Endourological treatment for lumbar ureteral stones. What are the benefits of flexible ureterorenoscopy?

INTRODUCTION AND OBJECTIVES: Currently, there are no established criteria regarding treatment for lumbar ureteral stones. The objective of this work is to present our results in the endourological treatment of this pathology, analyzing the variables associated with the use of the flexible ureterorenoscope. MATERIAL AND METHODS: Retrospective review of 103 patients who underwent retrograde URS with semi-rigid or flexible ureterorenoscope. Proximal location: L2-L3. Medial location: L4-L5. Semirigid URS was the initial treatment, with conversion to flexible URS when it was required to complete the procedure. Success was defined as absence of residual fragments (6 weeks). Demographic, surgical, immediate postoperative variables, and those related to the stone, were analyzed. Their correlation with the use of the flexible ureterorenoscope was evaluated. RESULTS: Mean age: 57.2 years (SD 15.6); there were 73 men (70.9%). Stone size: 8 mm (range 4-30; IQR 4.5). Proximal location: 58 (56.3%). Previous JJ: 44.7%. Previous nephrostomy: 10.7%. Semirigid URS with conversion to flexible URS: 51 (49.5%). Impacted stones: 28.2%. Intraoperative complications: 2 (1.9%). Postoperative JJ: 84.5%. Immediate postoperative complications: 23 (22.3%) (Clavien-Dindo I-II: 91.3%). Postoperative ureteral stricture: 5.8%. Success: 88.4%. Residual fragments: 12 (11.7%). Spontaneous passage: 6 (50%). Greater performance of flexible URS in proximal ureteral stones (p = 0.001) of more than 11 mm (p = 0.02) in univariate analysis, and in proximal stones [OR 3.5; 1.5-8.1; p = 0.004] in multivariate analysis. CONCLUSIONS: Endourological treatment obtained a high success rate in our sample. Size greater than 11 mm and proximal ureteral location in univariate and multivariate analysis, respectively, behaved as predictors of flexible URS.

Therapeutic optimization through goal-oriented prescription in nursing homes.

Background People living in nursing homes are highly vulnerable and frail. Polypharmacy and inappropriate prescription (IP) are also common problems. Objectives The objectives of the study are (i) to study the baseline situation and calculate the frailty index (FI) of the residents, (ii) to assess the results of routine clinical practice to do a pharmacotherapy review (patient-centred prescription (PCP) model) (Molist Brunet et al., Eur Geriatr Med. 2015;6:565-9) and (iii) to study the relationship between IP and frailty, functional dependence, advanced dementia and end-of-life situation. Setting Two nursing homes in the same geographical area in Catalonia (Spain). Method This was a prospective, descriptive and observational study of elderly nursing home residents. Each patient's treatment was analysed by applying the PCP model, which centres therapeutic decisions on the patient's global assessment and individual therapeutic goal. Main outcome measure Prevalence of polypharmacy and IP. Results 103 patients were included. They were characterized by high multimorbidity and frailty. Up to 59.2% were totally dependent. At least one IP was identified in 92.2% of residents. Prior to the pharmacological review, the mean number of chronic medications prescribed per resident was 6.63 (SD 2.93) and after this review it was 4.97 (SD 2.88). Polypharmacy decreased from 72.55% to 52.94% and excessive polypharmacy fell from 18.62% to 5.88%.The highest prevalence of IP was detected in people with a higher FI, in those identified as end-of-life, and also in more highly dependent residents (p < 0.05). Conclusions People who live in nursing homes have an advanced frailty. Establishing individualized therapeutic objectives with the application of the PCP model enabled to detect 92.2% of IP. People who are frailer, are functionally more dependent and those who are end-of-life are prescribed with inappropriate medication more frequently.

Síndrome 49, XXXXY: aspectos bucales y abordaje clínico / 49, XXXXY Syndrome: oral aspects and clinical approach

El cariotipo 49 XXXXY, es una forma rara de polisomía, considerada una variante del Síndrome de Klinefelter, descripto en el año 1960, siendo muy escasa la información publicada en la literatura científica en el área de la odontología. Algunas de las características fenotípicas predominantes en este síndrome son: rasgos faciales dismórficos, microcefalia, clinodactilia, retardo mental, hipogonadismo y naomaláis esqueletales, siendo la sinostosis radiolunar la más característica. En el 100 por ciento de los casos se ha descripto retraso motor y del lenguaje y en el 50 a 100 por ciento se pueden observa paladar fisurado, malformaciones genitourinarias, hernia inguinal y defectos óseos. Uno de los aspectos bucales relevantes de los pacientes con este síndrome es la presencia de taurodoncia. El propósito de este trabajo es describir las características bucales, las anomalías dentales y su abordaje clínico en forma ambulatoria, en un paciente de 6 años de edad con síndrome de 49 XXXXY

Understanding response and resistance to oestrogen deprivation in ER-positive breast cancer.

Oestrogens (E) and oestrogen receptor alpha (ERα) play fundamental roles in the development and progression of more than three-quarters of breast cancers (BC). The ability to influence the natural history of BC by hormonal manipulation is well established and endocrine therapies represent the cornerstone of systemic management for women with ERα-positive disease. Endocrine agents abrogate oestrogenic signalling through distinct and incompletely overlapping mechanisms, either impeding the transcriptional activity of ERα or diminishing E-synthesis. In post-menopausal women, E-production is chiefly attributable to the enzymatic conversion of androgens in extra-gonadal tissues by the cytochrome P-450 superfamily member aromatase. Greater understanding of steroid biosynthesis has underpinned rational drug design and pharmacological development of potent and specific aromatase inhibitors (AIs). Contemporary agents induce profound E-suppression in post-menopausal women and are first-line neo-adjuvant, adjuvant and metastatic therapies, with greater efficacy and tolerability than tamoxifen. The principal qualifier for endocrine treatment, including AIs, remains ERα expression. However, it is increasingly apparent that ERα expression is not synonymous with sensitivity to treatment and insufficient to account for the considerable heterogeneity of response. Better predictive biomarkers of de novo resistance are required to improve patient selection and identify those poor-responders who may benefit from alternative or additional systemic treatment from the outset. Among patients who do respond well initially, many relapse during their clinical course and there is also an unmet need for biomarkers of acquired resistance. The majority of women who relapse on AIs continue to express functional ERα which remains a legitimate target for second-line endocrine therapy. Understanding and overcoming acquired resistance to AIs requires a greater appreciation of ERα biology and the mechanisms though which E-dependence can be subverted. In this article, we review the impact of therapeutic E-deprivation on the natural history of ERα-positive breast cancer. Consideration is given to established and emerging biomarkers and/or determinants of response and resistance to E-deprivation. In vitro and in vivo evidence of the molecular mechanisms underpinning the transition from sensitivity to resistance are reviewed in the context of current models of ERα activity and their potential translational relevance.

Enhanced expression of the PDGFR/Abl signaling pathway in aromatase inhibitor-resistant breast cancer.

BACKGROUND: We have found that the platelet-derived growth factor receptor (PDGFR)/Abl signaling pathway is up-regulated as a determinant of the acquisition of resistance to estrogen deprivation in vitro. We aimed to determine its clinical relevance in aromatase inhibitor (AI)-resistant breast cancer. PATIENTS AND METHODS: We identified a cohort of 45 patients with estrogen receptor-positive breast cancer who had been treated with an AI, subsequently relapsed and had biopsy material available from both the presentation and post-AI recurrent lesion. PDGFRα, PDGFRß and Abl expression was assessed in formalin-fixed paraffin-embedded sections. RESULTS: Tumor protein expression of PDGFRα (1.39-fold, P=0.0065), PDGFRß (4.32-fold, P=0.006) and Abl (1.8-fold, P=0.001) was increased at the point of relapse. Tumor and stromal expression of PDGFRα as well as PDGFRß was significantly correlated in pre-treatment and relapse samples. High post-treatment tumor and stromal PDGFRß levels were associated with a short time to treatment failure (TTF). Expression of PDGFRα in relapsing tumor specimens was correlated with Abl expression and Ki67 levels. Furthermore, changes in Abl correlated significantly with changes in ER expression. CONCLUSIONS: These clinical data support a role for enhanced PDGF/Abl signaling in AI-resistant disease and provide a rationale for targeting the pathway in endocrine-resistant breast cancer.

Polychlorinated biphenyl congeners that increase the glucuronidation and biliary excretion of thyroxine are distinct from the congeners that enhance the serum disappearance of thyroxine.

Polychlorinated biphenyl (PCB) congeners differentially reduce serum thyroxine (T(4)) in rats, but little is known about their ability to affect biliary excretion of T(4). Thus, male Sprague-Dawley rats were orally administered Aroclor-1254, Aroclor-1242 (32 mg/kg per day), PCB-95, PCB-99, PCB-118 (16 mg/kg per day), PCB-126 (40 µg/kg per day), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (3.9 µg/kg per day), or corn oil for 7 days. Twenty-four hours after the last dose, [(125)I]T(4) was administered intravenously, and blood, bile, and urine samples were collected for quantifying [(125)I]T(4) and in bile [(125)I]T(4) metabolites. Serum T(4) concentrations were reduced by all treatments, but dramatic reductions occurred in response to Aroclor-1254, PCB-99 [phenobarbital (PB)-type congener], and PCB-118 (mixed-type congener). None of the treatments increased urinary excretion of [(125)I]T(4). Aroclor-1254, PCB-118, TCDD, and PCB-126 (TCDD-type congener) increased biliary excretion of T(4)-glucuronide by 850, 756, 710, and 573%, respectively, corresponding to marked induction of hepatic UDP-glucuronosyltransferase (UGT) activity toward T(4). PCB-95 and PCB-99 did not induce UGT activity; therefore, the increased biliary excretion of T(4)-glucuronide was related to the affinity of congeners for the aryl hydrocarbon receptor. The disappearance of [(125)I]T(4) from serum was rapid (within 15-min) and was increased by Aroclor-1254, PCB-99 and PCB-118. Thus, reductions in serum T(4) in response to PCBs did not always correspond with UGT activity toward T(4) or with increased biliary excretion of T(4)-glucuronide. The rapid disappearance of [(125)I]T(4) from the serum of rats treated with PB-like PCBs suggests that increased tissue uptake of T(4) is an additional mechanism by which PCBs may reduce serum T(4).

An in vitro model showing adaptation to long-term oestrogen deprivation highlights the clinical potential for targeting kinase pathways in combination with aromatase inhibition.

Aromatase inhibitors (AI) have improved the treatment of oestrogen receptor positive (ER+) breast cancer. Despite the efficacy of these agents over 40% of patients relapse with endocrine resistant disease. Here we describe an in vitro model of acquired resistance to long-term oestrogen deprivation (LTED). The LTED cells retain expression of the ER and appear hypersensitive to oestrogen as a result of altered kinase activity. Furthermore analysis of temporal changes in gene expression during the acquisition of resistance highlight growth factor receptor pathways as key mediators of this adaptive process.

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance.

Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERalpha)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERalpha. In this study, we show that in ERalpha-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERalpha phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERalpha transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAM(R)-1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERalpha-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERalpha-positive breast cancers and in particular in tamoxifen-resistant tumors.

EGFR/HER2 inhibitor AEE788 increases ER-mediated transcription in HER2/ER-positive breast cancer cells but functions synergistically with endocrine therapy.

BACKGROUND: Cross-talk between receptor tyrosine kinases and the oestrogen receptor (ER) is implicated in resistance to endocrine therapy. We investigated whether AEE788 (a combined inhibitor of EGFR, HER2 and VEGFR) plus tamoxifen or letrozole enhanced the individual anti-tumour effects of these agents. METHODS: Breast cancer cell lines modelling endocrine-resistant and -sensitive disease were engineered to express aromatase (A) and examined using proliferation, western blotting and ER-alpha transcription assays. RESULTS: AEE788 enhanced the anti-proliferative effect of tamoxifen and letrozole in ER(+) cell lines (MCF-7 2A, ZR75.1 A3 and BT474 A3). This associated with an elevated G1 arrest and nuclear accumulation of p27. It is noteworthy that AEE788 alone or in combination with endocrine therapy increased the expression of progesterone receptor (PGR) and TFF1 in BT474 A3 cells. This may indicate a mechanism of resistance to AEE788 in ER(+)/HER2(+) breast cancers. In a ZR75.1 A3 xenograft, AEE788 alone or in combination with tamoxifen provided no further benefit compared with letrozole. However, letrozole plus AEE788 produced a significantly greater inhibition of tumour growth compared with letrozole alone. CONCLUSION: These data suggest that AEE788 plus letrozole in breast cancer overexpressing HER2 may provide superior anti-tumour activity, compared with single agents.

The anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 breast cancer cells refractory to long-term oestrogen deprivation through down-regulation of oestrogen receptor and IGF signalling.

Long-term culture of MCF-7 wild-type (wt) cells in steroid-depleted medium (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of ERalpha and enhanced growth factor signalling. In this study, we aimed to compare the effects of the pure anti-oestrogen ICI 182,780 (ICI) with the competitive anti-oestrogen tamoxifen (TAM) on oestrogen and IGF signalling in these cells. Wt MCF-7 and LTED cells were treated with a log 7 concentration range of E2, TAM or ICI. Effects on cell growth, ERalpha transactivation, expression of ERalpha, ERbeta and components of the IGF pathway were measured with and without insulin. In the presence of insulin, growth of LTED cells was refractory to TAM but inhibited by ICI and E2. In the absence of insulin, LTED cells showed persistent hypersensitivity to E2, and remained inhibited by ICI but were largely unaffected by TAM. ICI but not TAM inhibited ER-mediated gene transcription and treatment with ICI resulted in a dose-dependent reduction in ERalpha levels whilst having no effect on ERbeta expression. IGF-I receptor and insulin receptor substrate 2 levels were increased in LTED versus the Wt MCF-7 cells, and ICI but not TAM reduced their expression in a dose-dependent fashion. Thus IGF signalling as well as ERalpha expression and function are enhanced during LTED. While the resultant cells are resistant to TAM, ICI down-regulates ERalpha, reducing IGF signalling and cell growth. These results support the use of ICI in women with ER-positive breast cancer who have relapsed on an aromatase inhibitor.

Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience.

De novo resistance to endocrine therapy is a near-universal feature of oestrogen receptor (ER)- negative breast cancer. Although many ER-positive breast cancers also show no response to tamoxifen or aromatase inhibitors on objective clinical grounds the large majority show reduced proliferation indicating that some oestrogen dependence is present in almost all ER-positive breast cancer. In neoadjuvant studies HER2 positivity is associated with poor response rates to tamoxifen but not aromatase inhibitors, consistent with preclinical models. Acquired resistance to tamoxifen is associated with decreases in ER positivity but most recurrent lesions remain ER-positive. A small proportion of these show increased HER2 expression and in these patients increased phospho-p38 may contribute to the tamoxifen-resistant phenotype. There is an unfortunate paucity of clinical and biological data on acquired resistance to aromatase inhibitors.

Consensus statement. Workshop on therapeutic resistance in breast cancer: impact of growth factor signalling pathways and implications for future treatment.

Anti-hormones (notably tamoxifen), chemotherapy and modern radiotherapeutic approaches are invaluable in the management of breast cancer, and collectively have contributed substantially to the improved survival in this disease. Moreover, there is promise that these successes will continue with the emergence of other endocrine agents (for example, aromatase inhibitors and pure anti-oestrogens). However, de novo and acquired resistance comprises a significant problem with all treatment approaches examined to date. This Workshop aimed to evaluate the contribution made by growth factor signalling pathways in the various resistant states, primarily focusing on resistance to anti-hormonal strategies and spanning experimental models and, where possible, clinical breast cancer data. The successes and limitations of therapeutic targeting of these pathways with various signal transduction inhibitors (STIs) were evaluated in model systems and from emerging clinical trials (including epidermal growth factor receptor inhibitors such as gefitinib). It was concluded that growth factor signalling is an important contributor in the development of endocrine resistance in breast cancer and that use of STIs provides a promising therapeutic strategy for this disease. However, the cancer cell is clearly able to harness alternative growth factor signalling pathways for growth and cell survival in the presence of STI monotherapy and, as a consequence, the efficacy of STIs is likely to be limited by the acquisition of resistance. A number of strategies were proposed from studies in model systems that appeared to enhance anti-tumour actions of existing STI monotherapy, notably including combination therapies targeting multiple pathways. With the increased availability of diverse STIs and improved drug delivery, there is much hope that the more complex therapeutic strategies proposed may ultimately be achievable in clinical practice.

Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention.

Interest in chemoprevention in oncology using suppressants of prostaglandin (PG) synthesis has been stimulated by epidemiological observations that the use of aspirin and other non-steroidal inflammatory drugs (NSAIDs) is associated with reduced incidence of some cancers, including cancer of the breast. The main target of NSAID activity is the cyclooxygenase (COX) enzyme. Two isoforms of COX have been identified: COX-1, the constitutive isoform; and COX-2. the inducible form of the enzyme. COX-2 can undergo rapid induction in response to many factors such as bacterial lipopolysaccharides, growth factors, cytokines and phorbol esters. COX-2 is overexpressed in some malignancies including carcinoma of the breast. It has been suggested that such enhanced expression may lead to increased angiogenesis such that the inhibition of COX-2 might have a general anticancer effect via decreased blood vessel formation. In addition, an association between COX-2, its main product PGE2 and aromatase activity in human breast cancer suggests that such inhibitors might have an additional, specific prophylactic mechanism for this tumour. New COX-2 inhibitors are already licensed for use in the treatment of arthritis and are well tolerated. Their potential role in chemoprevention of mammary carcinogenesis in rats has already been investigated. What remains to be seen is if these findings can be extrapolated to human studies.

Oncological applications of gene therapy.

Despite the rapid technological advances that continue to sustain the field of cancer gene therapy, few individual patients have benefited from the revolution so far. The plethora of clinical trials described confirms that each malignancy will have its own ideal strategy based on the associated molecular defects, and there has been rapid progress from this viewpoint. At the same time, there has been a renewed appreciation for the limitations to gene therapy, which include low efficiency of gene transfer, poor specificity of response and methods to accurately evaluate responses, and lack of truly tumor-specific targets at which to aim. As with all new therapies, we are climbing a steep learning curve in terms encountering treatment-related toxicities, as well as profound ethical and regulatory issues.

Gene therapy: recent progress in the clinical oncology arena.

Despite the rapid technological advances that continue to sustain the field of cancer gene therapy, few individual patients have benefited from the revolution so far. The plethora of clinical trials described confirms that each malignancy will have its own ideal strategy based on the associated molecular defects, and there has been rapid progress from this viewpoint. At the same time, there has been a renewed appreciation for the limitations to gene therapy, which include low efficiency of gene transfer, poor specificity of response and methods to accurately evaluate responses, and lack of truly tumor-specific targets at which to aim. As with all new therapies, we are climbing a steep learning curve in terms encountering treatment-related toxicities, as well as profound ethical and regulatory issues.

Genetic prodrug activation therapy for breast cancer: A phase I clinical trial of erbB-2-directed suicide gene expression.

PURPOSE: This trial was designed to test the safety and efficacy of a tumor-specific genetic prodrug activation therapy targeted by use of the human erbB-2 gene promoter. The erbB-2 oncogene is overexpressed in approximately 20% of cases of breast cancer and is associated with poor prognosis. PATIENTS AND METHODS: Twelve breast cancer patients received transcriptionally targeted gene therapy in a phase I clinical trial using direct intratumoral injection of plasmid construct combined with systemic administration of prodrug. The genetic prodrug activation therapy is specifically targeted to erbB-2-overexpressing breast cancer cells by use of a therapeutic cassette that contains the Escherichia coli cytosine deaminase gene driven by the tumor-specific erbB-2 promoter, thus allowing activation of fluorocytosine to the active cytotoxic fluorouracil only within tumor cells that express the oncogene. RESULTS: The approach was shown to be safe and to result in targeted gene expression in up to 90% of cases. Using a number of different assays, we demonstrated that significant levels of expression of the suicide gene were specifically restricted to erbB-2-positive tumor cells, confirming the selectivity of the approach. CONCLUSION: The results of this study, the first targeted gene therapy for breast cancer and the first to use the cytosine deaminase system in human subjects, are encouraging for the development of genetic prodrug activation therapies that exploit the transcriptional profile of cancer cells.

Essentials of radiation oncology chart design.

Medical Dosimetrists are commonly called upon to participate in the design of radiation oncology treatment records. The Medical Dosimetrist is uniquely qualified to provide input in the areas of treatment planning, simulation and delivery documentation. An idealized chart can facilitate the planning and delivery of quality patient care and lead the user to document such care. This publication outlines the essential minimum requirements for inclusion in a radiation oncology treatment chart. Conventional treatment record keeping has been by hard-copy documentation. Paperless treatment record models are presently being tested for efficacy. Either approach should seek to: maintain quality of patient care, enhance communication, and provide integrity in documentation.

Neuropathic pain in cancer patients: mechanisms, syndromes, and clinical controversies.

The identification of a neuropathic pain syndrome in a cancer patient requires a focused clinical evaluation based on knowledge of common neuropathic pain syndromes. If a tumor is directly involved in the etiology of the pain, oncologic treatment is an initial consideration and may include surgery, radiation, or chemotherapy. There is no single accepted algorithm for the analgesic treatment of neuropathic pain and a systematic approach utilizing therapeutic trials of specific agents at gradually increasing doses is warranted. A trial of opioids, perhaps in combination with an NSAID, is warranted. If the pain is relatively unresponsive to an opioid, a trial with an adjuvant analgesic is reasonable. For example, a tricyclic antidepressant might be selected early for patients with continuous dysesthesia, and early treatment with an anticonvulsant might be used if the pain is predominantly lancinating or paroxysmal. Other adjuvant analgesics can be selected if there is insufficient response to these agents. A trial of sympathetic blockade, pharmacologic, anesthetic or surgical, should be considered in patients with evidence of causalgia or reflex sympathetic dystrophy. Physiatric modalities such as massage, heat, or cold; counterstimulation or transcutaneous electrical nerve stimulation (TENS), and orthopedic interventions, such as braces and splints may be useful. Epidural injections or neurostimulation of the spinal cord or brain can be considered in selected cases where appropriate expertise is available. Treatment of neuropathic pain remains a challenge for both clinicians and patients. The complexity of syndromes and underlying etiologic mechanisms warrants further clinical trials to determine the best treatment modalities for individual pain syndromes.