Comparison of Prices and Affordability of Cancer Medicines in 16 Countries in Europe and Latin America.

BACKGROUND: There are concerns that high prices of cancer medicines may limit patient access. Since information on prices for cancer medicines and their impact on affordability is lacking for several countries, particularly for lower income countries, this study surveys prices of originator cancer medicines in Europe and Latin America and assesses their affordability. METHODS: For 19 cancer medicines, public procurement and ex-factory prices, as of 2017, were surveyed in five Latin American (LATAM) countries (Brazil, Chile, Colombia, Mexico, and Peru) and 11 European countries (Austria, France, Germany, Greece, Hungary, the Netherlands, Poland, Romania, Spain, Sweden, and the UK). Price data (public procurement prices in LATAM and ex-factory prices in Europe) in US dollar purchasing power parities (PPP) were analyzed per defined daily dose. Affordability was measured by setting medicines prices in relation to national minimum wages. RESULTS: The prices of cancer medicines varied considerably between countries. In European countries with higher levels of income, PPP-adjusted prices tended to be lower than in European countries of lower income and LATAM countries. Except for one medicine, all surveyed medicines were considered unaffordable in most countries. In European countries of lower income and LATAM countries, more than 15 days' worth of minimum wages would be required by a worker to purchase one defined daily dose of several of the studied medicines. CONCLUSIONS: The high prices and large unaffordability of cancer medicines call for strengthening pricing policies with the aim of ensuring affordable treatment in cancer care.

Surveillance pouchoscopy for dysplasia: Cleveland Clinic Ileoanal Pouch Anastomosis Database.

BACKGROUND: No formal guidelines exist for surveillance pouchoscopy following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis. METHODS: All adults who had previously had IPAA for ulcerative colitis, and underwent a pouchoscopy between 1 January 2010 and 1 January 2020, were included. RESULTS: A total of 9398 pouchoscopy procedures were performed in 3672 patients. The majority of the examinations were diagnostic (8082, 86·0 per cent; 3260 patients) and the remainder were for routine surveillance (1316, 14·0 per cent; 412 patients). Thirteen patients (0·14 per cent of procedures) were found to have biopsy-proven neoplasia at the time of pouchoscopy; seven had low-grade dysplasia (LGD) (0·07 per cent; all located in the anal transition zone), none had high-grade dysplasia (HGD) and six (0·06 per cent) had invasive adenocarcinoma (4 in anal transition zone and 6 in pouch). Of the six patients with adenocarcinoma, four had neoplasia at the time of proctocolectomy (2 adenocarcinoma, 1 LGD, 1 HGD); all six were symptomatic with anal bleeding or pelvic pain at the time of pouchoscopy, had a negative surveillance pouchoscopy examination within 2 years of diagnosis of adenocarcinoma, had palpable masses on digital rectal examination, and had visible lesions at the time of pouchoscopy. CONCLUSION: Surveillance pouchoscopy is not recommended in asymptomatic patients because significant neoplasia following IPAA for ulcerative colitis is rare.

ANTECEDENTES: No existen unas recomendaciones formales para vigilancia endoscópica en pacientes a los que se les ha realizado un reservorio ileoanal (ileal pouch anal anastomosis, IPAA) por una colitis ulcerosa (ulcerative colitis, UC). MÉTODOS: Se incluyeron todos los pacientes adultos a los que se les había realizado previamente un IPAA por UC y se sometieron a una endoscopia del reservorio. RESULTADOS: Se realizaron un total de 9.398 procedimientos endoscópicos en 3.672 pacientes entre el 1/1/2010 y el 1/1/2020. La mayoría de las exploraciones fueron diagnósticas (n = 8.082; 86%; 3.260 pacientes) y el resto fueron de seguimiento (n = 1.316; 14%; 412 pacientes). Se descubrió que 13 pacientes tenían una neoplasia demostrada por biopsia (0,14%) en el momento de la endoscopia; siete pacientes tenían displasia de bajo grado (low-grade displasia, LGD) (0,074%; localizada en todos los casos en la zona de transición anal), ninguno tenía displasia de alto grado (high-grade displasia, HGD) y seis (0,064%) tenían un adenocarcinoma invasivo (cuatro en la zona de transición anal) y dos en el reservorio). De los seis pacientes con adenocarcinoma, 4 tenían neoplasia en el momento de la proctocolectomía (2 adenocarcinoma, uno LGD, uno HGD). Todos estos pacientes tenían síntomas de hemorragia anal o dolor pélvico en el momento de la endoscopia, se les había practicado una endoscopia previa reciente del reservorio en los dos años anteriores, presentaban una masa palpable en la exploración digital rectal, así como lesiones visibles en la endoscopia del reservorio. CONCLUSIÓN: La vigilancia endoscópica del reservorio no se recomienda en pacientes asintomáticos porque es raro que aparezca una neoplasia después del IPAA por UC.

Brain-derived neurotrophic factor inhibits osmotic swelling of rat retinal glial (Müller) and bipolar cells by activation of basic fibroblast growth factor signaling.

Water accumulation in retinal glial (Müller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Intravitreal administration of neurotrophins such as brain-derived neurotrophic factor (BDNF) is known to promote survival of retinal neurons. Here, we show that exogenous BDNF inhibits the osmotic swelling of Müller cell somata induced by superfusion of rat retinal slices or freshly isolated cells with a hypoosmotic solution containing barium ions. BDNF also inhibited the osmotic swelling of bipolar cell somata in retinal slices, but failed to inhibit the osmotic soma swelling of freshly isolated bipolar cells. The inhibitory effect of BDNF on Müller cell swelling was mediated by activation of tropomyosin-related kinase B (TrkB) and transactivation of fibroblast growth factor receptors. Exogenous basic fibroblast growth factor (bFGF) fully inhibited the osmotic swelling of Müller cell somata while it partially inhibited the osmotic swelling of bipolar cell somata. Isolated Müller cells displayed immunoreactivity of truncated TrkB, but not full-length TrkB. Isolated rod bipolar cells displayed immunoreactivities of both TrkB isoforms. Data suggest that the neuroprotective effect of exogenous BDNF in the retina is in part mediated by prevention of the cytotoxic swelling of retinal glial and bipolar cells. While BDNF directly acts on Müller cells by activation of TrkB, BDNF indirectly acts on bipolar cells by inducing glial release of factors like bFGF that inhibit bipolar cell swelling.

Osteopontin inhibits osmotic swelling of retinal glial (Müller) cells by inducing release of VEGF.

Osmotic swelling of retinal neurons and glial cells is an important pathogenic factor of retinal edema formation. Here, we show that the neuroprotective factor osteopontin (OPN), which is released from retinal glial (Müller) cells after stimulation of the cells with glial cell line-derived neurotrophic factor (Del Río et al., 2011, Glia 59:821-832), inhibits the swelling of rat Müller cells induced by hypoosmotic exposure of retinal slices in the presence of barium ions and H2O2, respectively, and in slices of postischemic retinas. OPN did not inhibit the hypoosmotic swelling of bipolar cells in slices of control and postischemic retinas. The inhibitory effect of OPN on Müller cell swelling was dose-dependent, with a half-maximal effect at ∼0.6 ng/ml. The effect of OPN was abrogated in the presence of pharmacological blockers of vascular endothelial growth factor (VEGF) receptor-2, metabotropic glutamate receptors, and purinergic receptors (P2Y1, adenosine A1 receptors), as well as of a neutralizing anti-VEGF antibody. The data suggest that OPN induces the release of VEGF, glutamate, ATP, and adenosine from Müller cells. The effect of OPN was also prevented by blockers of voltage-gated sodium channels (tetrodotoxin), T-type voltage-gated calcium channels (kurtoxin), potassium channels (clofilium), and chloride channels 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). The swelling-inhibitory effect of OPN was dependent on intracellular calcium signaling, activation of phospholipase C and protein kinase C, and vesicular exocytosis of glutamate. In retinal slices, Müller glial cells display immunoreactivity of OPN. The data suggest that Müller cell-derived OPN has (in addition to the effects on photoreceptors and retinal neurons) autocrine effects. The neuroprotective effects of OPN may be in part mediated by the prevention of cytotoxic Müller cell swelling and the release of VEGF and adenosine from Müller cells.

Personalised medicine as a challenge for public pricing and reimbursement authorities ­ A survey among 27 European countries on the example of trastuzumab.

OBJECTIVES: To survey possible funding models and pricing practices as well as prices for the treatment package of trastuzumab and its accompanying diagnostic test in European countries, as an example of personalised medicines. METHODS: Qualitative descriptive data on national pharmaceutical pricing and funding policies applied to trastuzumab and its accompanying diagnostic test were obtained from a survey among competent authorities from 27 European countries as of August 2011. Further, price data (for the years 2005-2013) of trastuzumab in the respective European countries were surveyed and analysed. RESULTS: In 2011, testing and treatment mainly took place in hospitals or in specific day-care ambulatory clinics. In the European countries either both trastuzumab and the accompanying diagnostic test were funded from hospital budgets (n = 13) or only medicines were funded from the third party payers such social insurances and the test from hospital budgets (n = 14). Neither combined funding of both medicine and diagnostic test by third party payers was identified in the surveyed countries nor did the respondents from the competent authorities identify any managed entry agreements. National pricing procedures are different for trastuzumab versus its diagnostic test, as most countries apply price control policies for trastuzumab but have free pricing for the diagnostic test. The ex-factory price is, on average, €609 per 150 mg vial with powder in 2013; in nine countries the price of trastuzumab went down from 2005 till 2013. CONCLUSION: The example of trastuzumab and its accompanying diagnostic test highlights some problems of the interface between different funding streams (out-patient and hospital) but also with regard to the interface between the medicine applied in combination with a medical device. The findings suggest a need for further developing and refining policy options to address the identified interface issues.

[Bouts of chest pain]. / Anfallsartige Thoraxschmerzen.

We report on a 46-year-old man with vasospastic angina. The differential diagnosis, the eventful course of the patient and in particular the clinical image with diagnostic approach, therapy and prognosis of vasospastic angina are discussed.

Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers.

Here, we report the alterations in renal water handling in healthy volunteers during a 6 h thermoneutral water immersion at 34 to 36 degrees C. We found that water immersion is associated with a reversible increase in total urinary AQP2 excretion.

Mechanisms of sodium and chloride transport across isolated sheep reticulum.

1. 22Na+ and 36Cl- fluxes across isolated reticular epithelium of sheep were measured by using the Ussing-chamber technique. 2. Net NaCl absorption driven by Na(+)-K(+)-ATPase was observed under short-circuit conditions. 3. Evaluation of fluxes measured under voltage-clamp conditions indicated that Na+ absorption is mainly electroneutral. 4. Mucosal application of bumetanide, hydrochlorothiazide, or low dose amiloride (10(-4) M) produced no changes in Na+ transport whereas addition of higher doses of amiloride (> or = 10(-3) M) led to a reduction in net Na+ transport. Short chain fatty acids (SCFA) enhanced the amiloride-sensitive Na+ transport. 5. Alterations of JmsNa induced by inhibitors or by SCFA were always accompanied by qualitatively similar changes of JsmNa. Amiloride-sensitive JsmNa was also decreased at low mucosal Na+ concentration. 6. DIDS, SITS, and nitrate reduced both JmsCl and JsmCl. SCFA did not influence chloride transport. 7. It is concluded that Na+ transport is mediated by Na(+)-H+ exchange and by transport processes operating as Na+ self-exchange. Mucosal-to-serosal chloride transport seems partly to depend on anion exchange systems.

Short-chain fatty acids and CO2 as regulators of Na+ and Cl- absorption in isolated sheep rumen mucosa.

Unidirectional 22Na+ and 36Cl- fluxes were determined in short-circuited, stripped rumen mucosa from sheep by using the Ussing chamber technique. In both CO2/HCO3(-)-containing and CO2/HCO3(-)-free solutions, replacement of gluconate by short-chain fatty acids (SCFA, 39mM) significantly enhanced mucosal-to-serosal Na+ absorption without affecting the Cl- transport in the same direction. Short-chain fatty acid stimulation of Na+ transport was at least partly independent of Cl- and could almost completely be abolished by 1 mM mucosal amiloride, while stimulation of Na+ transport was enhanced by lowering the mucosal pH from 7.3 to 6.5. Similar to the SCFA action, raising the PCO2 in the mucosal bathing solution led to an increase in the amiloride-sensitive mucosal-to-serosal Na+ flux. Along with its effect on sodium transport, raising the PCO2 also stimulated chloride transport. The results are best explained by a model in which undissociated SCFA and/or CO2 permeate the cell membrane and produce a raise in intracellular H+ concentration. This stimulates an apical Na+/H+ exchange, leading to increased Na+ transport. The stimulatory effect of CO2 on Cl- transport is probably mediated by a Cl-/HCO3- exchange mechanism in the apical membrane. Binding of SCFA anions to that exchange as described for the rat distal colon (Binder and Mehta 1989) probably does not play a major role in the rumen.

[Therapy goals from the viewpoint of patients: what is the role of partnership?]. / Therapieziele aus der Sicht von Patienten: Welche Rolle spielt die Partnerschaft?

The topic of this investigation is the significance of the real field of reference of psychosomatic patients in inpatient psychotherapy. Data on expected therapeutic results and changes experienced by patients with a steady partner were submitted to evaluation by content analysis. The greatest importance is attached in each case to individual growth, followed by symptoms and interpersonal relationships. All patients place more emphasis on the actual field of reference at the end than at the beginning of therapy; this difference is more strongly pronounced in patients without couples interviews. Evidently patients with couples interviews assess their partnership more realistically than those without them. Moreover, therapists have presumably developed "an ear for the partner" irrespective of whether or not the partner is included.

[Studies on the condition of marginal periodontium depending on the shape of the bridgework body]. / Untersuchungen zum Zustand des marginalen Periodontiums in Abhängigkeit von der Brückenkörpergestaltung.

Within an 8-years-longitudinal study 40 patients with 30 tangential and 28 open bridges were examined. The accumulation of plaque as well as the degree of inflammation of the gingiva adjacent to the bridgework binder and the bridgework bodies were determined by means of selected indices, and the data obtained were compared to those evaluated when the bridges were fitted in. The results show that the accumulation of plaque (on) with open bridge was slightly elevated as compared to tangential bridges whereas the inflammation of the gingiva was significantly increased with tangentially shaped bridgework bodies. For this reason open bridges should be used further more in areas, where aesthetics play only a secondary role.