Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS).

BACKGROUND: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). METHODS: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. RESULTS: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. CONCLUSIONS: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

Germline genome protection: implications for gamete quality and germ cell tumorigenesis.

BACKGROUND: Germ cells have a unique and critical role as the conduit for hereditary information and therefore employ multiple strategies to protect genomic integrity and avoid mutations. Unlike somatic cells, which often respond to DNA damage by arresting the cell cycle and conducting DNA repair, germ cells as well as long-lived pluripotent stem cells typically avoid the use of error-prone repair mechanisms and favor apoptosis, reducing the risk of genetic alterations. Testicular germ cell tumors, the most common cancers of young men, arise from pre-natal germ cells. OBJECTIVES: To summarize the current understanding of DNA damage response mechanisms in pre-meiotic germ cells and to discuss how they impact both the origins of testicular germ cell tumors and their remarkable responsiveness to genotoxic chemotherapy. MATERIALS AND METHODS: We conducted a review of literature gathered from PubMed regarding the DNA damage response properties of testicular germ cell tumors and the germ cells from which they arise, as well as the influence of these mechanisms on therapeutic responses by testicular germ cell tumors. RESULTS AND DISCUSSION: This review provides a comprehensive evaluation of how the developmental origins of male germ cells and their inherent germ cell-like DNA damage response directly impact the development and therapeutic sensitivity of testicular germ cell tumors. CONCLUSIONS: The DNA damage response of germ cells directly impacts the development and therapeutic sensitivity of testicular germ cell tumors. Recent advances in the study of primordial germ cells, post-natal mitotically dividing germ cells, and pluripotent stem cells will allow for new investigations into the initiation, progression, and treatment of testicular germ cell tumors.

A phase I and pharmacokinetic study of novel taxane BMS-188797 and cisplatin in patients with advanced solid tumours.

This phase I study investigated the maximum tolerated dose and pharmacokinetics of a 3-weekly administration of BMS-188797, a paclitaxel derivate, at three dose levels (DLs) (80, 110 and 150 mg m(-2) DL), combined with cisplatin (standard dose 75 mg m(-2)). In 16 patients with advanced malignancies treated, one patient experienced dose-limiting febrile neutropenia, sepsis and severe colitis at the 150 mg m(-2) DL; at the 110 mg m(-2) DL one episode of dose-limiting grade 3 diarrhoea/nausea occurred. Grade 3/4 haematological toxicities were leucopenia/neutropenia; grade 3 nonhaematological toxicities were neuropathy, nausea, diarrhoea and stomatits. Objective response was seen in four patients, with three complete remissions in ovarian and cervical cancer patients. Pharmacokinetics of BMS-188797 appeared linear through the 110 mg m(-2), but not through the 150 mg m(-2) DL. The mean+/-SD values for clearance, distribution volume at steady state and terminal half-life during cycle 1 were 317+/-60 ml min(-1) m(-2), 258+/-96 l m(-2) and 30.8+/-7.7 h, respectively. The maximum tolerated and recommended phase II dose for BMS-188797 was 110 mg m(-2) (1-h infusion, every 3 weeks) combined with cisplatin 75 mg m(-2).

Cisplatinum rechallenge in relapsed ovarian cancer patients with platinum reinduction therapy and carboplatin hypersensitivity.

Hypersensitivity reactions have been reported as limiting side effect in patients re-exposed to carboplatin for relapsed gynecologic malignancy. This study analyzed the incidence, clinical features, management, and outcome of carboplatin-associated hypersensitivity reactions. We performed a retrospective study and analyzed medical records of all gynecological cancer patients treated with carboplatin in our institution from 2000 to 2003. No hypersensitivity reactions were observed in 171 patients during the first carboplatin-containing chemotherapy. All six carboplatin-associated hypersensitivity reactions occurred in 69 patients who were re-exposed to carboplatin (9%). The median number of carboplatin cycles prior to hypersensitivity reaction was nine (range, 8-13). Cisplatin rechallenge was performed in five patients, and no hypersensitivity occurred. An increase in neurotoxicity (National Cancer Institute Common Toxicity Criteria grade 2) was documented in two patients who had residual neurotoxicity grade 1 due to prior taxane treatment. Cisplatinum rechallenge is a feasible strategy to overcome carboplatin hypersensitivity. However, close monitoring of neurotoxicity is necessary, particularly in patients with residual neurotoxicity due to prior platinum- and taxane-containing chemotherapy.

The generation and characterization of a cell line derived from a sporadic renal angiomyolipoma: use of telomerase to obtain stable populations of cells from benign neoplasms.

Angiomyolipomas are benign tumors of the kidney derived from putative perivascular epithelioid cells, that may undergo differentiation into cells with features of melanocytes, smooth muscle, and fat. To gain further insight into angiomyolipomas, we have generated the first human angiomyolipoma cell line by sequential introduction of SV40 large T antigen and human telomerase into human angiomyolipoma cells. These cells show phenotypic characteristics of angiomyolipomas, namely differentiation markers of smooth muscle (smooth muscle actin), adipose tissue (peroxisome proliferator-activator receptor gamma, PPARgamma), and melanocytes (microophthalmia, MITF), thus demonstrating that a single cell type can exhibit all of these phenotypes. These cells should serve as a valuable tool to elucidate signal transduction pathways underlying renal angiomyolipomas.

Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma.

Neurofibromatosis 1 (NF1) is a common autosomal dominant cancer predisposition syndrome, in which 15% to 20% of affected individuals develop astrocytomas. Neurofibromin, the protein product of the NF1 gene, functions as a tumor suppressor, largely by inhibiting Ras activity. While loss of neurofibromin has been implicated in the molecular pathogenesis of other NF1-associated tumors, there is no formal evidence demonstrating loss of neurofibromin function in NF1-associated astrocytomas. In this report, we describe an NF1 patient from whom both astrocytoma tumor tissue as well as corresponding non-neoplastic white matter were available for analysis. Loss of neurofibromin expression was observed in the tumor and was associated with elevated levels of Ras-GTP. However, elevated Ras-GTP levels were not the result of oncogenic Ras mutations, altered p120-GAP function, growth factor receptor activation, or abnormal p53, Rb, or p16 expression. Furthermore, increased Raf-MAPK and PI3-K/Akt activity was detected in the NF1 astrocytoma compared with the corresponding normal white matter. These results support a role for neurofibromin as the critical GAP in the molecular pathogenesis of NF1 astrocytomas.

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation.

Individuals affected with neurofibromatosis 1 (NF1) harbor increased numbers of GFAP-immunoreactive cerebral astrocytes and develop astrocytomas that can lead to blindness and death. Mice heterozygous for a targeted Nf1 mutation (Nf1+/-) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neurofibromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is sufficient for abnormal astrocyte proliferation. Here, we report that Nf17+/- mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/- astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were cocultured with C17 neuronal cells. This C17 neuronal cell-induced Nf1+/- increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-ras-dependent effect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These findings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be sufficient for the development of astrocytic growth abnormalities in patients with NF1.

Septicemia in 980 patients at a university hospital in Berlin: prospective studies during 4 selected years between 1979 and 1989.

A total of 980 episodes of clinically and bacteriologically proven septicemia were included in four prospective 1-year studies at a 1,300-bed university hospital in Berlin between 1979 and 1989. The incidence was 8.1 per 1,000 admissions. The percentage of patients with severe underlying diseases increased significantly from 67% to 95% over the decade. Septicemia due to gram-positive bacteria decreased from 47.3% in 1979 to 43.7% in 1986 and increased again to 51.2% in 1989. Septicemia due to gram-negative organisms decreased constantly from 45.0% in 1979 to 39.8% in 1989. The most frequently isolated species were Escherichia coli (26.4%), Staphylococcus aureus (18.9%), coagulase-negative staphylococci (10.2%), enterococci (7.7%), viridans streptococci (6.4%), Klebsiella species (5.5%), and pneumococci (5.0%). The overall mortality rate decreased significantly from 33.6% in 1979 to 20.8% in 1989. Mortality for episodes of septicemia due to gram-positive bacteria (25.5%) was higher than that for septicemia due to gram-negative bacteria (18.3%). Mortality rates associated with polymicrobic and fungal septicemia were higher than the overall mortality rate.

Disordered pathways of fibrin turnover in lung lavage of premature infants with respiratory distress syndrome.

Premature infants who have self-limited respiratory distress syndrome (RDS) rapidly improve, whereas infants with a complicated respiratory course are more likely to develop bronchopulmonary dysplasia (BPD), a chronic lung disorder that is the result of prolonged lung injury and impaired healing. The balance of competing activities of coagulation and fibrinolysis may contribute to the premature lung's response to acute injury and determine, in part, whether there is early resolution or protracted alveolar inflammation. To determine the relative activities of the coagulation and fibrinolytic pathways in neonatal lung injury, procoagulant (PC) and plasminogen activator (PA) activities were measured in undiluted cell-free lung lavage samples obtained serially over the first 28 days of life from 11 infants with self-limited RDS, 11 infants with evolving BPD, and 5 mechanically ventilated control infants without lung disease. Lung lavage from all three groups contained readily detectable procoagulant activity due mainly to the tissue factor-Factor VII complex. Plasminogen activator activity was relatively high in control lavage samples but depressed on the first day of life in the two groups of infants with lung disease: median, 0.3814 IU/ml (control); 0.0541 IU/ml (RDS); and 0.0454 IU/ml (BPD), p < 0.05 in each case compared with control. Two infants with severe lung disease had no detectable plasminogen activator activity in lung lavage on the first day of life. Depressed fibrinolytic activity correlated with severity of lung disease assessed radiographically and by pulmonary function measurements. Plasminogen activator activity was due to both tissue plasminogen activator and urokinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Alimentary duplication presenting as an hepatic cyst in a neonate.

A large hepatic cyst was excised from an infant who presented on the first day of life with an abdominal mass. Intraoperative, gross, and microscopic observations indicated that this was a cystic duplication of the ileum that extended into the liver. The cyst had a gastric mucosal lining, and there was evidence of ulceration. The occurrence of an alimentary duplication within the liver has been described in only one previous report.

CT of severe renal trauma in children: evaluation and course of healing with conservative therapy.

Over a 2-year period, blunt renal injuries were classified on a four-point scale: grade 1, contusions; grade 2, tears limited to the cortex (renal lacerations); grade 3, tears extending to the collecting system (renal fractures); and grade 4, renal vascular pedicle injuries. We report our findings in nine children with grade 2 and grade 3 blunt renal injuries who were evaluated with CT. One patient had a nephrectomy; the other eight were managed nonsurgically. Six patients had follow-up CT scans 5-19 months later to assess healing. Scars were evident in each case, and the extent of deformity paralleled the magnitude of the initial injury. One patient with a grade 2 injury and two patients with grade 3 injuries healed with small focal scars; three patients with grade 3 injuries healed with large polar scars. In five patients, the CT findings were compared with the findings on 99mTc-DTPA renal imaging. The injured kidneys contributed 30-45% (mean, 38%) of total renal function. In six patients with renal trauma who were treated conservatively, the involved kidneys healed and significant kidney function was preserved, although early surgical intervention might have been beneficial for one of these patients. Prospective studies are needed to evaluate further the effectiveness of this conservative approach.

A direct interaction between Photosystem I and the chloroplast coupling factor.

A regulation of the ATP-synthesizing complex by electron-transport rate has been found. The site of regulation could be localized within the Photosystem I region. The regulatory effect probably is produced by direct interactions between neighbouring charged protein complexes. The primary result is an increase in the percentage of those binding sites adopting a low-affinity state. This seems to lead to an enhanced leakage of protons out of the thylakoids, especially under those experimental conditions employing low nucleotide concentrations. Changes in the P/2e ratio can be observed, especially if the total ADP + ATP concentration used in the experiment is below 200 microM.

A regulatory effect of the electron transport chain on the ATP synthase.

By the application of different experimental conditions, a variation of the apparent affinity of the chloroplast coupling factors 0-1 (CF0CF1) complex toward nucleotides was observed. This effect was paralleled by varying P/e2 ratios even in presence of millimolar ADP concentrations. This observations indicates that the electron transport system has a regulatory effect on the ATP synthase system. Different effects of mobile ionophores (uncouplers) and channel forming ionophores (gramicidin), respectively, indicated that either membrane-oriented charges--probably protons--or an electric potential difference was involved in the regulatory mechanism. When measuring photosystem II-dependent effects only, no regulation of the CF0CF1 complex could be detected in physiologically intact thylakoid preparations. This means that the regulatory active site must be localized between the 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone, (DBMIB) inhibition site and the methylviologen acception site.

[Septicemia. Etiology, epidemiology, clinical aspects and prognosis in 446 patients]. / Sepsis. Aetiologie, Epidemiologie, Klinik und Prognose bei 446 Patienten.

Between 1979 and 1982 446 patients with clinically and bacteriologically established septicaemia were ascertained in a prospective study in a university hospital complex with 1200 beds. This corresponded to an incidence of 8,4 cases of septicaemia in 1000 admissions. In 47.1% of patients the infection had been acquired as out-patient, 52.9% were hospital-acquired. 53.1% of patients were more than 60 years of age, 71.3% had predisposing underlying diseases or risk factors. Main signs of infection were increased temperatures of more than 38.5 degrees C (77.8%), anaemia and leukocytosis. The fairly equal distribution of gram-positive (207) and gram-negative (200) organisms was remarkable. The most frequently isolated bacterial species were E. coli (25.3%), Staph. aureus (21.8%), streptococci (11.1%), Staph. epidermidis (8.4%), enterococci (8.2%), and Klebsiellae (6.5%). 29.1% of patients succumbed. Nosocomial disease, liver cirrhosis, underlying malignant diseases, infections with Staph. aureus, enterococci, pneumococci, Pseudomonas aeruginosa and polymicrobial aetiology had an unfavourable prognostic influence. Thus, frequency and mortality of septicaemic diseases remain of unchanged considerable relevance in medical and surgical units. At present, aetiology and treatment will again have to consider gram-negative organisms to an increased extent.

Sudden deafness: histopathologic correlation in temporal bone.

The histopathological study of two cases of sudden deafness is presented. The temporal bones showed cochleosaccular abnormality. The most striking pathological changes were collapse of the organ of Corti, atrophy of the tectorial membrane, atrophy of the stria vascularis, decrease in the number of the cochlear nerves, collapse of the saccular membrane and partial absence of the sensory epithelial layer in the saccular macula. These changes are quite similar in type to those occurring in labyrinthitis of known viral etiology and to those in previously reported cases of sudden deafness which were assumed to be of viral origin. This evidence suggests that a viral infection was the most probable etiology of sudden deafness in these ears. In addition, unusual findings of endolymphatic hydrops limited to the extreme basal end of the cochlear duct were found in Case 1. A patent cochlear aqueduct and circumscribed perilymphatic labyrinthine ossification in the superior seimicircular canal were also observed. With these histopathological findings, the possibility of viral infection via the meninges as well as via the hematogenous route into the inner ear is proposed.