Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.

Cancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and can be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population. Clones primed to tumour initiation in vivo display two distinct transcriptional states at baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories. Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes.

[Analysis of medication prescription in an Argentinian geriatric hospital]. / Análisis de la prescripción de medicamentos en una comunidad geriátrica Argentina.

BACKGROUND: Although polypharmacy may be justified in elderly patients with multiple diseases, it may be dangerous, especially when it includes potentially inappropriate medications (PIM). AIM: To identify inappropriate medication and factors associated with the most relevant prescriptions among older people. MATERIAL AND METHODS: Cross-sectional observational analysis of drugs prescribed during the first trimester of 2010 to 179 older adults aged 77 ± 8 years (98 women), living in a geriatric reference hospital in Argentina. The use of potentially inappropriate medications (PIM) in elderly patients was analyzed using Beers Criteria updated to 2012. RESULTS: The mean number of drugs prescribed per individual was 6.1 ± 2.7. The most commonly used drugs were anti-ulcer agents (58.1%), agents acting on the renin-angiotensin system (54.2%), antithrombotic medications (50.8%) and benzodiazepines (50.8 %). The use of antacids and anti-ulcer agents, psychotropic drugs and PIM was significantly higher among patients using six or more drugs daily, compared to the less medicated group (odds ratio (OR) = 6.8, 95% confidence intervals (CI) 3.5-13.2; OR=15.0, 95%CI 5.9-38.4; OR=5.0; 95%IC 2.6-9.8, respectively). Thirty one percent of participants using non-steroidal anti-inflammatory drugs, were not receiving medications for gastric protection. One to four drugs included in the Beers list were prescribed to 66% of participants. CONCLUSIONS: Despite the high prevalence of use of antacids and anti-ulcer agents, these drugs were not prescribed to a significant proportion of patients using non-steroidal anti-inflammatory drugs. Strategies to optimize pharmacotherapy in the elderly population are urgently required.

The solitary fibrous malignant tumour of the kidney: clinical and pathological considerations on a case revisiting the literature.

The solitary fibrous tumours (SFT) are rare spindle cell neoplasms which generally originate from the pleura; also described are cases of SFT in other locations, included the genital-urinary tract. Described in the ambit the kidney are 19 cases of SFT and such rarity of localisation makes rather unknown the histogenesis and the prognosis of the lesion. We report the case of a 72 year old lady who attended our Unit for a mass which was clinically palpable at the level of the left hemiabdomen. Following an abdominal ultrasound scan a neoformation was highlighted which a successive tomodensitographic test indicated as being of likely pertinence of the middle third of the left kidney; the mass had a diameter of approximately 19 cm. A radical nephrectomy has been conducted. The histological examen highlighted a solitary fibrous tumour: the presence of hypercellularity, of cellular pleiomorphism and of a high number of mitosis has led to a histopathological diagnosis of malignancy of the neoplasm under examination. Departing from this case a review of the literature is carried out. The SFT of the kidney can have an aggressive character and more the present has hystopathological characters and clinical results are still rather unknown.

Quality of life outcomes of combination zidovudine- didanosine-nevirapine and zidovudine-didanosine for antiretroviral-naive advanced HIV-infected patients.

OBJECTIVES: To evaluate the quality of life outcomes in antiretroviral-naive patients randomized to zidovudine plus didanosine versus zidovudine plus didanosine plus nevirapine for treatment of advanced HIV disease (the Istituto Superiore di Sanità 047 trial). DESIGN: A 48-week randomized, double-blind trial. METHODS: Sixty patients were enrolled and evaluated over 24 weeks. Quality of life was assessed using a modified version of the Medical Outcomes Study-HIV Health Survey. For analysis, we calculated two summary scores reflecting the physical (PHS) and the mental (MHS) components of health. RESULTS: Although the three-drug combination was superior at inducing immunologic and virologic responses, the two-drug regimen was superior for both PHS and MHS, especially at week 8 where differences were both statistically and clinically significant (5.8 and 9.2 points, respectively, P< 0.02 for both). Quality of life changes paralleled trends in body weight and Karnofsky performance status score. CONCLUSION: Although a three-drug antiretroviral therapy regimen was superior in terms of short term virologic/immunologic response, the two-drug regimen was better in terms of quality of life. In general, triple therapy remains the most effective treatment option. However, quality of life assessments can yield results that may be discordant with and complementary to those obtained using conventional endpoints. Comparative trials should collect a comprehensive range of outcome measures, including patient-reported quality of life, in order to provide clinicians and patients with additional information that may influence treatment decisions.

Reversible carnitine palmitoyltransferase inhibitors with broad chemical diversity as potential antidiabetic agents.

A series of carnitine related compounds of general formula XCH(2)CHZRCH(2)Y were evaluated as CPT I inhibitors in intact rat liver (L-CPT I) and heart mitochondria (M-CPT I). Derivative 27 (ZR = -HNSO(2)R, R = C(12), X = trimethylammonium, Y = carboxylate, (R) form) showed the highest activity (IC(50) = 0.7 microM) along with a good selectivity (M-CPT I/L-CPTI IC(50) ratio = 4.86). Diabetic db/db mice treated orally with 27 showed a significant reduction of serum glucose levels.

Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity.

In an attempt to synthesize potential anticancer agents acting by inhibition of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. The compounds were tested for their cytotoxic activity in vitro against H460 non-small lung carcinoma cell line, the activity being for 24 out of 37 compounds in the 0.01-0.3 microM range. A QSAR analysis indicated that lipophilicity is the main parameter correlated with cytotoxicity. Investigation of the DNA-Topo I-drug cleavable complex showed a rough parallelism between cytotoxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex suggests that for the most potent compounds, e.g., 15, the cytotoxicity was at least in part related to stabilization of the complex, as also supported by the persistence of the DNA-enzyme complex in drug-treated cells. The in vivo antitumor efficacy of the most potent analogue (15) was evaluated in direct comparison with topotecan using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibition of tumor growth and rate of complete response.

Colposcopic findings in virgin and sexually active teenagers.

The colposcopic findings in 86 virgin teenagers are reported and compared with a matched control group of 172 sexually active teenagers. The results show that an atypical transformation zone may be observed in virgins and that the prevalence rate of this condition is different when compared with that of sexually active teenagers. These data suggest that: 1) the presence of a colposcopically observed atypical epithelium is due to a normal maturation process occurring in young women after the menarche, and 2) coitus is responsible for the prolongation of this process in sexually active teenagers.

Clinical status and parasitic infection in a Wichí Aboriginal community in Salta, Argentina.

In a study, carried out in 2000, of the clinical and parasitological status of a Wichi Aboriginal community living in the suburbs of Tartagal, northern Salta, Argentina, 154 individuals were screened for parasitic infections. Ninety-five faecal samples were also obtained from the same population. Ninety-three percent of the subjects were positive for 1 or more of the parasites investigated by direct test and 70.5% of them had parasitic superinfection. The most frequent helminths were Strongyloides stercoralis (50.5%) and hookworm (47.4%). We found low reinfection rates and a long reinfection period after treatment and provision of safe water and sanitation. Serum reactivity of these patients was analysed by enzyme-linked immunosorbent assay and indirect immunofluorescent assay and 22.1% of them had anti-Toxocara antibodies, 16.2% were positive for a complex antigen of Leishmania braziliensis, 29.9% were positive for a complex Trypanosoma cruzi antigen, and 17.5% were positive for a specific Trypanosoma cruzi antigen, Ag 163B6/cruzipain.

Endometrial adenocarcinoma with psammoma bodies.

Psammoma bodies were found in less than 9% of 235 cases of endometrial carcinoma, considering both biopsies and surgical specimens. They may originate in papillary adenocarcinoma and do not indicate a slightly infiltrating or a well-differentiated tumor. The clinical profile of patients closely resembles that of women with endometrial carcinoma, but survival appears worse.

[Erectile dysfunction in Peyronie's disease. Experience in 132 patients]. / Disfunzioni dell'erezione nella malattia di La Peyronie. Esperienza su 132 pazienti.

BACKGROUND: The exact percentage of sexual dysfunctions resulting from Peyronie's disease remains very difficult to evaluate even today. The purpose of the present paper is to examine the series observed in our Department in order to make an assessment of the erectile function of patients found to be suffering from Peyronie's disease. METHODS: Over the course of 9 years, 132 patients have come to our observation; they were originally examined for sexual function disturbances or for other pathologies of a uro-andrological nature. RESULTS: In all, a total of 208 lesions were observed. Only 21 patients (22.5%) were found to be completely asymptomatic at the time of diagnosis. The most frequent symptom was shaft curvature (alone or in association with pain: 47%). The most commonly observed site for plaques was the back of the corpus cavernosum (43%). Impotentia erigendi was observed in 29 patients (22%) whereas impotentia coeundi was found in 50 (38). The functionally most significant lesions were those affecting the septum or in some way involved with the septum: 19 of 29 patients with impotentia erigendi presented such lesions. CONCLUSIONS: Considering the generally progressive course of the disease, the therapeutic approach taken by our Department is to fit a prosthesis to patients who have been suffering from Peyronie's disease for at least six months; conservative therapy is only undertaken in the rare cases of patients who have a perfectly preserved erection but who suffer from impotentia coeundi (as a result of curvature or pain).

[Vesico-cutaneous fistula of the thigh as a late manifestation]. / Fistola vescico-cutanea della coscia a manifestazione tardiva.

Vesico-cutaneous fistulas rarely occur in the urinary tract (1.7% of all urinary fistulas). Trauma, neoplasias, inflammation and iatrogenic pathologies are among the principal causes. The external mouth of the fistula is usually found in the hypogastric area, scrotum, perineum and rarely elsewhere. This report describes the case of a 48 year old woman who, after severe trauma suffered bladder laceration, treated only with cystorraphy. Sepsis and gangrene followed involving the pubic area and the right thigh, associated with acute renal and adrenal gland cortex failure. After emergency treatment, the patient was discharged with an indwelling catheter. Ten months later she was referred to our urology clinic because of a suspected bladder-vaginal fistula. The indwelling catheter was removed and the bladder resumed functioning well. Six months later the external mouth of the fistula appeared on the right inner thigh. NMR confirmed the diagnosis of a vesico-cutaneous fistula. Surgery resolved the abnormality.

Prostate cancer: correlation between local and systemic disease.

BACKGROUND: Prostate cancer is in Italian men the second neoplasm for incidence. Transrectal ultrasonography (TRUS) is still today a cheap test, not very invasive, well accepted by the motivated patient and sufficiently accurate for the valuation of the local status disease. We proposed our data to verify if a careful local ultrasonographic study of prostatic carcinoma could or not predict its systemic course. METHODS: We have valued 136 out patients affected by prostate cancer and treated with either palliative medical therapy or radiotherapy. The follow-up varies from 12 to 132 months. The local, evaluation of the disease done through TRUS in longitudinal and/or axial scan (the dimension of the gland, the volume and ultrasonographic characteristics of the lesion, capsular involvement and estimation of the surrounding structures: seminal vesicles, vesica, rectum). RESULTS: In the long run, considering the local and systemic course of the disease, we have noticed accordance globally in 116 patients (85.3%); 13 patients showed only systematic progression (9.5%) while in 7 patients, we have noticed a local but not a systemic variation. CONCLUSIONS: We can deduce that periodical carrying-out of the TRUS (twice a year) constitute a reliable index not only of local procedure of the pt. but also predicting the systemic course of the disease, making the routine carrying out of the other check-up unnecessary, that could be reserved for cases with precise clinical indication.

[Socio-sanitary analysis of the first 300 voluntary interruptions of pregnancy carried out in the obstetrical-gynecological division of the Bassini Hospital of Milan]. / Analisi socio-sanitaria sulle prime 300 interruzioni volontarie di gravidanza effettuate dalla Divisione Ostetrico-Ginecologica dell'Ospedale Bassini di Milano.

PIP: 300 abortion seekers were interviewed to investigate the causes leading to interruption of pregnancy, and the characteristics of the women themselves. 19% were below 20, and 10% below 18 years of age; 26% were immigrants from the south of Italy, and most had a very low educational and socioeconomic status. About 30% were housewives, and 57% were married. 90% of partners were favorable to the intervention, while the great majority of parents did not know about it. Socioeconomic reasons were given more often for the request of abortion. 67.7% of interventions were performed after the 8th week of pregnancy; 93% of women declared they would have seeked abortion any way, even if it had not been legal. The most used contraceptive method at the time of conception was coitus interruptus; the pill or the IUD were used by only 1.5% of women, while 25% did not use any form of contraception.^ieng

[Our experience of parenteral nutrition (PN) in general surgery]. / Nostra esperienza in tema di nutrizione parenterale (NP) in chirurgia generale.

The problems caused by malnutrition in postoperative complications are well know as is the importance of parenteral nutrition (NP). Thanks to the improvement in instruments and methods, NP can be used not only in intensive therapy departments, but also in less well equipped ones. The Authors report their experience of the use of NP in 77 patients from January 1978 to December 1989 treated in the Surgical Department of the Civil Hospital of Susa (TO), USSL 36, Regione Piemonte.

[Zoonotic parasitosis transmitted by dogs in the Chaco Salteño, Argentina]. / Parasitosis zoonóticas transmitidas por perros en el Chaco Salteño.

Toxocara canis and Ancylostoma spp. are geohelmints that parasites dogs and can eventually affect humans, mainly children, causing visceral and cutaneous larva migrans respectively, constituting a serious public health problem. This study was carried out in two towns located in the xerophilous forest Chaco salteño where humans live closely with many animals, including dogs. Hematological values and anti-Toxocara canis antibodies, determined by ELISA in serum, were evaluated in 98 children from this area. Thirty-six children presented with eosinophilia of 10% or higher in peripheral blood. Twenty out of 98 (20.4%) children had antibodies against antigen from L2 larvae of Toxocara canis. A high percentage (55.6%) of the children with eosinophilia presented anti-Toxocara canis antibodies. Nine children had multiple serpiginous lesions typical of cutaneous larva migrans. Feces from dogs were collected in the area where children lived, in order to search for parasite contamination. Three different techniques of stool examination were employed and eggs were counted. Out of the 106 feces examined, parasites were found in 82 samples (77.4%). Ancylostoma spp eggs were found in 74 (69.8%) samples and eggs from Toxocara canis were found in 19 (17.2%). The average number of T. canis and Ancylostoma spp eggs/gr of feces, were 200 and 3,871 respectively. Giardia spp (14.5%), Trichuris vulpis (7.6%), Genus Endamoeba (2.8%) and Taenia spp (1.9%) were also identified in the stools. Sanitary control and health education in order to control these parasitoses are emphasized.

[Urethral diverticuli in women: role of diagnostic methods in the preoperative assessment]. / Diverticoli uretrali nella donna: ruolo delle metodiche diagnostiche nell'inquadramento preoperatorio.

From 1985 to 1993 we observed 9 female patients with urethral diverticula. All patients underwent first clinical examination and then US (suprapubic and transrectal or transvaginal scans) and X-ray cystography which demonstrated the communication between the diverticula and the urethra, MRI was also performed, in order to explain the rapports between the diverticulum and the sphyncter. All patients underwent surgery and 8 were cured. No cases of incontinence were observed.

[Locally advanced prostatic cancer and systemic involvement]. / Cancro prostatico localmente avanzato ed interessamento sistemico.

In a group of 115 patients with prostatic cancer, the correlation between the local and systemic evolution of the neoplasm has been evaluated. In 80 patients non local and systemic up-staging of the tumor was observed. In further 18 patients both local and systemic staging uppers and in the remaining 17 patients no correlation between local and systemic evolution was observed. In conclusion, in this series, the prostatic cancer demonstrated an high concordance in both local and systemic evolution and then the modifications of local staging can be used as a predictive parameter of systemic evolution of the prostatic cancer.

[Echographic features of testicular neoplasms. Our experience]. / Caratteri ecografici delle neoplasie testicolari. Nostra esperienza.

14 patients with primitive testicular cancer underwent US and afterwards surgery. A comparison between echo-pattern and hysto-pathology was done with the following results: sharp limits and ipoechoic homogeneous pattern in leydigioma and low-staging seminoma. Presence of anechoic areas and irregular limits: teratoma and embrionary carcinoma with no correlation with the staging. Inclusively no correlation between echo-pattern and staging of neoplasm or presence of neoplastic lymphnodes was observed.

[Vesico-intestinal fistula in Crohn disease: the role of echography in its diagnosis]. / Fistole vescico-enteriche in corso di morbo di Crohn: ruolo dell'ecografia nella diagnosi.

Ultrasound is in widespread use in the study of gastrointestinal pathologies. In Crohn disease it is helpful in diagnosing complications such as thickening of the bowel loop walls, abscesses, lymph node enlargement and vesical-enteric fistulas. This report presents two cases in which vesical-enteric fistulas were visualized by US; confirming a diagnosis of Crohn's disease in one case, and diagnosing the fistula during the follow-up in the second patient in whom Crohn's disease had previously been diagnosed.

[Traumatic injuries of the urethra: an echographic study]. / Lesioni traumatiche dell'uretra: studio ecografico.

US in the lower urinary tract usually explores the bladder and the prostatic urethra. In this study we used US instead of x-rays to visualize the remaining urethra in 42 patients. US was useful in the presence of urethral trauma. The site and extent of injury, particularly peri-urethral lesions (hematomas, urinary collection and abscesses in relation to the urethra) were observed. Ultrasound's efficacy and reproducibility were also useful in post-operative follow-ups.