A randomized phase II trial of sequential gemcitabine plus vinorelbine followed by gemcitabine plus ifosfamide versus gemcitabine plus cisplatin in the treatment of chemo-naive patients with stages III and IV non-small cell lung cancer (NSCLC)

BACKGROUND: Third-generation platinum-based combinations are established as first-line treatment for advanced non-small cell lung cancer (NSCLC). Non-platinum regimens could be an alternative if they show similar efficacy with better tolerability. This randomized phase II trial compared the objective tumor response rate (ORR) of sequential gemcitabine plus vinorelbine followed by gemcitabine plus ifosfamide versus gemcitabine plus cisplatin. Secondary objectives included time to disease progression (TTP), overall survival and toxicity. METHODS: Chemo-naive patients with stages III and IV NSCLC and Karnofsky performance status >70 were assigned to receive either (a) gemcitabine 1000mg/m(2) plus vinorelbine 25mg/m(2) on days 1 and 8 for 2 cycles, followed by gemcitabine 1000mg/m(2) on days 1 and 8 plus ifosfamide 2000mg/m(2) on day 1 (GV-GI arm) for 2 cycles or (b) gemcitabine 1250mg/m(2) on days 1 and 8 with cisplatin 70mg/m(2) on day 1 (GC arm) for 4 cycles. RESULTS: Between July 2001 and January 2003, 102 patients were enrolled (50 on the GV-GI arm and 52 on the GC arm). Patient characteristics were balanced between arms (GV-GI arm: median age 59 years, 84% male, 22 stage IIIB, 24 stage IV, 4 stage IIIA; GC arm: median age 56 years, 87% male, 27 stage IIIB, 23 stage IV, 2 stage IIIA). Of the 101 patients evaluable for response, ORR was significantly higher on the GC arm than on the GV-GI arm (25% versus 6%, respectively; p=0.007). No complete responses occurred. TTP was longer on the GC arm than on the GV-GI arm (median 135 and 79 days, respectively), although this difference was not statistically significant (p=0.065). Survival was not significantly different between the arms (median 293 and 197 days, respectively; p=0.16). Although significantly more thrombocytopenia was reported on the GC arm (22% and 4%, respectively; p=0.02), it did not lead to more transfusions (15 transfusions in 5 patients versus 14 transfusions in 6 patients, respectively). There was no significant difference in other safety parameters between treatment arms. CONCLUSIONS: GC appears to produce better response in advanced NSCLC than GV-GI, with a trend towards longer TTP. Except for more thrombocytopenia with GC, similar toxicity profiles were observed.     

Thermal sensory and pain thresholds in the tongue and chin change with age,but are not altered in burning mouth syndrome

Background: Burning mouth syndrome (BMS) is a chronic orofacial pain syndrome that occurs in middle‐aged and postmenopausal women and poses a therapeutic challenge to dermatologists and dentists. It has been suggested previously that BMS is a small‐fiber neuropathy. Aims: This study was designed to examine thermal sensory and pain thresholds in the oral mucosa and chin, both innervated by the trigeminal nerve, in patients with BMS, as well as in healthy controls. In addition, the study proposed to examine whether there are any differences in oral thermal and pain sensations between the advanced age group, where BMS is prevalent and a younger group. Results: Thermal and pain thresholds of BMS patients did not differ significantly from those of healthy subjects. An increased threshold to thermal warmth and a decreased threshold for cold sensation for the tongue and chin were noted in the group over 50 years in comparison with younger subjects, indicating a decreased sensitivity to thermal stimuli. The group over 50 years of age displayed an increased sensitivity to cold pain and a decreased sensitivity to hot pain in the tongue (compared with the chin). Conclusion: BMS patients do not demonstrate alterations in thermal and pain detection, thus failing to support a true small nerve neuropathy in this condition.     

Parkes-Weber Syndrome and double orifice atrial septal defect as a combined rare cause of severe pulmonary hypertension

The International Journal of Cardiovascular Imaging -     

Prominent dysautonomia in a patient with POEMS syndrome

POEMS syndrome is a rare, multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and/or skin changes. Here we present an unusual case of a patient with POEMS syndrome who exhibited a prominent autonomic neuropathy.     

Age dependence of tolerance to anoxia and changes in cytosolic calcium in rabbit renal proximal tubules

Calcium(Ca²⁺)-dependent processes mediate, in part, anoxic cell injury. These may account for the difference in sensitivity to anoxia between certain immature and mature renal cells. To address this question, we studied the effects of anoxia on cytosolic free Ca²⁺ concentration ([Ca²⁺]_i), cell integrity, and transport functions in microdissected proximal convoluted tubules (PCT) of <3-week-old (newborn) and >12-week-old (adult) rabbits. Tubules were loaded with 10 μM fura-2 AM by incubation for 60 min at 37°C, and then superfused with isosmotic saline solution gassed with either 95%O₂-5%CO₂ (control group) or 95%N₂-5%CO₂ (anoxia group) for 30 min. [Ca²⁺]_i was measured ratiometrically; cell damage was assessed by nuclear binding of propidium iodide (PI). Anoxia resulted in a fourfold increase in [Ca²⁺]_i in adult tubules (from resting values of 245±10 to 975±100 nM, P <0.001), whereas in newborn tubules the rise was significantly less (from resting values of 137±5 to 165±5 nM, P <0.001 between anoxic groups). Transient exposure to 100 mM potassium chloride, which depolarizes the PCT cells, induced increases in [Ca²⁺]_i from baseline, to 920±90 nM in tubules from adult and to 396±16 nM in those from newborn rabbits (P <0.001 between age groups). After exposure to ligands such as parathyroid hormone (PTH) and ATP, [Ca²⁺]_i increased in both newborn and adult tubules, but to lower levels in newborn tubules. The response to PTH and ATP was transient in both age groups, [Ca²⁺]_i returning to baseline levels after 2 min. Following anoxia, tubules from adult animals exhibited staining of all cell nuclei by 1 min exposure to PI, indicative of gross permeabilization of the cells. Nuclei of anoxic immatures tubules did not stain with PI. The sodium-dependent uptakes of a glucose analogue (¹⁴C-α-methyl-glucopyranoside) and phosphate (³²Pi) were preserved in agarose-filled tubules of newborns after anoxia, whereas in those of adults recovery from anoxia was associated with drastic reduction in the uptake of these solutes. Overall, our results suggest that: (1) during anoxia, cell Ca²⁺ rises to critical levels in PCTs of adults compared with those of <3-week-old animals, (2) Ca²⁺ influx occurs via a pathway activated by exposure to high [K⁺]_o, presumably voltage-sensitive Ca²⁺ channels or reversal of Na⁺-Ca²⁺ exchange, (3) these pathways are either less active or less abundant in proximal tubules of newborn compared with adult rabbits, and (4) secondary active transport activity and cellular integrity are well preserved after anoxia in PCT cells of newborn but not of adult rabbits. Received June 27, 1995; received in revised form December 1, 1995; accepted December 8, 1995     

Role of 5-HT1A and 5-HT3 receptors in serotonergic activation of sensory neurons in relation to itch and pain behavior in the rat

Serotonin (5-hydroxytryptamine, 5-HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. The serotonergic receptors expressed by primary afferent neurons involved in these sensory functions are not fully identified and appear to be to a large extent species dependent. Moreover, the mechanisms through which 5-HT receptor activation is coupled to changes in neuronal excitability have not been completely revealed. Using a combination of in vitro (calcium and voltage imaging and patch-clamp) and in vivo behavioral methods, we used both male and female Wistar rats to provide evidence for the involvement of two 5-HT receptor subtypes, 5-HT1A and 5-HT3, in mediating the sustained and transient effects, respectively, of 5-HT on rat primary afferent neurons involved in pain and itch processing. In addition, our results are consistent with a model in which sustained serotonergic responses triggered via the 5-HT1A receptor are due to closure of background potassium channels, followed by membrane depolarization and action potentials, during which the activation of voltage-gated calcium channels leads to calcium entry. Our results may provide a better understanding of mammalian serotonergic itch signaling.