PARP inhibitors and metastatic castration-resistant prostate cancer: uture directions and pitfalls.

PARP inhibitors (PARPi) gained major interest among prostate cancer researchers in the last few years, thanks to the outstanding results coming from the PROfound an TRITON2 studies. Following that, PARPi gained approval also in metastatic, castration-resistant prostate cancer (mCRPC) with mutations in homologous repair (HR) - related genes. Nevertheless, some questions still remain unanswered concerning the management of drug resistance and PARPi-sensitivity in patients harboring alterations in various DNA damage response (DDR) related genes, not only BRCA1 and BRCA2. In this perspective article we focus on the key issues concerning PARPi in mCRPC, specifically those related to drug sensitivity and resistance mechanisms, exploring the possible role of combination therapeutic approaches and trying to depict potential future addresses in translational oncology research.

Radical metastasectomy followed by sorafenib versus observation in patients withclear cell renal cell carcinoma: extended follow -up of efficacy results from the randomized phase II RESORT trial.

Background: The RESORT trial showed no longer relapse free survival (RFS) with sorafenib following radical metastasectomy in metastatic renal cell carcinoma. We present the updated 42-month follow-up data.Methods: The phase II RESORT trial randomized patients to sorafenib or observation within 12 weeks from surgery. RFS was the primary endpoint.Results: We analyzed 68 patients (32 in sorafenib and 36 in the observation arm), randomized between November 2012 and November 2017. Eighty-one percent in the sorafenib arm and 80% in the observation arm had one metastasis . At a median follow-up of 42 months (interquartile range 31-58), in the observation arm the median RFS was 35 months, RFS probability was 57% (95% CI 42-76%) at 24 and 44% (95% CI 30-65%) at 48 months. In the sorafenib arm, median RFS was 21 months, RFS probability was 50% (95% CI 34-71%) at 24 and 32% (95% CI 18-57%) at 48 months (p = 0.342;HR 1.35;95% CI 0.72-2.54). Forty-seven percent and 37.5% of the patients in the two arms, respectively, are disease free. The site of relapses was independent of the previous metastasectomy site.Expert commentary: Sorafenib after metastasectomy did not improve RFS, but surgery in selected patients should be considered in order to potentially improve survival.Clinical trial registration: www.clinicaltrials.gov identifier is NCT0144480.

Orbitally induced oscillations in the East Antarctic ice sheet at the Oligocene/Miocene boundary.

Between 34 and 15 million years (Myr) ago, when planetary temperatures were 3-4 degrees C warmer than at present and atmospheric CO2 concentrations were twice as high as today, the Antarctic ice sheets may have been unstable. Oxygen isotope records from deep-sea sediment cores suggest that during this time fluctuations in global temperatures and high-latitude continental ice volumes were influenced by orbital cycles. But it has hitherto not been possible to calibrate the inferred changes in ice volume with direct evidence for oscillations of the Antarctic ice sheets. Here we present sediment data from shallow marine cores in the western Ross Sea that exhibit well dated cyclic variations, and which link the extent of the East Antarctic ice sheet directly to orbital cycles during the Oligocene/Miocene transition (24.1-23.7 Myr ago). Three rapidly deposited glacimarine sequences are constrained to a period of less than 450 kyr by our age model, suggesting that orbital influences at the frequencies of obliquity (40 kyr) and eccentricity (125 kyr) controlled the oscillations of the ice margin at that time. An erosional hiatus covering 250 kyr provides direct evidence for a major episode of global cooling and ice-sheet expansion about 23.7 Myr ago, which had previously been inferred from oxygen isotope data (Mi1 event).

General cognitive abilities and patterns of adaptation: for Serial Color-Word Test norms based on reading times.

In a pool of 859 clinical and nonclinical Serial Color-Word Test protocols, significant positive correlations were observed between reading times on the Stroop task and measures of linear and nonlinear change. Especially nonlinear change, both within and between the five subtests, showed high correlations with reading times. To derive new time-related norms, the sample was divided into five time groups of the same size and stratified medians were calculated for each of the variables of the test. The new classification procedure should permit an assessment of patterns of adaptation less dependent on the general level of perceptual-cognitive functioning.

Pond-river interactions in a pampean basin /Salado river, Buenos Aires, Argentina): an approach

Se realizó una investigación en el Río Salado en conjunto con la laguna San Miguel que se conecta con el río. Las condiciones fisico-químicas eran similares para los dos cuerpos de agua. En condiciones de alto nivel, concentraciones de fósforo y plancton. La influencia del río determinó niveles altos de nutrientes y polifenoles. En diciembre 1995-marzo 1996 hubo una sequía y la laguna se secó por completo y el flujo del río no pasó de los 100m3/segundo. La fuente del fósforo y polifenoles es el río, así que en condiciones de aguas bajas esas concentraciones disminuyeron. El plancton demostró afinidad a condiciones de alta salinidad

Campylobacter jejuni/coli in commercially reared beagles: prevalence and serotypes.

A 5 year longitudinal study involving 187 commercially reared beagles from three suppliers was undertaken to determine prevalence and serotypes of Campylobacter jejuni and C. coli. Campylobacter jejuni or C. coli was isolated from the feces in 62 of 177 asymptomatic beagles and 8 of 10 dogs with diarrhea for an overall prevalence of 37%. A total of 36 isolates were serotyped on the basis of thermostable antigens with 20 antisera prepared against frequently occurring serotypes isolated from humans with campylobacter associated enteritis (15 C. jejuni, 5 C. coli serotypes). Of these isolates, 17 (47%) serotyped with antisera to 7 C. jejuni serotypes frequently isolated in human cases of enteric campylobacteriosis (serotypes 1, 4, 10, 16, 18, 19, 37). One C. coli reacted to antisera 24, 34, 37, one strain of C. coli to antisera type 37, and another C. coli to antisera type 34. All three C. coli belonged to serotypes frequently encountered in diarrheic human patients.

Campylobacter jejuni infection in the ferret: an animal model of human campylobacteriosis.

Campylobacter infection in weanling ferrets (Mustela putorius furo) was studied as an animal model for enteric campylobacteriosis in persons. The screening of fecal cultures on selective campylobacter media showed that Campylobacter jejuni/coli was not present in the normal enteric flora. Intragastric feeding of a mixture of cat feed and 2.5 X 10(8) C jejuni isolated from ferrets with naturally occurring proliferative colitis was accomplished. All ferrets (n = 8) became infected on 3 days after they were inoculated, and at 5 to 7 days, they had bile-tinged, liquid feces with excessive mucus and blood. Ferrets gradually recovered from the diarrhea, and feces were normal 10 to 14 days after inoculation was done. Feces contained C jejuni at 14, 23, 28, 39, 46, 60, 91, 101, 109 and 144 days. In the second experiment, weanling ferrets initially were treated with 10% sodium bicarbonate, and 1 X 10(10) C jejuni organisms were administered in the cat feed. Diarrhea with fecal leukocytes and occult blood with occasional mucus appeared in almost all of the 21 ferrets from days 4 through 7. Campylobacter jejuni was isolated from the blood of 11 ferrets between 3 hours and 14 days after they were inoculated. Campylobacter jejuni bactericidal antibodies were present in serum samples at 14 days, with titers of 1:16 to 1:32. Intestinal lesions including cellular infiltration with mononuclear and polymorphonuclear leukocytes were in the lamina propria of the pyloric mucosa and small intestine of infected and control ferrets. The colon of 3 infected ferrets had small focal infiltrates of neutrophils on the lamina propria; one ferret had perivascular cuffing.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic diarrhea associated with Campylobacter jejuni infection in a cat.

Campylobacter jejuni was isolated from a cat with chronic diarrhea. The diarrheic cat and another cat (which previously had diarrhea) in the same household had bactericidal antibody titers to the C jejuni. Clinical response to antibiotic therapy and not recovering Campylobacter sp from normal feces after treatment also supported the diagnosis of Campylobacter-associated diarrhea. Although the owner had a protracted episode of diarrhea, C jejuni was not isolated from the owner's feces, nor was a bactericidal antibody detected in the owner's serum.

Male reproductive capacity may recover following drug treatment with the L-10 protocol for acute lymphocytic leukemia.

Six men with acute lymphocytic leukemia (ALL) were studied prospectively to assess the effect of treatment with the L-10 protocol on reproductive capacity. Before therapy three men had fathered children (two, two children; one, three children); the others were sexually mature although no fertility studies had been done prior to or during their treatment. Each patient had a minimum of 3 1/2 years of continuous chemotherapy as part of this study. Semen analysis was done 10 to 52 months (median, 31.5 months) after completion of therapy. One patient had lower than normal sperm concentration but near normal total sperm count and normal motility; the others had a normal sperm concentration and motility. Sperm nuclei were isolated from each sample and analyzed by flow cytometry for resistance to DNA denaturation in situ; all samples had relatively high resistance to denaturation, consistent with a normal, fertile reproductive status. After completion of therapy, one patient fathered a normal child, and a second patient fathered one child with multiple congenital malformations followed by a second child who was normal.

Flow cytometry of breast carcinoma. III. Possible altered kinetics in axillary lymph node metastases.

The cell cycle distribution of human mammary carcinoma was determined by flow cytometry in 21 cases and compared with that of the same tumor concurrently metastatic in regional lymph nodes. The percentage of S-phase cells in the nodal metastasis as compared to the primary tumor was significantly lower in estrogen-binding-positive tumors than in estrogen-binding-negative tumors. Since we do not have evidence of clonal evolution in the metastases, it is possible that there is a local inhibitory effect of the lymph node on tumor cell proliferation in the case of some estrogen-binding-positive tumors.

Flow cytometry of lung carcinoma: a comparison of DNA stemline and cell cycle distribution with histology.

Flow cytometry studies of the DNA distribution of 33 lung tumors were carried out. All of the carcinomas (32 cases) had aneuploid DNA modal values, ranging from 2.15c to 5.05c; in the single case of carcinoid studied, the tumor cells were diploid. DNA ploidy levels tended to be higher for epidermoid than adenocarcinoma; they were the same in lymph node metastases as in the primary tumor. Cell cycle distributions calculated from the tumor cell DNA values showed considerable variation, ranging from 9% to 58% for the S phase and from less than 1% to 29% for the G2M phase. Whether these variations have clinical significance is not known at this time.

Flow cytometry of low stage bladder tumors: correlation with cytologic and cystoscopic diagnosis.

Flow cytometry examinations (FCM) were carried out on 110 bladder irrigation specimens from 84 urologic outpatients who had had prior conservative treatment for low stage bladder tumors. The specimens were easily obtained, and adequately cellular in all cases. Of 60 examinations on patients with no cytoscopic abnormalities, FCM and conventional cytology were both negative in 30 and both positive in 12 instances; there were 18 with positive FCM and negative cytology. Of 15 instances with cystoscopically benign appearing papillary lesions, FCM and cytology were both negative in three and both positive in three cases; FCM was positive and cytology negative in nine. Of 35 instances with suspicious cystoscopic findings, FCM and cytology were both positive in 19 and both negative in four; FCM was positive and cytology negative in 12. There were no examples of positive conventional cytology and negative FCM. These findings indicate that, after conservative treatment of low stage tumors, FCM of bladder irrigation specimens may be a more sensitive measure of cytologic abnormalities than is conventional cytology. Specimen collection is feasible as part of the routine urologic examination in an outpatient clinic.

Cell-cycle distribution of urothelial tumour cells as measured by flow cytometry.

The fraction of cells in S + G2 + mitosis from 54 urothelial tumours was calculated by flow cytometry after acridine orange (AO) staining of cells obtained by bladder irrigation or biopsy. Fluorescence signals emitted by the AO-stained DNA and RNA of each cell were separated optically and measured for 5,000 cells per specimen. The patients were classified by the histology of their tumours and clinical data into 5 diagnostic categories: NED (no evidence of disease, but history of bladder tumour), 3; papilloma, 8; non-invasive papillary carcinoma, 8; carcinoma in situ, 17 and invasive carcinoma, 18. The fraction of cells with DNA values in S + G2 + M of the cell cycle varied between 7 and 57% of the total, with a wide range within each diagnostic category, but no statistically significant differences between the groups. The proportion of cells in S + G2 + M from an individual tumour was not correlated with histologic grade or clinical behaviour. The possibility that some tumour cells with DNA values above G1 level are quiescent cells arrested at S or G2 is discussed.

Lymph node reactivity to experimental bladder tumor in preimmunized animals as measured by two parameter flow cytometry.

Lymph node lymphocyte reaction to an explanted, transplantable mouse bladder tumor (MBT-2) was investigated by flow cytometry in animals previously immunized with irradiated tumor cells. Nodal lymphocytes in representative samples from four different lymph node sites were differentially stained for DNA and RNA with the fluorescent dye acridine orange; cell proliferation and the increase in RNA content were measured. Immunization abrogated tumor growth; one immunization reduced tumor take to 25 per cent of the animals, and two immunizations to 14 per cent. Lymphocyte reactivity to the tumor was reflected both by an increase of DNA synthesizing cells and by diploid cells with high RNA. The latter response was more pronounced and thus the more sensitive parameter for measuring immunologic lymph node reactivity. The juxtatumoral node displayed the most pronounced reactivity, but all node sites showed some degree of reaction.