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Background: We aimed at evaluating the differential involvement of large myelinated Aβ‐, small myelinated Aδ‐, and unmyelinated C‐fibers in patients with diabetic polyneuropathy and how they contribute to neuropathic pain. Methods: We collected clinical and diagnostic test variables in 133 consecutive patients with diabetic polyneuropathy. All patients underwent Aβ‐fiber mediated nerve conduction study, Aδ‐fiber mediated laser‐evoked potentials and skin biopsy mainly assessing unmyelinated C‐fibers. Results: Pure large‐fiber and small‐fiber polyneuropathy were relatively uncommon; conversely mixed‐fiber polyneuropathy was the most common type of diabetic polyneuropathy (74%). The frequency of neuropathic pain was similar in the three different polyneuropathies. Ongoing burning pain and dynamic mechanical allodynia were similarly associated with specific small‐fiber related variables. Conclusions: Diabetic polyneuropathy mainly manifests as a mixed‐fiber polyneuropathy, simultaneously involving Aβ‐, Aδ‐, and C‐fibers. In most patients, neuropathic pain is distinctly associated with small‐fiber damage. The evidence that the frequency of neuropathic pain does not differ across pure large‐, pure small‐, and mixed‐fiber polyneuropathy, raises the possibility that in patients with pure large‐fiber polyneuropathy nociceptive nerve terminal involvement might be undetected by standard diagnostic techniques. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate the conduction velocity of the cold spinal pathway in healthy humans. Methods: Using a cold stimulator consisting of micro‐Peltier elements that was able to produce steep cooling ramps up to −300°C/s, we recorded cold‐evoked potentials after stimulation of the dorsal midline at C5, T2, T6 and T10 vertebral levels and calculated the conduction velocity of the cold spinal pathway. In all participants, we used laser stimulation to deliver painful heat (Aδ‐fibres–mediated) and warm (C‐fibres–mediated) stimuli to the same sites in order to compare the conduction velocity of the cold spinal pathway with that of the nociceptive and warm spinal pathways. Results: Cold stimulation evoked large‐amplitude vertex potentials from all stimulation sites. The mean conduction velocity of the cold spinal pathway was 12.0 m/s, which did not differ from that of the nociceptive spinal pathway (10.5 m/s). The mean conduction velocity of the warm spinal pathway was 2.0 m/s. Discussion: This study provides previously unreported findings regarding cold spinal pathway conduction velocity in humans that may be useful in the assessment of spinal cord lesions as well as in intraoperative monitoring during spinal surgery. Significance: This neurophysiological study provides previously unreported findings on cold spinal pathway conduction velocity in healthy humans. Cold‐evoked potentials may represent an alternative to laser‐evoked potential recording, useful to assess spinothalamic tract in patients with spinal cord lesions and monitor patients during spinal surgery. [ABSTRACT FROM AUTHOR]

Background: In this neurophysiological study, we aimed at verifying the nociceptive selectivity of the new, micropatterned electrode (150IDE), recently designed to generate an electric field limited to the intraepidermal free nerve endings.Methods: Using the new 150IDE, we recorded evoked potentials after stimulation of the face and hand dorsum in 22 healthy participants and in patients with exemplary conditions selectively affecting the nociceptive system. We also measured the peripheral conduction velocity at the upper arm and verified the nociceptive selectivity of 150IDE assessing the effect of a selective block of nociceptive nerve fibres of radial nerve with local anaesthetic infiltration. In healthy participants and in patients, we have also compared the 150IDE-evoked potentials with laser-evoked potentials.Results: In healthy participants, the 150IDE-evoked pinprick sensation and reproducible scalp potentials, with latency similar to laser-evoked potentials. The mean peripheral conduction velocity, estimated at the upper arm, was 12 m/s. The selective nociceptive fibre block of the radial nerve abolished the scalp potentials elicited by the 150IDE stimulation. In patients, the 150IDE-evoked potentials reliably detected the selective damage of the nociceptive system.Conclusions: Our neurophysiological study shows that this new 150IDE provides selective information on nociceptive system.Significance: 150IDE is a promising new tool for investigating nociceptive system in patients with neuropathic pain. [ABSTRACT FROM AUTHOR]

Backgrounds: Patients with diabetic polyneuropathy commonly suffer from ongoing burning pain and dynamic mechanical allodynia. In this clinical and skin biopsy study, we aimed at assessing how intraepidermal regenerating nerve sprouts are associated with these two types of pain.Methods: We consecutively enrolled 85 patients with diabetic polyneuropathy. All patients underwent skin biopsy at the distal leg. Intraepidermal nerve fibres were immunostained with the anti-protein gene product 9.5 (PGP9.5) to quantify all intraepidermal nerve fibres, and the growth-associated protein 43 (GAP43) to quantify regenerating nerve sprouts.Results: We found that the GAP43-stained intraepidermal nerve fibre density and the ratio GAP43/PGP9.5 were significantly higher in patients with ongoing burning pain than in those without. The area of receiver operating characteristic (ROC) curve for the ratio GAP43/PGP9.5 was 0.74 and yielded a sensitivity and specificity for identifying ongoing burning pain of 72% and 71%, respectively. Conversely, although the density of PGP9.5 and GAP43 intraepidermal nerve fibre was higher in patients with dynamic mechanical allodynia than in those without, this difference was statistically weak and the ROC curve analysis of skin biopsy variables for this type of pain failed to reach the statistical significance.Conclusion: Our clinical and skin biopsy study showed that ongoing burning pain was strongly associated with regenerating sprouts, as assessed with GAP43 immunostaining. This finding improves our understanding on the mechanisms underlying neuropathic pain in patients with diabetic polyneuropathy and suggests that the GAP43/PGP 9.5 ratio might be used as an objective marker for ongoing burning pain due to regenerating sprouts.Significance: Our skin biopsy study showing that regenerating sprouts, as assessed with GAP43-staining, were strongly associated with ongoing burning pain, improves our knowledge on the mechanisms underlying neuropathic pain in patients with diabetes. [ABSTRACT FROM AUTHOR]

Intercostobrachial neuropathy, often resulting in neuropathic pain, is a common complication of breast cancer surgery. In this 1-year longitudinal study, we aimed at seeking information on the frequency, clinical features, and course of painless and painful intercostobrachial neuropathy. We enrolled 40 women previously undergoing breast cancer surgery. In these patients, we collected, at 3, 6 and 12 months after surgery, clinical and quantitative sensory testing (QST) variables to diagnose intercostobrachial neuropathy, DN4 questionnaire to identify neuropathic pain, Neuropathic Pain Symptom Inventory to assess the different neuropathic pain symptoms, the Beck Depression Inventory to assess depressive symptoms, and SF36 to assess quality of life and Patient Global Impression of Change. Clinical and QST examination showed an intercostobrachial neuropathy in 23 patients (57.5%). Out of the 23 patients, five experienced neuropathic pain, as assessed with clinical examination and DN4. Axillary surgery clearance was associated with an increased risk of intercostobrachial neuropathy. Whereas sensory disturbances improved during the 1-year observation, neuropathic pain did not. Nevertheless, Beck Depression Inventory, SF36, and the Patient Global Impression of Change scores significantly improved over time. Our study shows that although intercostobrachial neuropathy is a common complication of breast cancer surgery, neuropathic pain affects only a minor proportion of patients. After 1 year, sensory disturbances partially improve and have only a mild impact on mood and quality of life. [ABSTRACT FROM AUTHOR]

Background: In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE-PREPs) is still debated.Methods: In this neurophysiological study we aimed at verifying the nociceptive specificity of SE-PREPs. We recorded LEPs, CHEPs and SE-PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin-induced nociceptive nerve fibre loss in the epidermis.Results: We found that whereas LEPs and CHEPs were suppressed after capsaicin-induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE-PREPs.Conclusion: The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE-PREP changes suggests that SE-PREPs do not provide selective information on nociceptive system function.Significance: Capsaicin-induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain-related evoked potentials by surface concentric electrode (SE-PREPs). These findings suggest that unlike LEPs and CHEPs, SE-PREPs are not selectively mediated by nociceptive system. [ABSTRACT FROM AUTHOR]

Background: Patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT) commonly suffer from pain. How this hereditary connective tissue disorder causes pain remains unclear although previous studies suggested it shares similar mechanisms with neuropathic pain and fibromyalgia.Methods: In this prospective study seeking information on the mechanisms underlying pain in patients with JHS/EDS-HT, we enrolled 27 consecutive patients with this connective tissue disorder. Patients underwent a detailed clinical examination, including the neuropathic pain questionnaire DN4 and the fibromyalgia rapid screening tool. As quantitative sensory testing methods, we included thermal-pain perceptive thresholds and the wind-up ratio and recorded a standard nerve conduction study to assess non-nociceptive fibres and laser-evoked potentials, assessing nociceptive fibres.Results: Clinical examination and diagnostic tests disclosed no somatosensory nervous system damage. Conversely, most patients suffered from widespread pain, the fibromyalgia rapid screening tool elicited positive findings, and quantitative sensory testing showed lowered cold and heat pain thresholds and an increased wind-up ratio.Conclusions: While the lack of somatosensory nervous system damage is incompatible with neuropathic pain as the mechanism underlying pain in JHS/EDS-HT, the lowered cold and heat pain thresholds and increased wind-up ratio imply that pain in JHS/EDS-HT might arise through central sensitization. Hence, this connective tissue disorder and fibromyalgia share similar pain mechanisms. WHAT DOES THIS STUDY ADD?: In patients with JHS/EDS-HT, the persistent nociceptive input due to joint abnormalities probably triggers central sensitization in the dorsal horn neurons and causes widespread pain. [ABSTRACT FROM AUTHOR]

Patients with peripheral and central nervous system diseases may suffer from different types of pain, namely nociceptive, neuropathic and mixed pain. Although in some cases, the distinction between these types of pain is clinically evident, yet in some patients an accurate differential diagnosis requires dedicated clinical examination, screening questionnaires and diagnostic techniques some of which are available only in specialized pain centres. This review briefly addresses the currently agreed definitions of the different types of pain and shows how clinical examination, pain questionnaires and diagnostic tests can help the clinicians in identifying neuropathic pain. [ABSTRACT FROM AUTHOR]

Background Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms. Methods Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain. Results The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex. Conclusions Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV)-related cryoglobulinemia commonly causes disabling complications including peripheral neuropathy and neuropathic pain. In this prospective clinical, neurophysiological, and skin biopsy study we aimed at assessing clinical characteristics and risk factors of peripheral neuropathy and neuropathic pain in patients with HCV-related cryoglobulinemia. We enrolled 69 consecutive patients with HCV-related cryoglobulinemia. We diagnosed neuropathic pain with the DN4 (Neuropathic Pain Diagnostic) questionnaire, and rated the various neuropathic pains with the Neuropathic Pain Symptom Inventory (NPSI). All patients underwent a standard nerve conduction study to assess Aβ-fiber function, laser-evoked potentials to assess Aδ-fiber function, and skin biopsy to assess C-fiber terminals. Of the 69 patients studied, 47 had a peripheral neuropathy, and 29 had neuropathic pain. Patients with peripheral neuropathy were older than those without ( P < 0.0001). While peripheral neuropathy was significantly associated with the duration of HCV infection ( P < 0.01), it was unrelated to the duration of cryoglobulinemia and cryocrit ( P > 0.5). The severity of peripheral neuropathy significantly correlated with the duration of HCV infection ( P < 0.05). Laser-evoked potential amplitudes were significantly lower in patients with than in those without neuropathic pain ( P < 0.05). Conversely, no difference was found in nerve conduction study and skin biopsy findings ( P > 0.05). Our findings show that peripheral neuropathy is related to age and HCV infection, rather than to cryoglobulinemia, and neuropathic pain is associated with damage to nociceptive pathways as assessed with laser-evoked potentials; this might be useful for designing more effective clinical interventions for these common HCV related-cryoglobulinemia complications. [ABSTRACT FROM AUTHOR]

Background: The guidelines on trigeminal neuralgia management that have been agreed and jointly published by the American Academy of Neurology and the European Federation of Neurological Societies recommend carbamazepine (CBZ) and oxcarbazepine (OXC) as the first-choice medical treatments in patients with trigeminal neuralgia (TN). The aim of this retrospective study was to analyze the natural history of classical trigeminal neuralgia in a large cohort of patients, focusing on drug responsiveness, side effects related to CBZ and OXC, and changes in pain characteristics during the course of disease. Findings: We selected the last 100 consecutive patients with typical TN who began treatment with CBZ and the last 100 with OXC. All had MRI scans and a complete neurophysiological study of trigeminal reflexes. Among them, 22 were excluded on the basis of neuroradiological or neurophysiological investigations, to avoid the inclusion of patients with possible secondary TN. The initial number of responders was 98% with CBZ with a median dose of 600 mg (range 200–1200), and of 94% with OXC, with a median dose of 1200 mg (range 600–1800). In a mean period of 8.6 months, 27% of responders to CBZ incurred in undesired effects to a level that caused interruption of treatment or a dosage reduction to an unsatisfactory level. In a mean period of 13 months, the same occurred to 18% of responders to OXC. Among patients who had a good initial response, only 3 patients with CBZ and 2 with OXC developed late resistance. During the course of disease, paroxysms worsened in intensity in 3% of patients, and paroxysms duration increased in 2%. We did not observe the onset of a clinically manifest sensory deficit at any time in any patient. Conclusions: Unlike common notion, in our large patient sample the worsening of pain with time and the development of late resistance only occurred in a very small minority of patients. CBZ and OXC were confirmed to be efficacious in a large majority of patients, but the side effects caused withdrawal from treatment in an important percentage of patients. These results suggest the opportunity to develop a better tolerated drug. [ABSTRACT FROM AUTHOR]

Cardioembolic stroke is generally caused by intracranial artery occlusion. Clots may be identified in the intracranial vessels by means of conventional neuroimaging in the acute phase. High-resolution ultrasonography may show some features suggestive of cardiac emboli when occluding extracranial carotid arteries. We describe a patient with cardioembolic ischemic stroke in the right hemisphere in whom a left internal carotid artery stenosis paradoxically protected the ipsilateral hemisphere from distal intracranial embolism. The patient also presented multiple acute ischemic embolic lesions in the right middle cerebral artery territory and in the right occipital lobe, which was fed by the posterior cerebral artery, anomally originating from the right carotid siphon. Interestingly, the left internal carotid artery-which showed a severe preexisting stenosis-was occluded by the cardiac clot, whereas the right internal carotid artery only presented a moderate stenosis that had probably allowed the clots to pass. Therefore, the severe left internal carotid artery stenosis may have blocked the cardiac embolus, preventing it from reaching the ipsilateral hemisphere. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound 41:22-27, 2013 [ABSTRACT FROM AUTHOR]

Patients with painful neuropathy frequently complain of pain in response to normally non-painful brushing, namely dynamic mechanical allodynia. Despite many animal studies suggesting that allodynia arises when the spontaneous firing in damaged nociceptive afferents sensitise second-order nociceptive neurons to Aβ-fibre input, no studies have sought to confirm this mechanism by investigating Aβ-fibre sparing in human patients with allodynia. In this study we compared data from Aβ-fibre-mediated nerve conduction studies and nociceptive-fibre-mediated laser-evoked potentials (LEPs) in 200 patients with distal symmetric polyneuropathy (114 with neuropathic pain, 86 without). Of the 114 patients with painful neuropathy studied, 44 suffered from allodynia. Whereas no statistical difference was found in nerve conduction study data between patients with and without allodynia, LEP amplitudes were larger in patients with allodynia than in those without ( P < 0.01 by Mann-Whitney U test). The lack of difference in NCS data between patients with and without allodynia suggest that this type of pain, rather than arising through second-order nociceptive neuron sensitization to Aβ-fibre input, might reflect a reduced mechanical threshold in sensitised intraepidermal nociceptive nerve terminals. [ABSTRACT FROM AUTHOR]

Abstract: Despite concerted efforts from pharmacologic research into neuropathic pain, many patients fail to achieve sufficient pain relief with medication alone. For this reason, increasing interest centres on neurostimulation techniques. We assessed whether transcutaneous spinal direct current stimulation (tsDCS) modulates conduction in ascending nociceptive spinal pathways. We measured changes induced by anodal and cathodal tsDCS over the thoracic spinal cord on face- and foot-laser evoked potentials (LEPs) and foot-cold pressor test responses in 20 healthy subjects. Whereas anodal tsDCS reduced the amplitude of the N1 and N2 components of foot-LEPs (P <0.05) neither anodal nor cathodal tsDCS changed LEPs evoked by face stimulation. Pain tolerance to the cold pressor test was significantly higher after anodal than after cathodal tsDCS (P <0.05). Conversely, no difference was found in the pain threshold or pain ratings to the cold pressor test between the two polarity conditions. Our data suggest that anodal tsDCS over the thoracic spinal cord might impair conduction in the ascending nociceptive spinal pathways, thus modulating LEPs and increasing pain tolerance in healthy subjects. [Copyright &y& Elsevier]

We aimed at assessing the prevalence of peripheral neuropathy in newly diagnosed, treatment-naïve patients with multiple myeloma. We enrolled 153 patients with multiple myeloma at initial diagnosis. All patients underwent neurological examination and nerve conduction study. Patients with suspected pure small fiber neuropathy underwent skin biopsy. Of the 153 patients included in this study, 7.2 % had a multiple myeloma-related neuropathy. All patients suffered from a distal symmetric sensory peripheral neuropathy, associated with age (P = 0.04). Our study on prevalence rate of multiple myeloma-related peripheral neuropathy might provide a basis for improving the clinical management of this condition. [ABSTRACT FROM AUTHOR]

In human epidermal growth factor receptor 2 (HER2+) expressing breast cancer subtype, the incidence of brain metastases is common and patients often die due to uncontrolled cranial disease. This is a case report of a HER2+ breast cancer woman with diffuse brain metastases that experienced long survival and clinical benefit from multiple radiotherapy treatments and combined systemic therapy, without increased toxicity. [ABSTRACT FROM AUTHOR]

Capecitabine is converted to 5-fluorouracil by thymidine phosphorylase, and mitomycin C is capable of upregulating the expression of thymidine phosphorylase suggesting a synergistic effect. Fifty-three patients (median age 62 years) with anthracycline- and taxane-resistant, metastatic breast cancer received mitomycin C 6 mg/m2 on day 1, and capecitabine (Xeloda) 2,000 mg/m2/day from day 1 to day 14 with cycles repeated every 4 weeks. Overall, 77.4% had visceral metastases and 33 were pretreated with ≥3 chemotherapy lines. A median of 6 cycles were given (range 1–19) with a complete response observed in 2 patients (3.9%), partial response in 17 (33.3%) and stable disease in 19 (37.2%). Overall response rate was 37.2% (95% CI, 24.0–50.5%), with a median duration of 10.4 months. Median time to progression was 8.1 months and median survival was 17.4 months (1- and 2-year survival rates of 60 and 28%, respectively). Toxicity was mild. The most frequent grade 3/4 events were neutropenia (5.7% of patients), diarrhea (3.8%), and deep venous thrombosis (3.8%). Capecitabine plus mitomycin C may represent an effective and manageable treatment option for advanced breast cancer patients resistant to anthracyclines and taxanes. This approach provides an alternative for pretreated patients with advanced breast cancer. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Elderly patients have been often excluded from or underrepresented in the study populations of combination chemotherapy trials. The primary end point of this study was to determine the response rate and the toxicity of the weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) regimen in elderly patients with advanced gastric cancer. The secondary objective was to measure the time to disease progression and the survival time. Methods: Chemotherapy-naive patients with advanced gastric cancer aged 70 or older were considered eligible for study entry. Patients received weekly oxaliplatin 40 mg/m2, fluorouracil 500 mg/m2 and folinic acid 250 mg/m2. All drugs were given intravenously on a day-1 schedule. Results: A total of 42 elderly patients were enrolled. Median age was 73 years and all patients had metastatic disease. The response rate according to RECIST criteria was 45.2% (95% CIs: 30%-56%) with two complete responses, 17 partial responses, 13 stable diseases and 10 progressions, for an overall tumor rate control of 76.2% (32 patients). Toxicity was generally mild and only three patients discontinued treatment because of treatment related adverse events. The most common treatment-related grade 3/4 adverse events were fatigue (7.1%), diarrhoea (4.8%), mucositis (2.4%), neurotoxicity (2.4%) and neutropenia (4.8%). The median response duration was 5.3 months (95% CIs: 2.13 — 7.34), the median time to disease progression was 5.0 months (95% CIs: 3.75 — 6.25) and the median survival time was 9.0 months (95% CIs: 6.18 — 11.82). Conclusion: OXALF represents an active and well-tolerated treatment modality for elderly patients with locally advanced and metastatic gastric cancer. [ABSTRACT FROM AUTHOR]

Background: The combination of capecitabine and gemcitabine at Fixed Dose Rate (FDR) has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. FDR gemcitabine infusion leads to enhanced intracellular accumulation of drug and possible augmented clinical effect. The goals of this phase I study were to determine the maximum-tolerated dose (MTD) of chronomodulated capecitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT), the safety profile of this way of administration. Methods: Patients with advanced solid tumours who had failed to response to standard therapy or for whom no standard therapy was available were elegible for this study. Capecitabine was administered orally according to following schedule: 1/4 of dose at 8:00 a.m.; 1/4 of dose at 6:00 p.m. and 1/2 of dose at 11:00 p.m. each day for 14 consecutive days, followed by a 7-day rest period. Results: All 27 patients enrolled onto the study were assessable for toxicity. The most common toxicities during the first two cycles of chemotherapy were fatigue, diarrhoea and hand foot syndrome (HFS). Only one out of the nine patients treated at capecitabine dose of 2,750 mg/m2 met protocol-specified DLT criteria (fatigue grade 4). However, at these doses the majority of cycles of therapy were delivered without dose reduction or delay. No other episodes of DLT were observed at the same dose steps and at the lower dose steps of capecitabine (1,500/1,750/2,000/2,250/2,500 mg/m2). The dose of 2,750 mg/m2 is recommended for further study. Tumor responses were observed in patients with metastatic breast and colorectal cancer. Conclusion: High doses of chronomodulated capecitabine can be administered with acceptable toxicity. The evidence of antitumor activity deserves further investigation in phase II combination chemotherapy studies. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to define the feasibility and efficacy of Xelox (capecitabine and oxaliplatin) administered through a new and original schedule in advanced pretreated colorectal cancer (CRC) patients. Methods: 36 metastatic CRC patients resistant at least to a previous 5-fluorouracil- and irinotecan-based chemotherapy line were included in the study. Treatment: Oxaliplatin 70 mg/m2 as continuous infusion for 12 h (8.00 a.m. to 8.00 p.m.) on days 1, 8 plus chronomodulated capecitabine 1,750 mg/m2/day per os (8.00 a.m. 25% of total dose; 6.00 p.m. 25% of total dose; 11.00 p.m. 50% of total dose), on days 1–14 every 21 days. 16 (44.4%) patients had previously received only 1 chemotherapy line for metastatic disease and 20 patients (55.6%) 2 chemotherapy lines. Moreover, 12 patients (33.3%) progressed after a first or second line of oxaliplatin-based regimen as well. Results: Most frequent related G3–4 adverse reactions were diarrhea (11.6%), nausea/vomiting (8.3%), neuropathy (8.3%), mucositis (8.3%), asthenia (16.7%) and hand-foot syndrome (5.5%). G3–4 anemia, leucopenia and liver toxicities were not observed. The overall response rate was 30.6% (11/36 patients). Disease stabilization was observed in 13 patients (36.1%) and progression in 12 patients (34.3%). Between the 12 oxaliplatin-resistant patients, the overall response rate was 25% (3 patients); 6 patients (54.5%) obtained a stable disease, and only 3 patients (25%) progressed. The median overall survival was 11.3 months (95% confidence interval 7.0–15.7 months), the median response duration 2.8 months (95% confidence interval 1.2–5.6 months) and the median time to progression 6.7 months (95% confidence interval 5.7–6.3 months). The 1-year survival rate was 53.8%. Conclusions: The high overall tumor growth control, the remarkable median time to progression and overall survival and the good safety profile are of particular interest for patients with heavy pretreated metastatic CRC. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Perrone G, Santini D, Vincenzi B, Zagami M, La Cesa A, Bianchi A, Altomare V, Primavera A, Battista C, Vetrani A, Tonini G&Rabitti C(2005)Histopathology46,561–568COX-2 expression in DCIS: correlation with VEGF, HER-2/ neu, prognostic molecular markers and clinicopathological features: There is considerable evidence that links COX-2 to the development of cancer. The aim of our study was to assess, by immunohistochemistry, COX-2 expression in ductal carcinomain situ(DCIS) and its possible correlation with HER-2/ neu, vascular endothelial growth factor (VEGF) expression and other common immunohistochemical parameters (p53, ER, PGR, Ki67).: Tissue samples of 49 archival cases of DCIS without any invasive component were analysed for COX-2, HER-2/ neu, VEGF, oestrogen and progesterone receptors, Ki67 and p53 by immunohistochemistry using specific antibodies. COX-2 expression was detected in 43 (87.8%) tissue samples, of which 12 (24.5%) were graded as weak, 22 (44.9%) as moderate and nine (8.4%) as high expression. Only six (12.2%) lesions were negative for COX-2 expression. VEGF expression was detected in 93.8% of samples; 66.7% of lesions were found to be positive for HER-2/ neuexpression. Furthermore, COX-2 expression was significantly correlated with VEGF expression (P = 0.003). A significant positive correlation was also observed between COX-2 and HER-2/ neuexpression (P < 0.0001).: Our results suggest that COX-2 is highly expressed in DCIS and takes part in the molecular pathway implicated in progression of breast cancer and may provide a rationale for targeting COX-2 in preinvasive breast cancer therapy. [ABSTRACT FROM AUTHOR]

Objectives: We retrospectively evaluated the relevance of thymidylate synthase (TS) expression in normal colonic mucosa as a predictive factor of toxicity in colorectal cancer patients receiving adjuvant fluorouracil (5-FU)-based chemotherapy. Methods: TS expression was immunohistochemically assessed on normal colonic mucosa from 50 patients with colorectal cancer Dukes’ stages B (15 patients) and C (35 patients) treated with 5-FU-based adjuvant chemotherapy. Results: The incidence of grade 2–3 diarrhea and stomatitis (according to WHO) was demonstrated to be significantly higher in patients with low nuclear TS expression in normal mucosa than in those with high TS expression (p < 0.0001). Moreover, patients with low TS expression in normal colonic mucosa developed weight loss and worsening of the performance status (according to ECOG score) more commonly than patients with high TS expression (p = 0.005 and p = 0.02, respectively). Furthermore, low TS expression in normal colonic mucosa significantly correlated with a higher rate of a delay of chemotherapy courses, dose reduction and treatment discontinuation. Conclusions: Immunohistochemical TS expression in normal colonic mucosa may represent an important predictive parameter for identifying a subset of patients with a high risk of developing severe 5-FU-related toxicities. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Bisphosphonates are endogenous pyrophosphate analogs in which a carbon atom replaces the central atom of oxygen. They are indicated in non-neoplastic diseases including osteoporosis, corticosteroid-induced bone loss, Paget disease, and in cancer-related diseases such as neoplastic hypercalcemia, multiple myeloma and bone metastases secondary to breast and prostate cancer. There is now extensive in vitro evidence suggesting a direct antitumor effect of bisphosphonates at different levels of action. Some new in vitro and in vivo studies support the cytostatic effects of bisphosphonates on tumor cells, and the effects on the regulation of cell growth, apoptosis, angiogenesis, cell adhesion, and invasion, with particular attention to biological properties. Well designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates may be clinically relevant. On the basis of their effects on macrophages, we may divide bisphosphonates into two distinct categories: aminobisphosphonates, which sensitize macrophages to an inflammatory stimulus inducing an acute-phase response, and non-aminobisphosphonates that can be metabolized into macrophages and that may inhibit the inflammatory response of macrophages. There is evidence of aminobisphosphonate-induced pro-inflammatory response, in particular, related to modifications of the cytokine network. Several in vivo studies have demonstrated an acute-phase reaction after the first administration of aminobisphosphonates, with a significant increase in the main pro-inflammatory cytokines. However, a peculiar aspect concerning the action of non-aminobisphosphonates seems to be an anti-inflammatory activity caused by the inhibition of the release of inflammatory mediators from activated macrophages, such as interleukin (IL)-6, tumor necrosis factor-a and IL-i. The inhibition of inflammatory responses is demonstrated in both in vivo and in vitro models. This activity suggests the use of non-aminobisphosphonates in several inflammatory diseases characterized by macrophage-mediated production of acute-phase cytokines, as prevention of erosions in rheumatoid arthritis, and of loosening of joint prostheses, as well as possibly in osteoarthritis, ankylosing spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy. [ABSTRACT FROM AUTHOR]

Presents the case of a 61-year-old man with eruptive, exanthematous psoriasis, who showed a complete and long-lasting regression of skin lesions following therapy with gemcitabine as a single anticancer agent for an advanced pancreatic adenocarcinoma. Pathogenesis; Mechanism of action of gemcitabine.

Details six case reports of patients with oxaliplatin-associated neurotoxicity. Atypical and acute neurosensory symptoms characterized by recurrent episodes of involuntary masticatory spasms; Data showing that the high incidence of the neurotoxicity strictly related to the duration of drug infusion.

Presents a case of patients with severe liver dysfunction after raltitrexed administration in an hepatitis C positive colorectal cancer patient. Case history of the patient; Impact of chemotherapy-induced immunosuppression on viral replication; Amplification of the intrinsic hepatotoxicity of ratitrexed.

Neuropathic pain, i.e. pain arising as a direct consequence of a lesion or disease of the somatosensory system, affects about the 7 % of the general population. In this short review, we describe the most reliable laboratory tools for assessing neuropathic pain, such as quantitative sensory testing, laser-evoked potential recordings and skin biopsy, procedures that selectively assess nociceptive pathways. [ABSTRACT FROM AUTHOR]