CXCR3 mediates ascites-directed tumor cell migration and predicts poor outcome in ovarian cancer patients.

Intraabdominal tumor dissemination is a major hallmark of epithelial ovarian cancer (EOC), but the underlying mechanisms have not been fully elucidated. The CXCR3 chemokine receptor supports migration of tumor cells to metastatic sites, but its role in ovarian cancer metastasis is largely unknown. Herein, we first screened two independent cohorts of high-grade serous ovarian cancers (HGSCs, discovery set n=60, validation set n=117) and 102 metastatic lesions for CXCR3 expression. In primary tumors, CXCR3 was particularly overexpressed by tumor cells at the invasive front. In intraabdominal metastases, tumor cells revealed a strong CXCR3 expression regardless of its expression in the corresponding primary tumor, suggesting a selection of CXCR3-overexpressing cancer cells into peritoneal niches. In support of this, CXCR3 mediated the migration of tumor cell lines OVCAR3 and SKOV3 toward malignant ascites, which was inhibited by a monoclonal anti-CXCR3 antibody in vitro. These results were prospectively validated in ascites-derived tumor cells from EOC patients ex vivo (n=9). Moreover, tumor cell-associated overexpression of CXCR3 in advanced ovarian cancer patients was associated with a reduced progression-free survival (PFS) and overall survival (OS), which remained independent of optimal debulking, age, FIGO stage and lymph node involvement (PFS: hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.30-3.45, P=0.003; OS: HR 2.36, 95% CI 1.50-3.71, P<0.001). These results in ovarian cancer patients identify CXCR3 as a potential new target to confine peritoneal spread in ovarian cancer after primary cytoreductive surgery.

Apolipoprotein B-100: employing the electrochemiluminescence technology of the Elecsys systems for the detection of the point mutation Arg(3500)Gln.

Apolipoprotein B-100 (apo B-100) plays an essential role in lipoprotein metabolism where it is involved in the clearance of LDL particles from the bloodstream. The mutation Arg3500Gln in the apo B-100 gene impairs the binding of the LDL particles to the LDL receptor, resulting in elevated LDL-cholesterol levels in the blood which, in turn, fuel the development of premature atherosclerosis. Here we describe a rapid, automated test for the detection of the most frequent mutation in the apo B-100 gene. This PCR-based test employs electrochemiluminescence as detection technology and allows the reliable discrimination of all genotypes. The assay has been especially developed for the non-specialized routine clinical chemistry laboratory by employing an analyzer and chemistry often present in this type of labof1tory. Because of its low costs and easy handling the assay can be performed on a daily basis.

Haemochromatosis: automated detection of the two point mutations in the HFE gene: Cys282Tyr and His63Asp.

Hereditary haemochromatosis (HH) is one of the most common inherited diseases among Caucasians. Two mutations in the HFE gene have been implicated in HH: 80 to 90% of the patients with HH are homozygous for the point mutation CYS282Tyr, while the majority of the remaining patients displays either a compound heterozygosity for the mutation CYS282Tyr and the point mutation HIS63Asp, or are homozygous for HIS63Asp. Though the disease can be treated easily, symptoms are non-specific, and onset and severity are influenced by environmental factors, and therefore the disease can remain undetected until decades of iron overload lead to irreversible damage in a variety of organs, which may result in their failure. In order to detect patients with HH, simple and cost-effective tests are needed. We have developed a rapid, automated, PCR-based test which makes use of a diagnostic restriction site in each of two amplified fragments. The test employs off-the-shelf chemistry and uses the automated detection process of an immunoassay analyzer that is available in many clinical laboratories, thus avoiding an additional investment in a more specialized PCR analyzer. Because of its low costs and easy handling, the assay is particularly suited for the routine clinical laboratories.

Temporal presentation of chronic cancer pain: transitory pains on admission to a multidisciplinary pain clinic.

Transitory flares of pain are well-recognized events in both untreated and treated patients suffering from chronic cancer pain. For the purpose of this survey, we refer to transitory pain (TP) as any event subjectively characterized by transience and pain intensity over a baseline pain. In Part I, TP was reported by 243 (39%) of 613 consecutive cancer pain patients. Gender, age, tumor site, stage, and therapy were not related to the presence of TP. Neuropathic baseline pain was associated with a higher prevalence of TP (P < 0.0001). TP was somatic in 39%, visceral in 22%, and neuropathic in 36% of patients. TP intensity was severe or worse in 92% of patients. Neuropathic TP was briefer and occurred more frequently than nociceptive TP. In Part II, further features of TP were surveyed in 55 patients. Patients reported spontaneous occurrence of TP (40%), a relationship to movement (36%), to the analgesic regimen (35%), to coughing (11%), and to various other factors (18%). Only half of the movement-related TP were predictable. Rescue medication was at least partially effective in 75% of patients. Change in position, rest, diversion, and physiotherapy were commonly employed to alleviate TP. This survey outlined a framework to characterize TP that may prove useful to clarify the definition, pathophysiology, and prevalence of these pains.

[Myoclonus resulting from high-dose epidural and intravenous morphine infusion]. / Myoklonien als Folge von hochdosierter epiduraler und intravenöser Morphininfusion.

BACKGROUND: Myoclonus is a possible side effect of opioid therapy, and have been described following systemic as well as spinal application. CASE REPORT: We report the case of a patient with metastatic carcinoma of the rectum who developed myoclonus following administration of high-dose epidural combined with iv morphine. This complication occurred with maximum daily doses of 300 mg epidurally and 80 mg intravenously and disappeared completely after dose reduction. Treatment trials are presented, the pathophysiology of the myoclonus is discussed. CONCLUSION: For treatment of opioid-induced myoclonus a dose reduction or a change of the opioid should be considered as well as symptomatic treatment with benzodiazepines or baclofen.

Transdermal fentanyl in the long-term treatment of cancer pain: a prospective study of 50 patients with advanced cancer of the gastrointestinal tract or the head and neck region.

This open prospective study evaluated the combination of initial dose titration with patient-controlled analgesia (PCA) and long-term treatment with transdermal fentanyl in 50 cancer patients requiring opioids for severe pain. The delivery rate of the first transdermal therapeutic system (TTS) was calculated from the self-administered intravenous fentanyl dose during the first 24 h. TTS were changed every 48-72 h, and a different patch size was chosen if necessary. Pain intensity (101-step numeric analog scale) and side-effects were assessed daily. The patients were treated for 66 +/- 101 days (range 3-535 days). The average delivery rate was 5.9 +/- 4.1 mg/d. Mean pain intensity decreased from initially 45 +/- 21 to 19 +/- 15 in the titration phase and 15 +/- 11 during long-term treatment. Three patients showed moderate respiratory depression. Other severe side-effects were not observed. Patient compliance and acceptance were excellent. The results suggest that intravenous PCA is useful for initial dose finding, and transdermal fentanyl is effective and safe during long-term treatment of cancer pain.

High-dose oral morphine in cancer pain management: a report of twelve cases.

We present 12 case reports from patients treated with more than 600 mg of morphine per day. We found no "opioid-nonresponsive pain" under treatment with a combination of morphine and nonopioids, supplemented with coanalgesics where appropriate. Side effects of morphine therapy were controlled with adjuvant drugs. Serious adverse effects were not observed. Episodes of break-through pain, dysphagia, and dyspnea caused by far advanced cancer disease were seen frequently.

[High-dose intrathecal clonidine in the treatment of neuropathic tumor pain. Two case reports.]. / Hochdosierte intrathekale Clonidingabe in der Behandlung neuropathischer Tumorschmerzen : 2 Fallberichte.

Two cases with perineal pain caused by recurrent carcinoma of the rectum are reported. Initially both patients suffered from predominantly nociceptive pain, which was treated adequately with spinal opioids. Tumor growth with epidural spread and infiltration of the plexus lumbosacralis caused severe neuropathic pain. Both patients were free of pain with a combination of spinal clonidine and opioids. Clonidine doses had to be increased up to 1.31 and 1.46 mg daily in order to provide adequate analgesia. Outpatient treatment was possible for several weeks with stable dosage. Bradycardia and hypotension occurred with initial dose titration and after dose increases and were treated with parasympathicolytic drugs and vasopressor agents. Both patients were given spinal clonidine until their death 4 1/2 and 4 months later. In the final stages, adjuvant systemic administration of morphine was necessary to control dyspnea.

Transdermal fentanyl in combination with initial intravenous dose titration by patient-controlled analgesia.

Two studies including a total of 70 patients evaluated the efficacy and side effects of a combination of initial patient-controlled analgesia (PCA) for dose finding with transdermal fentanyl administration. Patients, requiring strong opioids for severe cancer pain, received intravenous (i.v.) fentanyl on an on-demand basis over a 24 h period. The amount of fentanyl administered was then used for selecting a suitable transdermal therapeutic system (TTS), which remained in place for 72 h. The size of the second TTS was adjusted according to the amount of supplementary i.v. fentanyl required on day 3. Beginning on day 4, oral or subcutaneous morphine was made available as a rescue medication. The use of TTS fentanyl in combination with initial dose titration using PCA resulted in rapid and statistically significant pain relief in both studies. A respiratory rate below 8 per minute was observed in three patients. Due to adequate symptomatic treatment, other moderate and severe symptoms were relatively rare. TTS fentanyl was shown to be an effective, safe and simple method for long-term pain relief in cancer patients and presents an interesting novel option in the treatment of cancer pain.

[Pain assessment and therapy in bronchial carcinoma]. / Schmerzanalyse und -therapie beim Bronchialcarcinom.

In the period from 1983-1991 133 patients (102 men, 31 women) with lung cancer were treated in our pain clinic for 8083 days. Pain was associated with tumour infiltration in 86% of patients and related to therapy in 15%. Even in 6 of 8 patients who were admitted with a diagnosis of "postthoracotomy syndrome" and in all 4 patients with "postradiation syndrome" local recurrence was diagnosed during follow-up. All 17 cases of brachial plexus lesions were caused by local tumour spread. Symptomatic treatment according to WHO guidelines resulted in good pain relief in 92% of patients and on 82% of days. The incidence of dyspnea decreased from 51% of the patients to 16%. Strong opioids were used on 56% of treatment days. Parenteral or spinal administration of opioids was necessary on 3% of days only.

Prevalence and pattern of symptoms in patients with cancer pain: a prospective evaluation of 1635 cancer patients referred to a pain clinic.

In a prospective study, the prevalence of 15 physical symptoms and symptom groups was evaluated in 1635 cancer patients referred to a pain clinic. In addition to pain, patients suffered an average of 3.3 symptoms: insomnia (59%), anorexia (48%), constipation (33%), sweating (28%), nausea (27%), dyspnea (24%), dysphagia (20%), neuropsychiatric symptoms (20%), vomiting (20%), urinary symptoms (14%), dyspepsia (11%), paresis (10%), diarrhea (6%), pruritus (6%), and dermatological symptoms (3%). While symptom prevalence was influenced by tumor site, pain intensity, and opioid treatment, only a minor relationship was seen between symptoms and gender, age, or tumor stage. The data emphasize that it is not sufficient to simply address pain during the treatment of patients with cancer pain; a more global approach to symptom management is necessary.

The use of Quincke and Whitacre 27-gauge needles in orthopedic patients: incidence of failed spinal anesthesia and postdural puncture headache.

This study examined the incidence of failed spinal anesthesia and postdural puncture headache using a 27-gauge Whitacre and a 27-gauge Quincke needle in patients undergoing elective inpatient orthopedic procedures. The overall rate of failed spinal anesthesia was 8.5% [95% confidence interval (CI) = 4.6%-12.4%] (n = 17) in the Quincke group (n = 199) and 5.5% [95% CI = 2.3%-8.7%] (n = 11) in the Whitacre group (n = 199). This difference was not statistically significant. The overall incidence of postdural puncture headache (PDPH) was 0.8%; 1.1% [95% CI = 0%-2.4%] (n = 2) in the Quincke group and 0.5% [95% CI = 0%-1.5%] (n = 1) in the Whitacre group. These differences were not statistically significant. All headaches were classified as mild and resolved spontaneously with conservative management. The mean time for withdrawal of the stylet to appearance of cerebrospinal fluid was 10.8 +/- 6.9 s in the Quincke (n = 31) and 10.7 +/- 6.8 s in the Whitacre group (n = 33). These differences were not statistically significant. Our results suggest that both needles are associated with a very low incidence of PDPH and an incidence of failed anesthesia of 5.5%-8.5%.

[Survey on the booklet "Short guidelines for cancer pain-management" issued by the working group "cancer pain" of the german association for the study of pain.]. / Anleitung zur Tumorschmerztherapie : Umfrage zu einer Broschüre des Arbeitskreises "Tumorschmerz" der Deutschen Gesellschaft zum Studium des Schmerzes e.V.

INTRODUCTION: An interdisciplinary working group on cancer pain was founded by the German Association for the Study of Pain in 1991. The goal of this group is the development and dissemination of training and information material, guidelines and curricula in the fields of cancer pain, palliative medicine and the legal regulations for the prescription of opioids. METHODS: Two editions of short guidelines on cancer pain management have so far been distributed throughout germany (a total of 15 000 copies). In preparation for a revised version, a questionnaire with five questions was sent out to practitioners asking for information on the acceptability of the guidelines and their usefulness in the daily work in practice. RESULTS: Only 167 of 670 (25%) questionnaires were returned. In almost 75% of these, the guidelines were reported to be informative, and in almost 100% as easily comprehensible. For their daily work, 56% of the respondents found the guidelines very helpful and 40% rather helpful. CONCLUSIONS: The results of this survey clarify the need for concrete guidelines in cancer pain management which are at the same time readily understandable. The new edition of 40 000 copies of the "Abbreviated Guidelines for Cancer Pain Management" was published in October 1993. Because of the good response, a further booklet on "Cancer Pain Management in Children" is being planned.