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Objective To investigate whether recording from deep intracerebral (IC) electrodes can disclose laser evoked potential (LEP) components generated under the cerebral cortex. Methods LEPs were recorded to hand and/or perioral region stimulation from 7 patients suffering from Parkinson’s disease, who underwent implant of IC electrodes in the globus pallidum pars interna (GPi), in the subthalamic nucleus (STN) and in the pedunculopontine nucleus (PPN). LEPs were obtained from the IC electrode contacts and from the Cz vertex, referred to the nose. Results The scalp traces showed a triphasic response (P1-N2-P2). The IC electrodes recorded two main components (ICP2 and ICN2), showing the same latencies as the scalp N2 and P2 potentials, respectively. The ICP2-ICN2 complex was sometimes preceded by a ICP1 wave at the same latency of the scalp P1 response. Conclusions The LEP components recorded from the IC electrodes mirrored the ones picked up from the Cz lead, thus suggesting that they are probably generated by the opposite pole of the same cortical sources producing the scalp responses. Significance In the IC traces, there was no evidence of earlier potentials possibly generated within the thalamus or of subcortical far-field responses. This means that the nociceptive signal amplification occurring within the cerebral cortex is necessary to produce identifiable LEP components.

The topodiagnostic implications of hemiataxia following lesions of the human brainstem are only incompletely understood. We performed a voxel-based statistical analysis of lesions documented on standardised MRI in 49 prospectively recruited patients with acute hemiataxia due to isolated unilateral brainstem infarction. For statistical analysis individual MRI lesions were normalised and imported in a three-dimensional voxel-based anatomical model of the human brainstem. Statistical analysis revealed hemiataxia to be associated with lesions of three distinct brainstem areas. The strongest correlation referred to ipsilateral rostral and dorsolateral medullary infarcts affecting the inferior cerebellar peduncle, and the dorsal and ventral spinocerebellar tracts. Secondly, lesions of the ventral pontine base resulted in contralateral limb ataxia, especially when ataxia was accompanied by motor hemiparesis. In patients with bilateral hemiataxia, lesions were located in a paramedian region between the upper pons and lower midbrain, involving the decussation of dentato-rubro-thalamic tracts. We conclude that ataxia following brainstem infarction may reflect three different pathophysiological mechanisms. (1) Ipsilateral hemiataxia following dorsolateral medullary infarctions results from a lesion of the dorsal spinocerebellar tract and the inferior cerebellar peduncle conveying afferent information from the ipsilateral arm and leg. (2) Pontine lesions cause contralateral and not bilateral ataxia presumably due to major damage to the descending corticopontine projections and pontine base nuclei, while already crossed pontocerebellar fibres are not completely interrupted. (3) Finally, bilateral ataxia probably reflects a lesion of cerebellar outflow on a central, rostral pontomesencephalic level.

Objective Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a rare primary headache whose origins are unclear. To seek information on its pathophysiology, we studied the trigeminal Aβ and Aδ pathways by recording trigeminal reflexes and laser evoked potentials (LEPs) in patients with SUNCT. Methods Trigeminal reflexes and LEPs were recorded in 11 consecutive patients. Ten patients had neuroimaging evidence documenting idiopathic SUNCT and one had a posterior fossa tumour that compressed the trigeminal nerve thus causing symptomatic SUNCT. Results Whereas the patients with idiopathic SUNCT had normal trigeminal reflex and LEP responses, the patient with symptomatic SUNCT had abnormal responses. Conclusions Our neurophysiological findings show that idiopathic SUNCT spares the trigeminal sensory pathways whereas symptomatic SUNCT does not. Significance Neurophysiological testing can easily differentiate the idiopathic and symptomatic forms of SUNCT. It also suggests that the two forms are pathophysiologically distinct entities.

Aims of the study. - Nerve conduction studies have demonstrated that carbamazepine (CBZ), as well as other antiepileptic drugs (AEDs), can affect peripheral nerve conduction; reports on conventional somatosensory evoked potentials and CBZ are controversial. In a previous study, assessing laser-evoked potentials (LEPs) in CBZ-treated patients with idiopathic trigeminal neuralgia, we found that LEPs were dampened even after stimutation of the non-painful side, with a strong correlation between LEP latency and daily CBZ dose. No other study investigated the influence of AEDs on LEPs. In order to clarify the effect of CBZ on LEPs we sought possible LEP changes in epileptic patients taking CBZ.Materials and methods. - We studied LEPs after trigeminal and hand CO2-laser stimutation in 20 patients with epilepsy taking CBZ and 20 age-matched controls.Results. - Although the trigeminal LEP mean latency was slightly longer in epileptic patients (P = 0.11), we did not find significant differences between epileptic patients and controls for any LEP data. LEP data did not correlate with the daily CBZ dose, CBZ blood concentration, or duration of therapy (P > 0.3).Conclusion. - The tack of a CBZ-induced dampening of LEPs suggests that small-fibre pathways, compared to large-fibre, might be less susceptible to AED's toxic effect. Although the TN patients in our previous study were older than the epileptic patients in the present study, a possible combined effect induced by drug and age in patients with TN is unlikely because LEP latency is reportedly unaffected by age. The CBZ-induced effect in patients with trigeminal neuralgia is possibly related to pathophysiological changes specific to this disease. (c) 2005 Elsevier SAS. All rights reserved.

Our current understanding of brainstem reflex physiology comes chiefly from the classic anatomical-functional correlation studies that traced the central circuits underlying brainstem reflexes and establishing reflex abnormalities as markers for specific areas of lesion. These studies nevertheless had the disadvantage of deriving from post-mortem findings in only a few patients. We developed a voxel-based model of the human brainstem designed to import and normalize MRIs, select groups of patients with or without a given dysfunction, compare their MRIs statistically, and construct three-plane maps showing the statistical probability of lesion. Using this method, we studied 180 patients with focal brainstem infarction. All subjects underwent a dedicated MRI study of the brainstem and the whole series of brainstem tests currently used in clinical neurophysiology: early (R1) and late (R2) blink reflex, early (SP1) and late (SP2) masseter inhibitory reflex, and the jaw jerk to chin tapping. Significance levels were highest for R1, SP1 and R2 afferent abnormalities. Patients with abnormalities in all three reflexes had lesions involving the primary sensory neurons in the ventral pons, before the afferents directed to the respective reflex circuits diverge. Patients with an isolated abnormality of R1 and SP1 responses had lesions that involved the ipsilateral dorsal pons, near the fourth ventricle floor, and lay close to each other. The area with the highest probabilities of lesion for the R2-afferent abnormality was in the ipsilateral dorsal-lateral medulla at the inferior olive level. SP2 abnormalities reached a low level of significance, in the same region as R2. Only few patients had a crossed-type abnormality of SP1, SP2 or R2; that of SP1 reached significance in the median pontine tegmentum rostral to the main trigeminal nucleus. Although abnormal in 38 patients, the jaw jerk appeared to have no cluster location. Because our voxel-based model quantitatively compares lesions in patients with or without a given reflex abnormality, it minimizes the risk that the significant areas depict vascular territories rather than common spots within the territory housing the reflex circuit. By analysing statistical data for a large cohort of patients, it also identifies the most frequent lesion location for each response. The finding of multireflex abnormalities reflects damage of the primary afferent neurons; hence it provides no evidence of an intra-axial lesion. The jaw jerk, perhaps the brainstem reflex most widely used in clinical neurophysiology, had no apparent topodiagnostic value, probably because it depends strongly on peripheral variables, including dental occlusion.

The GISTs are rare tumours but even rarer is the localization in some districts. We reported two GISTs of the duodenum, two of the omentum and peritoneum, one of the rectum and one of a Meckel’s diverticulum. These exceptional locations are confirmed by the relative difficult diagnosis, obtained in some cases only by the surgical treatment despite the CT and MR. The endoscopy is useful in hemorrhagic and duodenum forms, only for the diagnosis and for the control of blood loss. Surgical treatment in all cases was decisive without the need to make use of adjuvant therapy, with positive long-term results, which excluded the disappearance of relapses or secondary lesions.

Pain is a subjective condition that cannot be objectively measured; for this reason, self patient-perspective is crucial. Recently, several screening tools to discriminate between nociceptive and neuropathic pain have been developed. We aimed at assessing the consistence and discrepancy of two widely used screening tools, The Douleur Neuropathique 4 (DN4) and the 6-item questionnaire (ID-Pain), by comparing their ability in discriminating neuropathic from nociceptive pain. DN4 and ID-Pain were administered to 392 Italian patients attending 16 outpatient services for peripheral nerve diseases. Based on medical history, clinical findings and diagnostic tools, patients were divided into two groups (neuropathic and nociceptive). Globally, ID-Pain identified neuropathic pain in 60 % of patients (38 % probable, 22 % likely). Interestingly also DN4 diagnosed neuropathic pain in 60 % of cases. A discrepancy was observed in 16 % of cases. DN4 and ID-Pain resulted to be highly interrelated in the identification of neuropathic pain. Sensitivity of DN4 was 82 % and specificity was 81 %, while ID-Pain (considering both probable and likely groups) showed sensitivity 78 % and specificity 74 %. Reliable screening tools for neuropathic pain are well related between them; hence, they are available for researchers and clinicians who may choose the most appropriate for their activity. Since the gold standard for the diagnosis and treatment of neuropathic pain cannot do without a neurological evaluation, perhaps DN4, that includes physician objective measures, may help reducing the percentage of dubious cases. Conversely, when needing a more agile tool (not needing a physician) ID-Pain may be adopted.

In patients with distal symmetric polyneuropathy we assessed non-nociceptive Abeta- and nociceptive Adelta-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 150 patients with distal symmetric polyneuropathy (68 with pain and 82 without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard nerve conduction study (NCS) to assess Abeta-fibre function, and laser-evoked potentials (LEPs) to assess Adelta-fibre function. Patients with pain had the same age (P0.50), but a longer delay since symptom onset than those without (P0.01). Whereas the LEP amplitude was significantly lower in patients with pain than in those without (P0.0001), NCS data did not differ between groups (P0.50). LEPs were more severely affected in patients with ongoing pain than in those with provoked pain (P0.0001). Our findings indicate that the impairment of Abeta-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that this type of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds.

BACKGROUND: There is good evidence that radiotherapy is beneficial in advanced rectal cancer, but its application in Italy has not been investigated. METHODS: We conducted a nationwide survey among members of the Italian Society of Colo-Rectal Surgery (SICCR) on the use of radiation therapy for rectal cancer in the year 2005. Demographic, clinical and pathologic data were retrospectively collected with an online database. Italy was geographically divided into 3 regions: north, center and south which included the islands. Hospitals performing 30 or more surgeries per year were considered high volume. Factors related to radiotherapy delivery were identified with multivariate analysis. RESULTS: Of 108 centers, 44 (41%) responded to the audit. We collected data on 682 rectal cancer patients corresponding to 58% of rectal cancers operated by SICCR members in 2005. Radiotherapy was used in 307/682 (45.0%) patients. Preoperative radiotherapy was used in 236/682 (34.6%), postoperative radiotherapy in 71/682 (10.4%) cases and no radiotherapy in 375 (55.0%) cases. Of the 236 patients who underwent preoperative radiotherapy, only 24 (10.2%) received short-course radiotherapy, while 212 (89.8%) received long-course radiotherapy. Of the 339 stage II-III patients, 159 (47%) did not receive any radiotherapy. Radiotherapy was more frequently used in younger patients (P < 0.0001), in patients undergoing abdominoperineal resection (APR) (P < 0.01) and in the north and center of Italy (P < 0.001). Preoperative radiotherapy was more frequently used in younger patients (P < 0.001), in large volume centers (P < 0.05), in patients undergoing APR (P < 0.005) and in the north-center of Italy (P < 0.05). CONCLUSION: Our study first identified a treatment disparity among different geographic Italian regions. A more systematic audit is needed to confirm these results and plan adequate interventions.

The aim of this study was to validate the Italian version of the Neuropathic Pain Symptom Inventory (NPSI) in patients with neuropathic pain due to peripheral nerve diseases, and also to evaluate the validity of a new NPSI score: a frequency weighted NPSI score (NPSI-FW). First, the original version of the NPSI was translated into Italian. Then the validity and reliability of the Italian NPSI (I-NPSI) were tested in 392 Italian patients consecutively referred to 16 Italian outpatient services for peripheral nerve diseases, by correlating the I-NPSI scores with other pain scales. The repeatability and responsiveness were assessed. A significant correlation between the I-NPSI scores and all the other pain measures was seen. Reproducibility and responsiveness were good. Our study shows the validity of the I-NPSI and demonstrates its reliability for assessing neuropathic pain in patients with peripheral nerve diseases. The I-NPSI scores represent reliable measurements to assess neuropathic symptoms and effectiveness of treatment on them.

Although many patients with multiple sclerosis (MS) complain of trigeminal neuralgia (TN), its cause and mechanisms are still debatable. In a multicentre controlled study, we collected 130 patients with MS: 50 patients with TN, 30 patients with trigeminal sensory disturbances other than TN (ongoing pain, dysaesthesia, or hypoesthesia), and 50 control patients. All patients underwent pain assessment, trigeminal reflex testing, and dedicated MRI scans. The MRI scans were imported and normalised into a voxel-based, 3D brainstem model that allows spatial statistical analysis. The onset ages of MS and trigeminal symptoms were significantly older in the TN group. The frequency histogram of onset age for the TN group showed that many patients fell in the age range of classic TN. Most patients in TN and non-TN groups had abnormal trigeminal reflexes. In the TN group, 3D brainstem analysis showed an area of strong probability of lesion (P

Carpal tunnel syndrome (CTS), a common entrapment neuropathy involving the median nerve at the wrist, frequently manifests with neuropathic pain. We sought information on pain mechanisms in CTS. We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non-nociceptive Abeta-fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive Adelta-fibres. In 40 patients (75 CTS hands) we also recorded laser-evoked potentials (LEPs) in response to stimuli delivered to the median nerve territory and mediated by nociceptive Adelta-fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI. We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain. Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non-nociceptive Abeta-fibres, spontaneous constant pain arises from damage to nociceptive Adelta-fibres.

In this study we investigate whether the cutaneous silent period (CSP)-an inhibitory response evoked in hand muscles by painful digital nerve stimulation-is useful for assessing nociceptive pathway function in patients with neuropathic pain. In 40 patients with peripheral neuropathy (21 without and 19 with neuropathic pain) we recorded the CSP in the abductor digiti minimi after fifth digit stimulation and also recorded laser evoked potentials (LEPs) after stimulation applied to the ulnar territory of the hand. Although the LEP amplitude was significantly lower in patients with pain than in those without (P0.005), the CSP duration did not differ between groups (P0.50). Pain intensity correlated significantly with LEP amplitudes (P0.005) but not with CSP duration (P0.5). Our findings indicate that the CSP is not useful for assessing nociceptive pathway function in patients with neuropathic pain.

Postherpetic neuralgia is an exceptionally drug-resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11-point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non-nociceptive myelinated A beta-fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated A delta- and unmyelinated C-fiber activation. We also Sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side (P < 0.001). The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the A delta and C-LEP amplitude reduction correlated with the intensity of constant pain (P < 0.01). Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological-clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to A beta-fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Contact heat stimuli have been reported to excite mechano-thermal nociceptors and to evoke brain potentials (CHEPs) from the limbs. We investigated whether contact heat evokes reproducible CHEPs from the trigeminal territory and may prove a reliable diagnostic tool in facial neuropathic pain. We applied contact heat stimuli to the perioral and supraorbital regions; CHEPs were recorded from the vertex in 20 controls and 2 patients with facial neuropathic pains, and reflex responses from the orbicularis oculi and masticatory muscles in 5 controls. We studied the correlation between CHEP data and perceptive ratings, site of stimulation, and age. Finally, we compared CHEPs with laser evoked potentials (LEPs). Contact heat stimuli at 51 degrees C evoked vertex potentials consisting of an NP complex similar to that elicited by laser pulses, though with a latency some 100-ms longer. Perioral stimulation yielded higher pain intensity ratings, shorter latency and larger amplitude CHEPs than supraorbital stimulation. CHEP data correlated significantly with age. Contact heat stimuli at 53 degrees C evoked a blink-like response in the relaxed orbicularis oculi muscle and a silent period in the contracted masseter muscle. In patients with facial neuropathic pain the CHEP abnormalities paralleled those seen with LEPs. We were unable to achieve reproducible signals related to C-receptor stimulation by contact heat stimuli at 41 degrees C in the ten subjects in whom they were tested. Contact heat stimulation, as well as laser stimulation, easily yields large-amplitude brain potentials and nociceptive reflexes, both related to the Adelta input. However CHEPs are not suitable for C-fibres potentials recording.

Although laser pulses activate concomitantly Adelta and C fibres, the corresponding brain evoked responses remain strictly limited to the Adelta component, without any potential consistent with C-fibre activation. To investigate whether this phenomenon depends on the order of arrival to the cortex ("first come first served" hypothesis) or is simply explained by A-to-C inhibition and/or lower energy associated with the desynchronised C-fibre input, we devised an experiment where the physiological order of arrival to the cortex was artificially inverted. Following a conditioning C-pulse, the cortical response to a second laser stimulus was significantly attenuated, whether it was Adelta or C. Thus, a C-volley was able to depress the response to a subsequent Adelta stimulus, in support of the "first come first served" hypothesis. However, the conditioning C-fibre stimulus attenuated significantly more a subsequent C-volley than a subsequent Adelta-volley, indicating that the suppression effect does not depend solely on the order of arrival to the cortex, but also on the ratio of energy per unit time conveyed by the successive inputs. This supports the notion that cortical evoked potentials to laser pulses (and probably to other sensory stimuli) reflect networks detecting rapid energy changes relative to a preceding baseline. The output of such networks should depend both on the time elapsed between successive inputs and on the relative energy per unit time conveyed by successive volleys. Such dedicated networks aimed at detecting energy changes may be related to orienting reactions, and can be dissociated from subjective perception.

The authors prospectively studied 120 consecutive patients with trigeminal neuralgia (TN) to identify the clinical and laboratory features that most accurately distinguished symptomatic from classic TN. After a standardized evaluation, they identified 24 patients with symptomatic TN. Age, sensory examination, and affected division were not useful in the differential diagnosis. In contrast, electrophysiologic testing of trigeminal reflexes accurately distinguished symptomatic from classic TN (sensitivity 96%, specificity 93%).

Laser-evoked potentials (LEPs) currently represent the most reliable and widely agreed method of investigating the A delta-fibre pathways. Many studies dealt with the usefulness of LEPs in peripheral and central nervous system diseases. We aimed at gaining normative values for LEP data.Using a CO2 laser stimulator we recorded LEPs after face, hand, and foot stimulation in 100 normal subjects. We measured the perceptive threshold, latency and amplitude of the main vertex components, and their side-to-side differences. We also studied the correlations between LEP data and age and body height, as well as gender differences.Laser perceptive threshold increased and LEP amplitude decreased from face to foot (P0.0001). The latency of hand and foot-LEPs correlated significantly with body height (P0.0001). The amplitude, though not the latency, correlated with age (P0.0001). LEP data did not significantly differ between genders (P0.1).This study provides normative values for the main LEP data and their absolute and side-to-side limits, highlighting the physiological differences related to, body height, age, gender and stimulation site.Our data may help to improve the clinical reliability of LEPs as a diagnostic tool.

We evaluated the reliability of laser-evoked potentials (LEPs) as a diagnostic tool in patients with post-herpetic neuralgia (PHN), i.e. a chronic painful condition that causes small-diameter fibre dysfunction. Furthermore, we sought information on pathophysiology of PHN pain.We recorded 'late' LEPs after stimulation of the supraorbital, upper cervical, lower cervical, upper thoracic, mid thoracic, and lower thoracic territories in 12 control subjects and 40 patients with PHN. We also determined the correlation of LEP data with age, duration of disease, and severity and quality of pain.At all stimulation sites, laser pulses invariably evoked high-amplitude brain potentials related to small-myelinated (A-delta) fibre activation. The laser perceptive threshold and LEP latency correlated with the distance of the dermatome from the brain (P0.001). In patients, the perceptive threshold was higher and the LEP amplitude was lower in the affected dermatome than on the contralateral side (P0.001). We found no significant LEP-clinical correlation except for a correlation between LEP abnormality and age.Being sensitive and reliable in assessing sensory function also in proximal dermatomes, LEPs are a promising diagnostic tool in radiculopathies. Although PHN severely impairs small myelinated fibres, the lack of a significant correlation between LEP abnormalities and pain suggests that pain in PHN does not chiefly arise from a dysfunction of small-myelinated afferents.

Background: In patients with trigeminal neuralgia, results of clinical examination of sensory function are normal. Reflex and evoked potential studies have already provided information on large-afferent (non-nociceptive) function. Using laser-evoked potentials (LEP), the authors sought information on small-afferent (nociceptive) function. Methods: The brain potentials evoked by CO 2 –laser pulses directed to the perioral and supraorbital regions were studied in 67 patients with idiopathic or symptomatic trigeminal neuralgia and 30 normal subjects. Of the 67 patients, 49 were receiving carbamazepine. Results: All patients with symptomatic and 51% of those with idiopathic trigeminal neuralgia had frankly abnormal LEP on the painful side. The mean latency was significantly higher and mean amplitude lower on the painful than the nonpainful side. However, even on the nonpainful side, the mean latency was significantly longer than that of the age-matched controls. The nonpainful-side latency correlated significantly with the carbamazepine dose. Conclusions: LEP detect severe impairment of the nociceptive afferent system on the painful side of patients with idiopathic as well as symptomatic trigeminal neuralgia. A dysfunction of small-myelinated afferents may play an important role in the pathophysiology of neuralgic pain. Carbamazepine markedly dampens these brain potentials. The authors propose that this effect may result from inhibition of nociceptive transmission in the cingulate gyrus.

Purpose: Theoretical data and experimental assumptions indicate that intraperitoneal hyperthermic chemotherapy may play a role in the treatment of peritoneal carcinomatosis. The feasibility, tolerability and pharmacokinetics of intraperitoneal hyperthermic perfusion with mitoxantrone were studied in patients with pretreated ovarian cancer. Methods: After cytoreductive surgery, 11 patients underwent intraperitoneal hyperthermic perfusion with mitoxantrone. A heated (42–43 °C) solution of the drug (28 mg/m2) was recycled through a perfusion apparatus into the abdominal cavity for 90 min. Treatment was repeated every month for two to four cycles. In six patients blood and peritoneal perfusate samples were collected at 0.5, 1, 1.5, 2, 4, 8, 16 and 24 h after drug administration and mitoxantrone was assayed by an HPLC method. Results: Although treatment was generally well tolerated, all patients developed transient intestinal subocclusion. Maximal mitoxantrone plasma concentrations (Cmax), times to Cmax (Tpeak) and area under the curves (AUC) were highly variable between subjects (Cmax 14–337 ng/ml; Tpeak 0.5–8 h; AUC 222–4130 ng · ml−1 · h). The plasma to peritoneal fluid AUC ratio was significantly higher during the second (0.177) than during the first cycle (0.066), suggesting a cycle-dependent increase in systemic bioavailability. Furthermore, when comparing present data with those reported previously, hyperthermic perfusion may have lowered the mitoxantrone levels in the peritoneal fluid without greatly influencing plasma levels. Conclusions: Intraperitoneal mitoxantrone administered under hyperthermia to advanced ovarian cancer patients is feasible and well tolerated. Mitoxantrone pharmacokinetics may be altered by repeated intraperitoneal administration (increased bioavailability) and by hyperthermic perfusion (possibly, increased peritoneal tissue uptake).

Interleukin 6 (IL-6), an autocrine growth factor for many tumors, seems to favour tumor spread to the liver. Our aims were first to evaluate the pattern of portal and systemic IL-6 levels in patients with pancreatic cancer (PC, n =18) and chronic pancreatitis (CP, n =22) compared with controls (CS, n =20); and second, to ascertain whether there was any relation between IL-6 levels and tumor spread or PC-associated Diabetes mellitus. For all subjects, a fasting serum sample was obtained from a cubital vein; a portal serum sample was obtained from nine PC and three CP patients. In cubital and portal sera we measured IL-6, interleukin 1 beta (IL-1b), CA 19-9, c-reactive protein (CRP) and amylase. Systemic IL-6 levels were significantly higher in PC patients than in CS. In PC, portal IL-6 levels were significantly higher than the corresponding systemic values. The same pattern was found in the three CP patients, whereas IL-1b, CA 19-9, CRP and amylase portal levels were the same as systemic values. No correlation was found between PC stage and systemic or portal IL-6 levels. Portal IL-6 levels were correlated with the corresponding fasting serum glucose values. A significant correlation was found between IL-6 values and CRP, ALT, total bilirubin, GGT and creatinine, but not amylase. In conclusion: (1) Portal IL-6, which is partly of pancreatic origin, is first metabolised in the liver; (2) Systemic IL-6 reflects hepatic and renal functions rather than local conditions in the pancreas; (3) IL-6 does not appear to influence PC spread; (4) IL-6, which is released in large amounts by the inflamed pancreas, may contribute to determining diabetes, thus interfering with the signal transducing pathways involved in glucose metabolism in liver cells.

Background—Helicobacter pylori species comprise different strains, cytotoxic and non-cytotoxic, which can be identified on the basis of their genomic pattern.Aims—(1) To evaluate the polymorphism of the vacA gene and to ascertain whether thecagA gene is present in patients with gastric adenocarcinoma. (2) To study the anti-H pylori antibody profile using western blotting.Patients—Twenty one patients with gastric adenocarcinoma and 71 with H pyloriassociated benign disease (nine gastric ulcer, 29 duodenal ulcer, 25 antral gastritis, and eight duodenitis).Methods—The polymerase chain reaction was used to verify the presence or absence ofcagA and to study the polymorphism of vacA in gastric mucosal samples obtained during endoscopy for patients with benign diseases and at surgery for patients with gastric adenocarcinoma. Fasting sera were used to assess anti-H pylori antibodies against different H pyloriantigens by western blotting.Results—cagAgene and the allele s1 of vacAwere significantly less frequent in patients with antral gastritis (60% and 60%) compared with patients with gastric adenocarcinoma (94% and 100%) and with other non-malignant gastroduodenal diseases (93% and 87%) (χ2=16.01, p2=13.97, pH pylori antigen were less frequently found than in patients with benign diseases.Conclusions—H pylori infection caused bycagApositive/vacA s1 strains is a frequent finding in patients with gastric adenocarcinoma. Prospective studies are needed to confirm whether the low incidence of positive serological response to the 74 kDa H pyloriantigen in patients with gastric adenocarcinoma is important.

BACKGROUND The first step of colorectal carcinoma spread depends on the ability of the tumor cells to degrade and invade the extracellular matrix (ECM). The objectives of the current study were to evaluate the serum pattern of laminin, C-terminal peptide of Type I (PIP), and N-terminal peptide of Type III (PIIIP) procollagens, markers of ECM synthesis, in the follow-up of patients after resection for colorectal carcinoma and to evaluate their role in predicting local recurrence or metastases. METHODS A total of 32 patients who had undergone resection for colorectal carcinoma were followed for a median period of 24 months (range, 6-36 months). Every 3 months, laminin, PIP, and PIIIP were measured in the sera together with the tumor markers carcinoembryonic antigen (CEA), CA 19-9, and tissue plasminogen activator (TPA). Twenty-one patients (Group 1) had no signs of recurrence, whereas the remaining 11 (Group 2) developed hepatic (n = 7) or pulmonary (n = 4) metastases. RESULTS No variations were observed in either group for laminin, CEA, CA 19-9, or TPA, whereas significant increases in PIP and PIIIP were observed in both groups 3 months after surgery. The increase in PIP and PIIIP at the 3-month follow-up was significantly greater in Group 1 than in Group 2. The difference between values at 3 months and basal values enabled a discrimination between Group 1 and Group 2, with a sensitivity of 36% and 91% and a specificity of 71% and 71% for PIP and PIIIP, respectively. CONCLUSIONS The authors believe PIIIP is useful as an early prognostic indicator of recurrence in the follow-up of patients who have undergone radical resection for colorectal carcinoma. Cancer 1997; 79:1299-303. © 1997 American Cancer Society.

Early diagnosis of colorectal cancer, a frequent neoplasia in industrialized countries, permits curative surgery. In this study we assessed the clinical role of serum tumor markers determination in diagnosing, staging, and grading colorectal cancer; the role of carcinoembryonic antigen (CEA), CA 19-9, tissue polypeptide antigen (TPA) and CA 72-4 in colorectal cancer follow-up was also assessed. In 114 patients with colorectal cancer, the oncofetal antigen CEA was compared with the membrane-associated glycoproteins CA 19-9, CA 242, and CA 72-4 and with the cytokeratins TPA, tissue polypeptide-specific antigen (TPS) and tissue polypeptide monoclonal antigen (TPM). Overall, the most sensitive indices were TPA and TPS (67% and 70%, respectively). Tumor stage influenced the levels of CEA, CA 19-9, and TPA, but not those of TPS, while tumor grade influenced CEA and TPS, but not CA 72-4, TPA, and TPM. TPA was the most sensitive index in identifying early or well-differentiated colorectal cancers. The sensitivity was enhanced when this marker was determined in combination with CEA, in diagnosing both advanced and early colorectal tumors. Seventy-seven patients were followed up after therapy for at least 18 months. CEA was the most sensitive index of recurrence (58%); however, this sensitivity is too low to consider tumor markers useful in colorectal cancer follow-up.

The distal splenorenal shunt (DSRS) was compared with the side-t-side portacaval shunt (PCS) in 93 prospectively matched cirrhotic patients with portal hypertension. After a mean follow-up of 38 months, no differences were observed in operative mortality, long term survival and variceal rebleeding between the two groups. There was no significant difference in terms of acute encephalopathy (22% in PCS group and 33% in DSRS group) and chronic encephalopathy (35% in PCS and 17% in DSRS). However, the only cases of severe and disabling chronic encephalopathy (CE) arose after PCS (p = 0.049). Actuarial curves of CE showed that the maximum rate of this complication (18%) in the DSRS group was reached 27 months after shunt surgery, whereas this value was reached and passed in PCS group only 4 months after shunt. CE occurred for a total duration of 20.1 months after PCS and only 11.1 months after DSRS (p = 0.003) and occupied 46.3% of the follow-up of PCS patients in contrast to 18.7% of the follow-up of DSRS patients (p = 0.001). DSRS is associated with a lower global incidence of CE without severe forms and provides a better quality of life than does a nonselective shunt.

This randomized double-blind controlled study analyzed the hemodynamic effects of penbutolol, a new levorotatory beta-blocker, using radionuclide angiography. Twenty cirrhotics with esophageal varices were randomized to two groups: 10 received 40 mg/day of penbutolol orally and the others placebo. Angioscintigraphy was performed before and after an 8-day treatment period. Three cases in the penbutolol group were lost due to software damage, hence the data of 17 patients were analyzed. The two groups were matched for age, sex, etiology of cirrhosis and hepatic function. The index of portal perfusion decreased significantly (-29%; p = 0.018) and the hepatic artery index increased significantly (+23%; p = 0.018), while no changes were observed after placebo. The heart rate decreased significantly after penbutolol (-9%; p = 0.028), while neither penbutolol nor placebo modified the ejection fraction. In conclusion, penbutolol decreased portal perfusion index (the compensatory increase in the hepatic artery index confirmed this change) without major modification of total hepatic blood flow or systemic hemodynamics. Angioscintigraphy is reasonably accurate, reproducible, safe and can be considered suitable for routine use in the assessment of liver hemodynamics.

In order to validate an angioscintigraphic method for the evaluation of the components of hepatic blood flow, the results of angioscintigraphy were compared with splanchnic angiography in 25 cirrhotics. Two indices of hepatic portal perfusion and a splenohepatic arterial index were calculated. These were correlated with portal diameter and hepatic artery diameter, respectively. No correlation was found between grades of portal perfusion according Nordlinger's criteria and these indices. The method is very simple and could be applied to evaluate the changes of liver hemodynamics induced by drugs or shunt surgery.

We have performed a side-to-side portacaval shunt as the treatment of choice in six cases of primary Budd-Chiari syndrome. All the patients (three men and three women, mean age 33 years) had marked hepatomegaly and massive ascites. Four patients had endoscopically proved esophageal varices with no episodes of bleeding. Preoperative angiographic studies, caval pressure measurement, laparoscopy, liver biopsy specimens, liver scanning, and liver function tests confirmed the diagnosis. A possible etiologic factor was evident in only two cases. A plain side-to-side portacaval shunt was performed in four patients, while two required the interposition of a graft. One patient died after surgery of hepatorenal syndrome. Four of the surviving patients are free of ascites and doing well at 29, 27, 25, and 6 months. The remaining patient subsequently developed cirrhosis and died 76 months after surgery. None of the patients who survived developed encephalopathy. Shunt patency was confirmed endoscopically by variceal decompression in the four patients with esophageal varices. We believe the side-to-side portacaval shunt is a reliable and effective procedure for the definitive management of primary budd-Chiari syndrome.

The distal splenorenal shunt (DSRS) was compared with the side-to-side portacaval shunt (PCS) in 93 prospectively matched patients with portal hypertension. After 38 months mean follow-up the two shunts had a different incidence of acute encephalopathy (22% in PCS group and 33% in DSRS group) and chronic encephalopathy (35% in PCS group and 17% in DSRS group), but the difference was not statistically significant. However, the only cases of severe and disabling chronic encephalopathy arose after PCS (p = 0.049). Actuarial curves of chronic encephalopathy showed that the maximum rate of encephalopathy (18%) in the DSRS group was reached 27 months after shunt surgery, whereas this value was reached and passed in PCS group only 4 months after shunt. Chronic encephalopathy occurred for a total duration of 20.1 months after PCS and only 11.1 months afer DSRS (p = 0.003) and occupied 46.3% of the follow-p of PCS patients, as contrasted to 18.7% of the follow-up of DSRS patients (p = 0.0001). DSRS is associated with a lower global incidence of chronic HE without severe forms and provides a better quality of life than does a nonselective shunt.

Preoperative clearance of a single dose of BSP was assessed in 72 candidates for porto-systemic shunt in cirrhosis of the liver. Comparison between those who had died (24) and those who had survived (48) several years later showed statistically significant differences with regard to equivalent liver volume, first uncorrected exponential (Ki), absolute clearance, and 45' retention. A certain degree of differentiation could be made out among the survivors, whereas those who had died could not be distinguished from the series as a whole, nor could correlations be established with the length of survival. No practical advantage was displayed by the more complex, computer-processed parameters as opposed to those that were more immediately available.

A prospective, controlled study comparing the clinical results of the selective distal splenorenal shunt procedure and the side-to-side portacaval shunt procedure was undertaken in 1980. Ninety-three cirrhotic patients with previous episodes of bleeding from esophageal varices underwent a distal splenorenal shunt procedure (47 patients). The operative mortality rate was 2 percent in both groups. The intraoperative decrease of portal hypertension after the portacaval shunt procedure was higher than after the distal splenorenal shunt procedure (p less than 0.05), and in those with patent shunts, there was a 0 percent incidence of early variceal rebleeding after the portacaval shunt procedure compared with a 9 percent incidence after the distal splenorenal shunt procedure (p less than 0.05). Both shunts, however, had similarly satisfactory results in preventing long-term variceal rebleeding (portacaval shunt 2 percent and distal splenorenal shunt 0 percent). Postoperative ascites was more common after the distal splenorenal shunt procedure (58 percent versus 24 percent; p less than 0.01). Analysis of actuarial survival curves showed no difference between the two procedures. The incidences of long-term episodes of chronic encephalopathy were not statistically different after both procedures. The only three instances of severe encephalopathy occurred in patients with the portacaval shunt (p less than 0.05). The distal splenorenal shunt also seemed to have a less negative effect on postoperative liver function than the portacaval shunt. These data suggest that the selective shunt should be viewed as a first choice strategy in the treatment of portal hypertension.

This paper analyzes experience with 106 patients treated primarily with DSRS during a ten year period. Operative mortality was 5% of cases. Shunt patency was evaluated by postoperative angiography in 70 patients. A shunt thrombosis and a recanalization of the splenic vein were noted in a patient who had a Britton's operation resulting in a side-to-side shunt. In the other 31 cases, shunt patency was indirectly confirmed by the absence of varices at postoperative or long-term endoscopic examination. At postoperative check, esophageal varices had disappeared in only 19% of patients. However, this rose to 60% at long-term check-up. Ten patients bled from varices in the postoperative period (9%). During the follow-up period, no patient bled from varices, while five patients bled from gastroduodenal lesions (5%). During the postoperative period, 52% of cases had ascites. In the long-term, ascites developed in only 15% of cases and was well controlled by standard medical treatment. Analysis of the actuarial curve showed a 5-year survival rate of 63%. During the follow-up period, 17% of patients experienced at least one episode of acute encephalopathy. Chronic encephalopathy appeared in 14% of cases: ten patients suffered a mild form (10%) and four (4%) a moderate form. No patient had severe chronic encephalopathy. DSRS is effective as treatment of portal hypertension with a low long-term morbidity despite a more troublesome early postoperative period.

The effect of anatomical variations of the hepatic artery on the performance of the anastomosis was assessed during 390 portacaval shunt operations as well as the degree to which technical difficulties could be anticipated from preoperative arteriography. Variations were detected in 25 p. cent of 130 patients examined by angiography but were confirmed during portal vein dissection in only 11 p. cent of cases. Technical difficulties due to hepatic artery variations were encountered in only 2 p. cent of the 390 anastomosis. Accidental section of a right hepatic artery occurred once only, and this before the routine use of angiography. Treatment was by aortohepatic by-pass using a saphenous graft. Portacaval anastomosis can be conducted in the presence of an hepatic artery variation bat technical difficulties cannot be predicted by preoperative digestive angiography.

Generally, when a splenectomy is performed to treat either a severe hypersplenism or another splenic affection in a cirrhotic patient with uncomplicated esophageal varices, the question arises whether to associate or not a prophylactic shunt. In fact, splenectomy alone does not lower the portal pressure and does not affect positively the esophageal varices. Because of this, 36% of these patients will eventually undergo a bleeding episode from varices. Furthermore, in the patients surviving the first bleeding, the occurrence of splenoportal thrombosis following splenectomy does prevent a therapeutic shunt to be performed. For this reason splenectomy with a complementary prophylactic shunt was performed in 24 patients. This operation, which showed 16% mortality rate, significantly prevented bleeding (0%). Furthermore in the treated patients, splenectomy has lowered the portal pressure. Encephalopathy occurred in 30% of cases, however the accuracy in the selection of patients together with a proper diet and medical treatment have avoided severe complications. The 5 year survival rate was 60%. Nevertheless, the indication to a prophylactic shunt must be limited to these particular cases.