Synergistic Survival: A New Phenomenon Connected to Adverse Events of First-Line Sunitinib Treatment in Advanced Renal Cell Carcinoma.

BACKGROUND: The aim was to assess the relationship between treatment efficacy and adverse events (AEs) for patients with advanced renal cell carcinoma treated with first-line sunitinib. PATIENTS AND METHODS: 274 patients were treated with sunitinib (50 mg/d, 4-weeks-on and 2-weeks-off schedule). Physical and laboratory evaluations were done every sixth week. AEs were diagnosed at every visit. Clinical response was assessed every 3 months. The objective response rate (ORR), median progression-free (mPFS) and median overall survival (mOS) and AEs were evaluated. Besides χ(2) and log rank tests, multivariate Cox regression analysis and for synergism 1-sided t tests were used. RESULTS: The ORR was 25%. After a median follow-up of 32 months, the mPFS and mOS were 9 and 19 months, respectively. Hypertension, diarrhea, hypothyroidism, mucositis, hand-foot syndrome (HFS), skin toxicity, and leukopenia were the most frequent treatment-associated AEs. Significantly longer (P < .01) mPFS and mOS were observed when hypertension, diarrhea, HFS, hypothyroidism, skin toxicity, or leukopenia occurred. A statistically significant synergistic effect of the listed AEs was observed for progression-free survival (P < .001) and overall survival (P < .001). Multivariate analysis revealed that besides the prognostic category, the higher number of AEs (3-6 vs. 0-2) was an independent marker of longer mPFS (24 vs. 5 months, respectively; P < .001) and mOS (51 vs. 9 months, respectively; P < .001). CONCLUSION: Results of this study provide evidence for the synergistically enhanced efficacy of sunitinib treatment in patients who present multiple AEs. These AEs are diagnosed routinely and their coexistence can help physicians to predict which group of patients would benefit the most from first-line sunitinib treatment.

[Treatment strategies for advanced prostate cancer]. / Kezelési stratégiák elorehaladott prosztatadaganatban.

There has been dramatic improvement in the diagnosis and treatment of prostate cancer recently. The treatment of localized disease became more successful with the application of new, sophisticated techniques available for urologic surgeons and radiotherapists. Nevertheless a significant proportion of patients relapses after the initial local treatment or is diagnosed with metastatic disease at the beginning. In the past five years, six new drugs became registered for the treatment of metastatic, castration-resistant prostate cancer, such as sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, the α-emitting radionuclide alpharadin and the receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor denosumab. The availability of these new treatment options raises numerous questions. In this review we present the standard of care of metastatic prostate cancer by disease stage (hormone naive/ hormone sensitive metastatic prostate cancer, non-metastatic castration-resistant prostate cancer, oligometastatic/multimetastatic castration-resistant prostate cancer) and the emerging treatment modalities presently assessed in clinical trials. We would also like to give advice on debatable aspects of the management of metastatic prostate cancer.

[Successful treatment of metastatic testicular tumor of extreme size]. / Extrém méretû metasztatikus heretumor sikeres kezelése.

Testicular cancer is the most common cancer in young males. Testicular cancer has one of the highest cure rates of all cancers: with modern chemotherapy treatment five-year survival rate exceeds 90 percent overall, and reaches almost 100 percent in early stages. However, these favorable results can only be achieved if these patients are transferred to a reference center, because better outcome was reported for patients who had been treated in a high volume center. Strict adherence to therapeutic protocol is vital for good results. We present a case of a testicular cancer patient with very advanced disease and poor performance status, who was deemed incurable by another oncological center. We achieved complete remission by strictly adhering to the protocol, and using all the available supportive measures. We would like to demonstrate the difficulties we were facing while treating this poor prognostic patient.

Midlife and late-life handgrip strength and risk of cause-specific death in a general Japanese population: the Hisayama Study.

BACKGROUND: Decreased handgrip strength has been reported to be a risk factor for all-cause death among the elderly. However, it is unclear whether handgrip strength measured in midlife is associated with risk of all-cause and cause-specific death in the general population. METHODS: We followed, prospectively, a total of 2527 community-dwelling Japanese (1064 men and 1463 women) aged ≥40 years for 19 years. Participants were divided into three groups according to the age-specific and sex-specific tertiles of handgrip strength (T1, lowest; T3, highest). RESULTS: During the follow-up period, 783 participants died, of whom 235 died of cardiovascular disease, 249 of cancer, 154 of respiratory disease and 145 of other causes. In the middle-aged group (40-64 years), multivariable-adjusted HRs (95% CIs) for all-cause death were 0.75 (0.56 to 0.99) in T2 and 0.49 (0.35 to 0.68) in T3 compared with T1 as a reference. Corresponding HRs (95% CI) in the elderly group (≥65 years) were 0.50 (0.40 to 0.62) and 0.41 (0.32 to 0.51), respectively. As regards the cause of death, higher levels of handgrip strength were significantly associated with decreased risks of cardiovascular death, respiratory death and death from other causes, but not of cancer, in the middle-aged and the elderly. CONCLUSIONS: Our findings suggest that handgrip strength levels in midlife and late life are inversely associated with the risks of all-cause and non-cancer death in the general Japanese population.

Behçet's disease in a patient with myelodysplastic syndrome.

A 75-year-old man presented with painful oral and groin ulcers. The lack of any infections and the location of the ulcers suggested Behçet's disease. Subsequently, pancytopenia developed and bone marrow examination revealed myelodysplastic syndrome. Cytogenetic examination revealed 7q- and 20q- but not 8+. Immunosuppressive therapy with cyclosporine and corticosteroid resulted in a dramatic improvement in both clinical signs and hematologic abnormalities.

Autoimmune progesterone dermatitis diagnosed by intravaginal progesterone provocation in a hysterectomised woman.

We report the case of a 39-year-old Hungarian woman who cyclically experienced painful, erythematous, patchy skin lesions on her face and chest. Because of her irregular menses and hysterectomy performed later on to manage endometriosis, it was difficult to link her symptoms to the menstrual cycle. But on the basis of the cyclic nature of the rash and the previous negative results - acne vulgaris, psoriasis, atopic dermatitis, lichen planus, systemic lupus erythematosus and infections were ruled out - autoimmune progesterone dermatitis was suspected. As progesterone is not available in aqueous solution for intradermal allergen test in Hungary, we performed progesterone provocation vaginally. The patient developed the usual skin lesions to vaginal progesterone exposure, which confirmed the diagnosis. The patient became symptom free to gonadotropine-analogue treatment and remained so even after the cessation of the therapy after 6 months. To our knowledge, this is the first case in the medical literature, in which autoimmune progesterone dermatitis was proved by vaginal progesterone provocation.

[Hyperinsulinemic hypoglycemia in adults. Case reports and a short review]. / Hyperinsulinaemiás hypoglykaemia felnottkorban. Esetismertetések és rövid áttekintés.

UNLABELLED: Persistent hyperinsulinemic hypoglycemia (nesidioblastosis) not caused by an insulinoma is rare in adults. Morphologically no insulin secreting tumor is present. Keystones of diagnosis are not only low glucose levels but to maintain normoglycemia by use of intravenous glucose and the presence of high insulin and C-peptide levels. Noninvasive and invasive diagnostic techniques are required to rule out a hormone secreting tumor. Both conservative and/or surgical therapy are suggested to prevent damaging effects of repeated hypoglycemia. CASE REPORT: Two patients with frequent and serious episodes of hypoglycemia are reported. In the 34-year-old female symptoms appeared with sweating, dizziness, trembling, nervousness and serious neuroglycopenic signs. In the 22-year-old male the main complaint was tympany, a rare and unusual sign of hypoglycemia, and intense feeling of esurience. The 24-hour fasting test was positive in both cases, i.e. it had to be stopped because of symptomatic hypoglycemia. No insulinoma could be localized, despite extensive search, therefore in both cases the diagnosis of adult-onset nesidioblastosis was set up, despite lack of histological confirmation. Diazoxide therapy resulted in symptom-free life for both patients. CONCLUSION: Several diagnostic methods and treatment options are suggested for the rare disease nesidioblastosis to balance defective insulin secretion. However, once the decision is made in favour of surgical therapy, there is a thin line between successful treatment, persistence of the disease, and pancreatic insufficiency. Therefore it is worth considering to try conservative therapy especially when surgery is of high risk. Our cases suggest that diazoxide therapy is an effective and safe alternative in the treatment of adult-onset nesidioblastosis.

Relationship between relative aerobic power and echocardiographic characteristics in male athletes.

The relationship between relative aerobic power (rel.VO(2)max) as a generally accepted indicator of endurance capacity and certain characteristics of the athlete's heart, such as body-size related (relative) left ventricular (LV) diastolic wall thickness (WTd), internal diameter (LVIDd), muscle mass (MM), WTd/IDd, heart rate (HR), fractional shortening (FS) and E/A ratio, were investigated in 346 young males (18-35 years, 291 athletes of various events and 55 nonathletic control subjects). Rel.VO(2)max was measured by spiroergometry; cardiac characteristics were determined by two-dimensionally guided M-mode and Doppler-echocardiography. When the groups were pooled, correlation of rel.VO(2)max with the cardiac parameters was significant: LVMM.BSA(-1.5)= 0.413, LVWTd.BSA(-0.5)= 0.327, LVIDd.BSA(-0.5)= 0.292, HR =-0.434, E/A = 0.272 (P < 0.001), but no significant relationship was seen with FS and WTd/IDd. In the endurance trained group, rel. VO(2)max correlated significantly with LVMM.BSA(-1.5), LVWT.BSA(-0.5), HR, and E/A, in the ballgame players with LVMM.BSA(-1.5), LVWT.BSA(-0.5), and E/A, in the power-and-sprint event athletes with HR and E/A. In the control group, no significant relationship was observed. Results indicate that in athletes having higher endurance capacity maximal oxygen consumption depends largely on cardiac condition, while in athletes with a lower endurance capacity it can be limited by peripheral conditions.

Prevention of electrical stimulation-induced increase of c-fos immunoreaction in the caudal trigeminal nucleus by kynurenine combined with probenecid.

The systemic administration of nitroglycerine, regarded as a migraine model, was previously observed to result in an increased number of c-fos immunoreactive secondary sensory neurons in the caudal trigeminal nucleus, which forward nociceptive impulses to the thalamus. The present investigation tested the hypothesis of whether kynurenine in combination with systemically administered probenecid protects second-order trigeminal neurons against stimulation arriving via central processes of trigeminal ganglion cells. Electrical stimulation of the trigeminal ganglion, one of the experimental migraine models, is known to induce an increase in the number of c-fos immunoreactive second-order nerve cells projecting to the thalamus. Since the synapses between first- and second-order trigeminal neurons are presumed to be mediated by excitatory amino acids, postsynaptic NMDA receptors should be inhibited by kynurenic acid, an endogenous NMDA receptor antagonist. Kynurenic acid, however, does not cross the blood-brain barrier, and its use as a neuroprotective agent is therefore not feasible. In contrast, kynurenine, from which kynurenic acid is formed on the action of kynurenine aminotransferase, passes the blood-brain barrier without difficulty. After the i.p. injection of kynurenine combined with probenecid it was found that the stimulation-induced increase in the c-fos immunoreactivity of the secondary sensory neurons does not occur.

Hippocampal (CA1) activities in Wistar rats from different vendors. Fundamental differences in acute ischemia.

Two-vessel occlusion, a frequently used model of global cerebral ischemia in rats, results in a dysfunction predominantly within the CA1 field of the hippocampus; it induces many processes with different time-scales. However, the great divergence in the results of the studies reported in the literature suggests valuable differences in response to hypoperfusion-induced ischemia among the laboratory rats used in these studies. In the present work, the acute effects of two-carotid occlusion-induced global ischemia (2VO) on the CA3 stimulation-evoked population spike activity in the CA1 region of Wistar rats from different suppliers (Charles-River and Harlan) were compared. In the acute electrophysiological experiments, the hippocampal CA1 responses revealed that the Charles-River rats immediately compensated the 2VO much better than did the Harlan rats. However, 3 days later, no difference could be observed between the CA1 activities of these rats. The presented data show that the Wistar rats from different vendors represent an important source of variability in the results of acute experiments on the hippocampal ischemia. These observations draw attention to the importance of the careful choice of the laboratory rats (both strains and breeds) used in such experiments.

Behaviour changes in a transgenic model of Huntington's disease.

Huntington's disease is an autosomal dominant inherited disorder, caused by an expanded polyglutamine region of a protein called huntingtin with unknown function. Transgenic mice expressing the N-terminal of huntingtin, containing 82 glutamines, exhibit a progressive disorder, which resembles to the human disease. In this study, we tested the longitudinal behaviour changes in this transgenic line in open-field and elevated-plus-maze tests. The motor performance deteriorated at 12 weeks of age and the disease progressed as indicated by the decreased total distance covered, the decreased mean velocity and the decreased exploratory behaviour. The level of anxiety was unchanged in transgenic mice as compared with their littermate controls. The motor deterioration was similar to that in other Huntington's disease models, while the level of anxiety was different. These tests are suitable means of following the progression of the disease and useful for studies of the effects of therapeutic interventions.

Role of kynurenines in the central and peripheral nervous systems.

Kynurenine (KYN) is an intermediate in the pathway of the metabolism of tryptophan to nicotinic acid. KYN is formed in the mammalian brain (40%) and is taken up from the periphery (60%), indicating that it can be transported across the blood-brain barrier (BBB). In the brain, KYN can be converted to two other components of the pathway: the neurotoxic quinolinic acid (QUIN) and the neuroprotective kynurenic acid (KYNA). QUIN is probably the most widely studied metabolite of KYN, because it may cause excitotoxic neuronal cell loss and convulsions by interacting with the N-methyl-D-aspartate (NMDA) receptor complex, a type of glutamate receptor. KYNA is another metabolite of KYN; its synthesis is catalysed by KYN aminotransferases. This is the only known endogenous NMDA receptor inhibitor, which can act at the glycine site on the receptor complex. Furthermore, KYNA non-competitively inhibits alpha7 nicotinic acetylcholine presynaptic receptors (nAChRs), inhibiting glutamate release, and regulates the expression of alpha4beta2 nAChR. It is well-known that the activation of excitatory amino acid (EAA) receptors can play a role in a number of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, stroke and epilepsy. Various studies have been made of whether the EAA receptor antagonist KYNA can exert a therapeutic effect in these neurological disorders. It has been established that KYNA has only a very limited ability to cross the BBB. Other KYNA derivatives have been synthesised (e.g. glucosamine-KYNA, 4-chloro-KYNA and 7-chloro-KYNA), which are well transported across the BBB and act on the glutamate receptors. Moreover, it has been demonstrated that probenecid, a known inhibitor of the transport of organic acids (e.g. KYNA), increases the cerebral concentration of KYNA. There is another new perspective to the maintenance of a high level of KYNA in the brain: the use of enzyme inhibitors, which can block the synthesis of the neurotoxic QUIN. These are some of the most promising possibilities as novel therapeutic strategies for the treatment of neurodegenerative diseases, in which the hyperactivation of amino acid receptors could be involved. The presence and importance of KYN derivatives in the periphery are also discussed in the light of recent publications.

Systemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocampus.

The metabolism of tryptophan along the kynurenine pathway yields several neuroactive intermediates, including kynurenic acid, which is one of the few known endogenous N-methyl-d-aspartate receptor inhibitors; in parallel with this, it is an alpha7 nicotinic acetylcholinergic receptor antagonist. On the basis of these properties, kynurenic acid might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, the use of kynurenic acid as a neuroprotective agent is practically excluded because kynurenic acid hardly crosses the blood-brain barrier. We recently synthetized a new compound, glucosamine-kynurenic acid, which is presumed to cross the blood-brain barrier more easily. In this study, the effects of systemically administered kynurenic acid and glucosamine-kynurenic acid on CA3 stimulation-evoked population spike activity in region CA1 of the rat hippocampus were compared. The effect of kynurenic acid or glucosamine-kynurenic acid was augmented by probenecid (200 mg/kg), which inhibits kynurenic acid excretion from the cerebrospinal fluid. The results showed that, while kynurenic acid administered i.p. or i.v. in doses of 17, 34, 68 or 136 micromol/kg did not cause any observable change in the animals, 136 micromol/kg glucosamine-kynurenic acid (either i.p. or i.v.) resulted in the sudden death of all the animals. The dose of 68 micromol/kg i.v., but not i.p., resulted in a sudden stoppage of breath, but the animals could be reanimated. As small a dose of glucosamine-kynurenic acid as 17 micromol/kg i.p. resulted in a reduction in population spike amplitudes; this effect was further augmented by probenecid, whereas neither 17 micromol/kg nor higher doses of pure kynurenic acid had a similar effect. The results presented here suggest that glucosamine-kynurenic acid passes the blood-brain barrier much more readily than does kynurenic acid.

A role for lymphotoxin in the acquisition of Ly49 receptors during NK cell development.

NK cells lyse tumor, virus-infected and allogeneic cells through a recognition system involving inhibitory and activating receptors, among which are the Ly49 molecules that recognize MHC class I proteins. To date, little is known about the regulation of Ly49 expression during NK cell development. In this study we report that the acquisition of Ly49 receptors by NK cells is significantly reduced in lymphotoxin (LT) alpha-deficient mice, whereas it is increased in LTalpha transgenic mice. Treating normal mice with LTbetaR-Ig fusion protein reduced Ly49 expression, indicating that regulation of Ly49 receptor expression occurs through the engagement of membrane LT to LTbetaR, and not soluble LT to TNFR. In addition, when LTalpha(-/-) mice were treated exogenously with recombinant IL-15, NK cell numbers as well as Ly49 acquisition were restored to wild-type levels. Finally, using real-time PCR analyses of bone marrow cells obtained from LT-deficient or transgenic mice, we show a direct correlation between LTbetaR activation and increased IL-15 transcription. These data suggest that LTbetaR-mediated signals regulate Ly49 expression at least in part through the activation of IL-15.

Comparative study on the effects of kynurenic acid and glucosamine-kynurenic acid.

Kynurenic acid (KYNA) is the only known endogenous N-methyl-D-aspartate (NMDA) receptor inhibitor and might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, its use as a neuroprotective compound is practically excluded because KYNA does not readily cross the blood-brain barrier (BBB). We recently synthetized a new compound, glucosamine-kynurenic acid (KYNA-NH-GLUC), which is presumed to cross the BBB more easily. In this study, the effects of KYNA and KYNA-NH-GLUC on behavior and cortical activity were investigated in adult rats. The results show that (1) on intracerebroventricular application, the behavioral changes induced by KYNA and by KYNA-NH-GLUC are quite similar; (2) on intravenous administration, KYNA (25 mg/kg) has no effect on the somatosensory-evoked cortical potentials, whereas KYNA-NH-GLUC (25 mg/kg) causes transient but appreciable reductions in the amplitudes of the evoked responses within 5 min after application; and (3) the results of in vitro studies demonstrated that both KYNA and KYNA-NH-GLUC reduced the amplitudes of the field excitatory postsynaptic potentials (fEPSPs). These observations suggest that the two compounds have similar effects, but that KYNA-NH-GLUC passes the BBB much more readily than does KYNA. These results imply that the conjugated NH-GLUC is of importance in the passage across the BBB.

Long-term effects of neonatal MK-801 treatment on spatial learning and cortical plasticity in adult rats.

RATIONALE AND OBJECTIVES: The long-term effects of neonatal treatment with MK-801 on spatial learning and cortical plasticity were investigated in adult rats. METHODS: Rat pups were injected twice daily with MK-801 (0.1 mg/kg) on postnatal days 7-19, participated in water maze testing between postnatal days 90 and 102, and were then studied electrophysiologically. RESULTS: Treatment with MK-801 in such a low dose resulted in a very slight impairment of performance in the water maze task, but not in the visual cue response. Besides the slight learning impairment, the electrophysiological study revealed a reduction in the capacity for plasticity in the primary motor cortex of the treated animals, which was pronounced in the controls. CONCLUSION: The study demonstrates that even a slight impairment in learning and memory function may be accompanied by a cortical plasticity deficiency that is detectable electrophysiologically.