expenditures of energy lead to a reorganization of the universe, hence to a change in its information status. Energy and information are interconvertible; physicists have been able to ignore the information parameter principally for two major reasons. First, historically, just as there was no need to define energy prior to the advent of increasingly complex, powered machinery and cannons (Galileo was a military engineer), so was there no need until the 20th Century to define information. It was the telephone engineers who first preoccupied themselves with developing a theory of information. The second reason is that physicists invented accounting devices such as potential energy and entropy to explain the apparent disappearance of energy yet maintain the law of the conservation of energy. The proposed theory would consider that what is conserved is the sum of information and energy. The mathematical relationship between information and entropy is provided by the equation: I = (Io)e-S/k while the conversion of energy into information involves the relationship: 1 J/degree K = 10(23) bits (approximately) Acceptance of the theory would require paradigm shifts in a number of interrelated areas.

Studies on Auxin Protectors: XI. Inhibition of Peroxidase-Catalyzed Oxidation of Glutathione by Auxin Protectors and o-Dihydroxyphenols.

Commercial horseradish peroxidase, when supplemented with dichlorophenol and either manganese or hydrogen peroxide, will rapidly oxidize glutathione. This peroxidase-catalyzed oxidation of glutathione is completely inhibited by the presence of auxin protectors. Three auxin protectors and three o-dihydroxyphenols were tested; all inhibited the oxidation. Glutathione oxidation by horseradish peroxidase in the presence of dichlorophenol and Mn is also completely inhibited by catalase, implying that the presence of Mn allows the horseradish peroxidase to reduce oxygen to H(2)O(2), then to use the H(2)O(2) as an electron acceptor in the oxidation of glutathione. Catalase, added 2 minutes after the glutathione oxidation had begun, completely inhibited further oxidation but did not restore any gluthathione oxidation intermediates. In contrast, the addition of auxin protectors, or o-dihydroxyphenols, not only inhibited further oxidation of gluthathione by horseradish peroxidase (+ dichlorophenol + Mn), but also caused a reappearance of glutathione as if these antioxidants reduced a glutathione oxidation intermediate. However, when gluthathione was oxidized by horseradish peroxidase in the presence of dichlorophenol and H(2)O(2) (rather than Mn), then the inhibition of further oxidation by auxin protectors or o-dihydroxyphenols was preceded by a brief period of greatly accelerated oxidation. The data provide further evidence that auxin protectors are cellular redox regulators. It is proposed that the monophenol-diphenol-peroxidase system is intimately associated with the metabolic switches that determine whether a cell divides or differentiates.

Studies on Auxin Protectors: IX. Inactivation of Certain Protectors by Polyphenol Oxidase.

Protector-II (Pr-II) of the Japanese morning glory (Pharbitis nil Choisy) was inactivated by exposure to polyphenol oxidase. An unidentified protector in the same molecular weight range obtained from sunflower was also inactivated by this enzyme. Earlier speculations that protectors might be lipoprotein in nature were negated by the fact that neither lipase nor protease inactivated the protectors. The protectors were also not inactivated by incubating with alpha-amylase, DNase, or RNase. Catechol mimics Pr and is inactivated by polyphenol oxidase. The oxidation of catechol to o-quinone is accompanied by a loss of chromophores that absorb ultraviolet light and the appearance of a reddish brown color. Similarly, when the relatively low molecular weight auxin protectors (Pr-II class) were incubated with polyphenol oxidase, their oxidation was also frequently associated with the formation of brown color, and oxidation with H(2)O(2) caused a loss of ultraviolet-absorbing chromophores. The data indicate that auxin protectors contain o-dihydroxyphenolic groups at their active site.That o-dihydroxyphenols inhibit indoleacetic acid oxidation has been demonstrated by numerous workers. It is suggested that the high molecular weight auxin protectors and the phenolic compounds described by other authors comprise part of a metabolic system concerned with the regulation of peroxidase-catalyzed redox reactions.

Studies on Auxin Protectors. VII. Association of Auxin Protectors With Crown Gall Development in Sunflower Stems.

Mature sunflower internodes contain only very low concentrations of auxin protectors. Wounding such internodes results in a temporary increase of protector substances. Inoculating the wounds with a virulent strain of Agrobacterium tumefaciens Conn results in a dramatic rise in protector substances, particularly the very high molecular weight protector "A", which continues as the tumors develop. The levels attained in tumor tissue are comparable to those normally encountered in meristematic tissue. Since the auxin protectors are antioxidants which inhibit the peroxidase-catalyzed oxidation of IAA, and in view of the findings by other workers that the meristematic tissues are maintained in a relatively reduced state, the presence of such large quantities of protector substances in the tumor tissue could explain the physiological and morphological similarity of tumor tissue to young meristematic tissue.

Studies on Auxin Protectors. V. On the Mechanism of IAA Protection by Protector-I of the Japanese Morning Glory.

The mechanism of auxin protection by auxin protector-I (Pr-I) of the Japanese morning glory was studied in vitro. Four lines of evidence indicate that Pr-I acts as a strong reductant which prevents the peroxidase-catalyzed oxidation of IAA: 1) The kinetics of the reaction are best explained on this basis. 2) The Pr-I-induced lag preceding auxin destruction by peroxidase is completely eliminated by a strong oxidant such as H(2)O(2) at a concentration which does not appreciably affect the reaction rate. 3) Strong organic reductants mimic the Pr-I-induced lag. And 4) when the reaction rate is altered by varying the concentrations of the reactants, or the temperature, the length of the Pr-I-induced lag varies inversely with the reaction rate.

Studies on Auxin Protectors. IV. The Effect of Manganese on Auxin Protector-I of the Japanese Morning Glory.

Auxin protector-I of the Japanese morning glory is inactivated by manganese. Experiments carried out in vitro indicate that in the absence of oxygen the manganic, but not the manganous, ion rapidly inactivates the protector. It is clear from these, and other data described in this report, and the results of other workers, that in the presence of oxygen, manganese accelerates auxin inactivation by means of 2 separate and distinct mechanisms: 1) manganese catalyzes the oxidation of auxin protectors, and 2) following the inactivation of the protectors, or in the absence of protectors, accelerates the oxidation of indoleacetic acid by endogenous peroxidases.

Distribution of Three Auxin Protector Substances in Seeds and Shoots of the Japanese Morning Glory (Pharbitis nil).

The existence of substances which inhibit the enzymatic destruction of auxin in shoots of the Japanese morning glory (Pharbitis nil Choisy) has been confirmed, as has the fact that these substances are distributed in a gradient diminishing from apex to base in a manner indicating a regulatory role in internode elongation and tissue maturation. In addition to the 2 auxin protector substances reported previously (protectors I and II) which appear to account for most of the inhibition of the enzymatic destruction of auxin in young, elongating stem tissue, a third substance, designated as protector A, has been found to be highly active in seeds, and shoot tips of mature plants: In germinating seeds, no protector I or II activity was observed; in stem tips, no protector II and only slight protector I activity was observed. In contrast, old tissue contained no detectable amounts of protector A, but did contain protectors I and II. Between these extremes along the shoot axis, mixtures of the 3 substances were found. The evidence can be interpreted to mean that protector A is degraded into protectors I and II and perhaps translocated in this form. Gel filtration studies indicate that protector A has a molecular weight exceeding 200,000 gm/mole.

Agrobacterium tumefaciens Conn. IV. Bacteriophage PB21 and its inhibitory effect on tumor induction.

Strain B2 of Agrobacterium tumefaciens Conn produces plaques when seeded against strain B6-806 of the same organism. From such a plaque, a highly virulent bacteriophage was obtained by use of D'Herelle's technique of selecting for virulent phage. On nutrient agar, this phage, PB2(1), produced large clear plaques which did not overgrow. Plaques produced on a glutamate medium and on White's plant tissue culture medium were even larger and in White's medium had a three-dimensional appearance. PB2(1) does not appear to be an oncogenic virus. To the contrary, the addition of phage under circumstances which insure mass lysis completely inhibited tumor initiation. Fewer than 10 phage particles present at the beginning of a 21-hr induction period were able, at times, to inhibit completely tumor induction by highly virulent bacteria (strain B6). The data lend further support to the concept that anything which interferes with the metabolic activity associated with the growth of the bacteria interferes with the tumor-inducing process. Attempts to use the phage to rid crown gall tissue of bacteria were unsuccessful.

Agrobacterium tumefaciens Conn. 3. Effect of thermal shock on bacteria in relation to tumorinducing ability.

Stonier, Tom (Manhattan College, Bronx, N.Y.), Robert E. Beardsley, Lowell Parsons, and James McSharry. Agrobacterium tumefaciens Conn. III. Effect of thermal shock on bacteria in relation to tumor-inducing ability. J. Bacteriol. 91:266-269. 1966.-Bacteria heated to 42 C for 30 min exhibit a decrease in tumor-initiating ability without a detectable loss in viability. The thermal shock inhibits subsequent bacterial growth for up to 1.5 hr. As bacterial growth recovers, so does tumor-initiating ability. Respiration of the culture is somewhat increased by the heat treatment. The data suggest that living, actively respiring bacteria do not induce tumors unless they are also growing. The results also point to the necessity for excluding bacterial growth inhibition when interpreting data on the effect of various agents on tumor initiation.