Small steps of improvement in small-cell lung cancer (SCLC) within two decades: A comprehensive analysis of 484 patients

Background

It is not clear whether or not the fate of patients suffering from small-cell lung cancer (SCLC) has improved. To better understand the course of disease, we aimed at documenting disease features at initial diagnosis, sequences of therapy modalities and outcome in consecutive patients over two decades. We postulated that SCLC patients might have benefitted from refined diagnosis and treatment options during the last decade.

Methods

All SCLC cases diagnosed at the Innsbruck University Hospital and associated institutions between 1991 and 2011 have been documented in detail in accordance with a prespecified protocol.

Results

A total of 484 patients diagnosed with SCLC were followed. The most important symptoms at initial diagnosis were cough, dyspnea and tumor pain in 55%, 51% and 44%, respectively. Patients who were operated during early stage of disease (n = 26) had a favorable 5-year, relapse-free survival (74%). A total of 112 patients with locally advanced disease were treated by radiochemotherapy in curative intent (RCT), and achievement of CR offered a chance of long term overall survival (OS), reaching 44% after 10-years. In the palliative setting (median OS in 304 evaluable patients, 9.7 months), a therapeutic progress in the more recent decade could not be observed. Parameters independently associated with favorable OS were: response to therapy and prophylactic brain irradiation in patients with RCT; and response, age <70 years and absence of LDH elevation in the palliative setting.

Conclusions

In this comprehensive view on SCLC, the findings on symptomatology, comorbidity, and spectrum of treatments may help to better understand individual courses of the disease. Overall, modern medicine failed to translate into substantial benefit of SCLC patients, except in patients in locally advanced disease receiving multimodal therapy.     

Voluntary ethanol consumption differs in adolescent and adult male rats using a modified sucrose-fading paradigm

Background: Initiation of alcohol consumption during adolescence is high, which usually begins with consumption of highly concentrated sweetened alcoholic beverages in adolescent humans. Enhanced voluntary ethanol (EtOH) intake has been observed previously in adolescent relative to adult rats under continuous access conditions using sweetened EtOH solutions. The present set of experiments investigated patterns of voluntary EtOH intake in adolescent and adult rats using sweetened EtOH solutions in a limited access paradigm. Methods: Rats were trained with modified sucrose‐substitution protocols that ended at either 5% sucrose‐20% EtOH (5S/20E) (Exp. 1) or 5% sucrose‐10% EtOH (5S/10E) (Exp. 2). Results: Voluntary EtOH consumption differences between the 2 age groups were apparent at higher (i.e., 10 and 20%), but not lower (i.e., 2 and 5%) EtOH concentrations. Adolescent rats consumed more EtOH on a g/kg basis only at 20% EtOH (Exp. 1). Adolescent rats voluntarily consumed more EtOH than adults when maintained at 5S/10E (Exp. 2). To assess whether these age‐related differences in voluntary EtOH intake were concentration dependent, rats were trained with 5S/20E and subsequently trained with decreasing EtOH concentrations (i.e., 5S/10E and 5S/5E). Adolescents consumed more EtOH when initially presented with the 5S/10E and 5S/20E EtOH concentrations, and subsequently at the lower 5S/5E EtOH concentration (Exp. 3). There were no differences in preference for the sucrose‐only solution, however adolescents tended to consume more sucrose at the 5S sucrose concentration (Exp. 4). Given that adolescents consumed more EtOH at the 5S/10E and 5S/20E, but not at the 5S/5E EtOH concentrations, preference for sucrose does not solely explain the age differences in voluntary EtOH intake observed. Conclusions: Overall, results replicate previous work, demonstrating adolescent rats consume more EtOH relative to adults. However, the present results were observed using sweetened EtOH solutions in a limited access paradigm. The present modified sucrose‐substitution paradigm may serve as a valid model of human adolescent drinking behavior.     

The usefulness of multimodal imaging for differentiating pseudopapilloedema and true swelling of the optic nerve head: a review and case series

Ophthalmic practitioners have to make a critical differential diagnosis in cases of an elevated optic nerve head. They have to discriminate between pseudopapilloedema (benign elevation of the optic nerve head) and true swelling of the optic nerve head. This decision has significant implications for appropriate patient management. Assessment of the optic disc prior to the advanced imaging techniques that are available today (particularly spectral domain optical coherence tomography and fundus autofluorescence), has mainly used diagnostic tools, such as funduscopy and retinal photography. As these traditional methods rely on the subjective assessment by the clinician, evaluation of the elevated optic nerve head to differentiate pseudopapilloedema from true swelling of the optic nerve head can be a challenge in clinical practice with patients typically referred for further neuroimaging investigation when the diagnosis is uncertain. The use of multimodal ocular imaging tools such as spectral domain optical coherence tomography, short wavelength fundus autofluorescence and ultrasonography, can potentially aid in the differentiation of pseudopapilloedema from true swelling of the optic nerve head, in conjunction with other clinical findings. By doing so, unnecessary patient costs and anxiety in the case of pseudopapilloedema can be reduced, and appropriate urgent referral and management in the case of true swelling of the optic nerve head can be initiated.     

Positive allosteric modulators of the human sweet taste receptor enhance sweet taste

To identify molecules that could enhance sweetness perception, we undertook the screening of a compound library using a cell-based assay for the human sweet taste receptor and a panel of selected sweeteners. In one of these screens we found a hit, SE-1, which significantly enhanced the activity of sucralose in the assay. At 50 μM, SE-1 increased the sucralose potency by >20-fold. On the other hand, SE-1 exhibited little or no agonist activity on its own. SE-1 effects were strikingly selective for sucralose. Other popular sweeteners such as aspartame, cyclamate, and saccharin were not enhanced by SE-1 whereas sucrose and neotame potency were increased only by 1.3- to 2.5-fold at 50 μM. Further assay-guided chemical optimization of the initial hit SE-1 led to the discovery of SE-2 and SE-3, selective enhancers of sucralose and sucrose, respectively. SE-2 (50 μM) and SE-3 (200 μM) increased sucralose and sucrose potencies in the assay by 24- and 4.7-fold, respectively. In human taste tests, 100 μM of SE-1 and SE-2 allowed for a reduction of 50% to >80% in the concentration of sucralose, respectively, while maintaining the sweetness intensity, and 100 μM SE-3 allowed for a reduction of 33% in the concentration of sucrose while maintaining the sweetness intensity. These enhancers did not exhibit any sweetness when tasted on their own. Positive allosteric modulators of the human sweet taste receptor could help reduce the caloric content in food and beverages while maintaining the desired taste.     

Routine scrotal ultrasonography during the follow‐up of patients with testicular cancer leads to earlier detection of asynchronous tumours and a high rate of organ preservation

Study Type – Diagnosis (case series)
Level of Evidence 4

OBJECTIVE

To compare outcomes of patients with asynchronous tumours detected before and after the introduction of scrotal ultrasonography (SUS) during routine follow‐up examinations.

PATIENTS AND METHODS

Since January 2001 SUS was also used during the follow‐up of patients with testicular cancer. A series of 16 consecutive patients with asynchronous bilateral testicular tumours diagnosed while still complying with routine follow up investigations were identified and divided into two groups; group A was diagnosed by palpation only, before 2001, and group B was diagnosed after 2000. The groups were compared statistically for the interval between asynchronous tumours, clinical stage, tumour diameter at the time of diagnosis and rate of testis‐sparing surgery.

RESULTS

All tumours in group A were diagnosed by palpation, but only two in group B were palpable at the time of diagnosis. The mean tumour diameter was statistically significantly smaller in group B (1.2 cm) than in group A (2.68 cm); testis‐sparing surgery was used in all of group B and only three patients in group A. After organ‐sparing surgery all patients had normal testosterone levels. All patients after organ‐sparing surgery had adjuvant scrotal radiotherapy because of germ cell tumour, and no patient had a local recurrence.

CONCLUSION

Our data indicate that using SUS for the remaining testicle in routine follow‐up visits of patients with testicular cancer leads to the earlier detection of smaller tumours and, consequently, a higher rate of organ preservation. The maintenance of physiological endocrine function might finally result in a better quality of life.     

Repeated binge ethanol administration during adolescence enhances voluntary sweetened ethanol intake in young adulthood in male and female rats

Binge alcohol consumption is a rising concern in the United States, especially among adolescents. During this developmental period alcohol use is usually initiated and has been shown to cause detrimental effects on brain structure and function as well as cognitive/behavioral impairments in rats. Binge models, where animals are repeatedly administered high doses of ethanol typically over a period of three or four days cause these effects. There has been little work conducted aimed at investigating the long-term behavioral consequences of repeated binge administration during adolescence on later ethanol-induced behavior in young adulthood and adulthood. The repeated four-day binge model may serve as a good approximate for patterns of human adolescent alcohol consumption as this is similar to a “bender” in human alcoholics. The present set of experiments examined the dose-response and sex-related differences induced by repeated binge ethanol administration during adolescence on sweetened ethanol (Experiment 1) or saccharin (Experiment 2) intake in young adulthood. In both experiments, on postnatal days (PND) 28-31, PND 35-38 and PND 42-45, ethanol (1.5, 3.0 or 5.0 g/kg) or water was administered intragastrically to adolescent rats. Rats underwent abstinence from PND 46-59. Subsequently, in young adulthood, ethanol and saccharin intake were assessed. Exposure to any dose of ethanol during adolescence significantly enhanced ethanol intake in adulthood. However, while female rats had higher overall g/kg intake, males appear to be more vulnerable to the impact of adolescent ethanol exposure on subsequently increased ethanol intake in young adulthood. Exposure to ethanol during adolescence did not alter saccharin consumption in young adulthood in male or female rats. Considering that adolescence is the developmental period in which ethanol experimentation and consumption is usually initiated, the present set of experiments demonstrate the importance of elucidating the impact of early binge-pattern ethanol exposure on the subsequent predisposition to drink later in life.     

Chronic ethanol exposure during adolescence increases basal dopamine in the nucleus accumbens septi during adulthood

BACKGROUND: In humans, adolescent exposure to alcohol is associated with the onset of adult alcohol dependency and suggests that early use potentiates vulnerability to addiction. The aim of the present study was to address whether chronic ethanol exposure during adolescence would alter nucleus accumbens septi (NAcc) dopamine (DA) levels in the adult brain. METHODS: Rats were injected daily from postnatal day (PND) 30 to 50 with either 0.75 g/kg/i.p. ethanol or saline followed by an ethanol-abstinent period from PND 51 to 65. Changes in extracellular DA levels in the anterior NAcc shell were measured via the no net flux (NNF) paradigm. RESULTS: Extracellular DA levels were greater in rats chronically treated with ethanol during adolescence (6.5 nM DA) in comparison with saline-exposed controls (3.6 nM DA). There were no differences in extraction fraction (E(d)), an indirect measure of DA reuptake, between ethanol-treated (87%) and nontreated (68%) rats. CONCLUSIONS: Together these findings suggest that changes in extracellular DA may be an underlying physiological mechanism in adolescent vulnerability to the rewarding properties of ethanol.