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.

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.

Pharmacological management of cancer pain.

Cancer pain remains a major cause of suffering. Improvements in its management have made unrelieved cancer pain unacceptable. While pharmacotherapy is the mainstay of cancer pain treatment, other options such as radiotherapy, nerve blocks, etc., have to be considered as well. A comprehensive approach must also address psychosocial issues. A successful pharmacotherapy programme for cancer pain requires careful assessment of the origin and cause of the pain. The selection of analgesics has to be rationalised using a sequential approach such as the WHO stepladder. Oral application by the block in an individually titrated dosage is recommended. Although morphine remains the most useful opioid, it should be used in combination with nonopioids. Co-analgesics, which contribute to analgesia without being classical analgesics, should be used to treat pain of specific origin. Here membrane-stabilizers, antidepressants and steroids play an often underestimated role in the treatment of neurogenic pain. Anxiolytics and major tranquillisers should be avoided because they cause sedation without improving quality of analgesia. Calcitonin, diphosphonates and spasmolytics are of minor importance in this regard. Finally, concomitant medication to treat side effects of the therapy may be necessary in formulating a comprehensive treatment plan.

Adverse effects of systemic opioid analgesics.

Adverse effects of opioids are multiple. They are most often receptor-mediated and inseparable from their desired effects. The most severe mishaps with opioids are related to their respiratory depressant effect, which is widely influenced by factors such as pain, previous opioid experience and awareness. Other relevant central nervous system effects of opioids include cough suppression, nausea and vomiting, rigidity, pruritus and miosis. The cardiovascular adverse effects of opioids are mainly related to histamine release and differ widely between agonists and agonist-antagonists. Gastrointestinal effects such as constipation, reflux and spasms of the bile duct are well described. Adverse effects on endocrine, immunological and haematological functions are possible, while allergic reactions are extremely rare. The adverse effects of long term use are overestimated. Systemic toxicity is negligible and development of tolerance is minimal while treating pain. In the clinical setting of pain control, addiction and withdrawal do not pose significant problems. Nevertheless, the possible effects of opioids on the unborn child should always be considered. Overall, opioids show a good record of safety. Their use should not be unduly limited by unfounded fears of adverse effects, but these effects should be avoided by anticipation and prevention.

Transdermal fentanyl: clinical pharmacology.

The transdermal therapeutic system (TTS) fentanyl has been designed for rate-controlled drug delivery. It provides a convenient regimen for the use of a drug previously limited by a short duration of action and a noninvasive parenteral route for a drug that is unsuitable for oral administration. TTS fentanyl has been developed to provide continuous controlled systemic delivery of fentanyl base for 72 hr. It is a rectangular, transparent unit composed of a protective peel strip and four functional layers. The amount of fentanyl released from each system (25 micrograms/hr per 10 cm2) is proportional to the surface area. So far, four patch sizes are available (10-40 cm2). When the system is applied, a fentanyl depot concentrates in the upper skin layers. Fentanyl plasma concentrations are not measurable until 2 hr after application, and it takes 8-16 hr latency until full clinical fentanyl effects are observed. Steady-state serum concentrations are obtained after several sequential 72-hr applications, and these are maintained for as long as a system is applied. Following removal, serum fentanyl concentrations decline gradually and fall about 50% in approximately 16 hr. This prolonged apparent elimination half-life occurs because fentanyl continues to be absorbed from the skin. Transdermal fentanyl transport is essentially the same between the chest, abdomen, and thigh. The skin-permeability constant is about 0.0125 mL/hr/cm2, much lower than the regional blood supply to a chest-skin area. Because of potential permeability variations among individuals, a special rate-controlling membrane in the system provides additional control of drug release.(ABSTRACT TRUNCATED AT 250 WORDS)

Cancer pain management according to WHO analgesic guidelines.

On admission to a pain management unit, 92.5% of 174 cancer patients suffered from more than moderate pain despite prior treatment. This inefficacy was mainly due to underdosage of drugs, inadequate intake schedule, and hesitation to use strong opioids. Following introduction of an oral drug therapy based on World Health Organization (WHO) guidelines, more than 80% of all patients described their pain as ranging between "none" and "moderate" on a six-step verbal rating scale at all times. To obtain these results, it was necessary to adapt the therapy to increasing pain in the course of terminal disease. Step III (strong opioids) gained more and more importance with time, and step I (nonopioids) was finally useful only in a minority of patients. Side effects played a minor role as a reason to change therapy. Oral drug therapy following these guidelines led to sufficient pain control in most patients over the whole study period (7,400 days); only 11% of the patients required other methods of pain management.

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.

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.

A long-term survey of morphine in cancer pain patients.

We surveyed 550 cancer patients who experienced pain and were treated with morphine for a total of 22,525 treatment days. Sufficient pain relief was achieved during more than 80% of this time using an average oral morphine dose of 82.4 mg--significantly lower than other studies. The use of this low dose, which was possible due to the concomitant administration of nonopioids and specific coanalgesics in most patients, resulted in a low incidence of side effects. Constipation and nausea/vomiting were the most common of these side effects. Physical dependence posed no practical problem in discontinuation of morphine treatment. Long-term opioid intake and development of tolerance did not appear to be linked; an increase in morphine dosage was most often explained by progression of the terminal disease. Addiction was a negligible problem, with only one observed case.

Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life.

The efficacy of the World Health Organization's guidelines for cancer pain relief was examined in 401 dying patients. At the time of death, only 3% of the patients experienced severe or very severe pain; whereas 52% had no pain at all, 24% experienced only mild or moderate pain, and 20% were unable to rate their pain intensity. Analgesic drugs were the mainstay of therapy during the last 24 hr of life, being administered by mouth in 47% and parenterally in 44% of the patients. Only 9% of the patients required no systemic analgesics. Nonopioid analgesics alone were effective in 5% and a combination of nonopioids and "weak" opioids were effective in 16% of the patients. In the remaining 70% of the patients "strong" opioids alone or in combination with nonopioid analgesics were necessary to achieve adequate pain reduction. Additional adjuvant drugs to treat special types of pain or other symptoms were prescribed in 90% of the patients. Nonpharmacological measures, such as radiotherapy, nerve blocks or neurosurgery played only a very minor role at this stage of the disease. This study shows that cancer pain can be treated satisfactorily until death.

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.

Validation of World Health Organization guidelines for pain relief in head and neck cancer. A prospective study.

In a prospective study of 167 patients with head and neck cancer, we assessed the causes and mechanisms of pain, as well as the efficacy and side effects of analgesic treatment, along World Health Organization (WHO) guidelines. The majority of patients had pain caused by cancer (83%) and/or treatment (28%), 4% had pain due to debility, and 7% had pain unrelated to cancer. Palliative antineoplastic treatment was performed in 32% of patients. Systemic analgesics were administered on 97% of a total of 8,106 treatment days, and coanalgesics or adjuvant drugs on 100%. The treatment proved to be very successful, as severe pain was experienced only during 5% of the observation period. In the absence of serious side effects, the most frequent symptoms observed were insomnia, dysphagia, anorexia, constipation, and nausea. The use of analgesic and adjuvant drugs along WHO guidelines to treat pain in head and neck cancer is highly effective and relatively safe.

The importance of non-opioid analgesics for cancer pain relief according to the guidelines of the World Health Organization.

In a retrospective study of 1070 cancer patients being treated according to guidelines of the World Health Organization during a period of 55,285 days, the importance, efficacy and side-effects of non-opioid analgesics were evaluated. The non-opioids were given alone on 6917 days and in combination with weak opioids on 15,253 days, with strong opioids on 24,246 days and with spinal opioids on 1008 days. In evaluating efficacy and safety, it was not possible to differentiate adequately between the effects of non-opioids, opioids and adjuvant drugs, but it was demonstrated that an adequate combination of these drugs was effective and safe in the treatment of cancer pain.

A computerized documentation system for cancer pain management units.

A cancer pain management unit can benefit markedly from a well-planned documentation system for administrative and scientific purposes. This article presents the principles of such a computerized system based on relational data base programs. The described system has been used by the authors for the last seven years. The successful documentation of more than 1400 patients over treatment periods of up to 2 years has provided detailed administrative and scientific information.

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.

Postoperative pain management and respiratory depression after thoracotomy: a comparison of intramuscular piritramide and intravenous patient-controlled analgesia using fentanyl or buprenorphine.

STUDY OBJECTIVE: To compare the analgesic efficacy of fentanyl, buprenorphine, and piritramide and to define the respiratory risk during conventional postoperative pain management and patient-controlled analgesia (PCA). DESIGN: Randomized, single-blind study. SETTING: Department of anesthesiology of an urban hospital. PATIENTS: Sixty patients (ASA) physical status II and III) recovering from unilateral thoracotomy performed under standardized general anesthesia including intercostal blockade. INTERVENTIONS: Patients were treated with intramuscular (IM) piritramide (7.5 to 15 mg as needed) or intravenous (IV) PCA with fentanyl (demand dose 34 micrograms) or buprenorphine (demand dose 80 micrograms) during the early postoperative period, using the On-Demand Analgesia Computer (ODAC, Janssen Scientific Instruments, Beerse, Belgium). MEASUREMENTS AND MAIN RESULTS: The mean postoperative observation period was 24 to 25 hours. During this time, patients requested 55.8 +/- 23.2 mg of piritramide, 1.04 +/- 0.54 mg of fentanyl, or 1.81 +/- 0.78 mg of buprenorphine. Analgesia in all groups was judged mostly good to excellent, with a preference for PCA. Side effects were only of minor intensity in all groups; euphoria or dysphoria occurred only with buprenorphine. Two patients using PCA and five patients having IM analgesia developed short periods of respiratory depression (respiratory rate less than or equal to 8 breaths/minute and/or oxygen (O2) desaturation less than or equal to 90%), which promptly responded to commands to breathe deeply. Respiration rates did not differ, and frequent arterial blood sampling showed normal mean partial pressures of oxygen (PO2) and carbon dioxide (PCO2) and arterial oxygen saturation (SaO2) in all subgroups. CONCLUSIONS: Opioid-induced respiratory depression occurred infrequently during postoperative pain management whether by conventional means or using PCA, even though high doses of opioid analgesics were required intermittently for adequate postoperative pain relief by either technique.

[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.

[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.

[Perineal pain and rectal cancer--prevalence in local recurrence]. / Perianalschmerz und Rektumkarzinom--Prävalenz beim Lokalrezidiv.

Between 1983 and 1989, 85 patients with either carcinoma of the rectum or a recurrence of a previously diagnosed rectal tumour (47 women and 38 men aged 20 to 87 years) were treated in our pain clinic. In 50 patients, the reason for referral was perineal pain which had been present for one week to two years (median six months, 25%-percentile six weeks, 75%-percentile six months). In some patients this was considered to be due to scar tissue formation by the referring doctors. The pain was classified somatic, visceral and neuropathic in approximately equal numbers of patients, and about half of them described more than one type of pain. The other 35 patients were suffering from pain at other sites. In 40 out of 50 patients with perineal pain, local tumour recurrence was diagnosed. In 29 patients, pain symptoms began with a median of 5.5 months before the tumour recurrence was diagnosed. In a further seven patients, other types of tumour dissemination in the pelvis were considered to be the cause of the perineal pain. In only three patients no evidence of tumour was found in the pelvis. A non-neoplastic cause of perineal pain could be definitely confirmed in only one patient on post-mortem examination. 35 patients reported no perineal pain on admission, although in 19 cases a local cancer recurrence was found. 13 of these patients suffered from pain in the area of sensory innervation of the lumbosacral plexus. From 16 patients without a diagnosis of local recurrence, only four reported pain in this area.(ABSTRACT TRUNCATED AT 250 WORDS)

[Interdisciplinary treatment of pancreatic cancer]. / Die Behandlung des Pankreaskarzinoms in interdisziplinärer Zusammenarbeit.

Resection of the pancreas due to carcinoma represents with an operative mortality of 3.5% and three-year-survival of 15% an operative strategy, which should be carried out as a therapy of choice only on selected patients with an early cancer stage (ex. T1). But no other treatment offers the chance of long-time survival and curation. There seems to be no influence of operative therapy on patient prognosis in advanced cancer stages. In these cases, palliative treatment (ex. biliodigestive anastomosis or transcutaneous biliary drainage) are methods of choice. A main palliative aspect should be a painless patient. This can be achieved by oral or i.v. medication and/or chemical neurolysis of plexus coeliacus.