Long-term neurotoxicity and Raynaud's phenomenon in patients treated with cisplatin-based chemotherapy for malignant ovarian germ cell tumor.

INTRODUCTION: The aim was to evaluate "overall neuropathy", defined as peripheral paresthesia and Raynaud's phenomenon, in long-term survivors of malignant ovarian germ cell tumors (MOGCTs) treated with cisplatin-based chemotherapy (CBCT). MATERIAL AND METHODS: Ninety-three MOGCT survivors recorded in Norway in 1980-2009 (median follow up: 15 years) were included in this analysis. Forty-nine received CBCT (CBCT group) and 44 received other or no chemotherapy (non-CBCT group). Applying the scale for chemotherapy-induced neurotoxicity, the prevalence of overall neuropathy (ie score >1 on a 0-3 scale) was compared between the two groups. Forty women from the CBCT group also underwent neurophysiological and neurological examinations; results from the neurological examination were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Effects version 4 (NCI-CTCAE scale v4). These women were then categorized into subgroups of low (≤3 cycles of CBCT, n = 23) and high CBCT (≥4 cycles of CBCT, n = 17). RESULTS: Twenty-eight (57%) women from the CBCT group reported overall neuropathy, compared with 20 (45%) in the non-CBCT group (P = .06). Of the 40 MOGCT survivors in the CBCT group who underwent neurophysiological and neurological examinations, 14 (35%) showed NCI-CTCAE grade ≥1 signs or symptoms of peripheral neuropathy. Pathological findings of NCI-CTCAE grade 2 or 3 signs or symptoms were found in four survivors (10%) from the high CBCT subgroup, all of whom also showed objective signs of neuropathy. CONCLUSIONS: Though about half of our MOGCT survivors reported overall neuropathy after CBCT, more severe pathological neurological/neurophysiological findings that impacted daily living were recorded in only 10% of them. Our observations of a similar prevalence of self-reported overall neuropathy in the CBCT and non-CBCT group, combined with limited objective neurological findings, warrant further study to increase the understanding of the specific pathophysiological pathways of long-term CBCT-induced neuropathy.

Pain relief in a neuropathy patient by lacosamide: Proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors.

BACKGROUND: Small fiber neuropathy (SFN) is a severe and disabling chronic pain syndrome with no causal and limited symptomatic treatment options. Mechanistically based individual treatment is not available. We report an in-vitro predicted individualized treatment success in one therapy-refractory Caucasian patient suffering from SFN for over ten years. METHODS: Intrinsic excitability of human induced pluripotent stem cell (iPSC) derived nociceptors from this patient and respective controls were recorded on multi-electrode (MEA) arrays, in the presence and absence of lacosamide. The patient's pain ratings were assessed by a visual analogue scale (10: worst pain, 0: no pain) and treatment effect was objectified by microneurography recordings of the patient's single nerve C-fibers. FINDINGS: We identified patient-specific changes in iPSC-derived nociceptor excitability in MEA recordings, which were reverted by the FDA-approved compound lacosamide in vitro. Using this drug for individualized treatment of this patient, the patient's pain ratings decreased from 7.5 to 1.5. Consistent with the pain relief reported by the patient, microneurography recordings of the patient's single nerve fibers mirrored a reduced spontaneous nociceptor (C-fiber) activity in the patient during lacosamide treatment. Microneurography recordings yielded an objective measurement of altered peripheral nociceptor activity following treatment. INTERPRETATION: Thus, we are here presenting one example of successful patient specific precision medicine using iPSC technology and individualized therapeutic treatment based on patient-derived sensory neurons.

Complaints to the Norwegian System of Patient Injury Compensation 2001-14 following nerve blockade. / Klager etter nerveblokade til Norsk pasientskadeerstatning 2001 ­ 14.

BACKGROUND: There has been a steady increase in cases reported to the Norwegian System of Patient Injury Compensation (NPE). We wished to look into what might characterise those cases of central and peripheral nerve blockade for anaesthesia that led to compensation claims. MATERIAL AND METHOD: Cases with codes for central and peripheral blockade within the field of anaesthesiology were retrieved from the NPE database for the period 2001 ­ 14. The cases were evaluated on the basis of variables including sex, age, type of anaesthesia, diagnosis, type of injury, site of injury, damages received, and written descriptions of treatment and injury. The expert reports were anonymised and reviewed in detail. RESULTS: A total of 339 patient compensation claims relating to nerve blockade were identified, of which 149 concerned spinal anaesthesia, 142 epidural anaesthesia, 21 combined spinal and epidural anaesthesia and 27 peripheral nerve blockade. The group consisted of 236 women and 103 men, and the average age was 46 years. The 339 cases comprised 0.8 % of all cases reported to the NPE in this period. A total of 107 claims resulted in compensation. Eighty-two million Norwegian kroner were paid out in total. INTERPRETATION: Peripheral and central nerve blockade accounts for only a small proportion of cases handled by the NPE. Only one in three applicants had their claim upheld, but when claims were upheld, the injuries were often severe and led to substantial pay-outs.

Chronic pain in breast cancer survivors: comparison of psychosocial, surgical, and medical characteristics between survivors with and without pain.

CONTEXT: According to the literature, 25%-60% of women treated for breast cancer, regardless of the stage, experience pain. Many risk factors have been suggested, with many possible confounding factors. OBJECTIVES: The aim was to investigate psychosocial, surgical, and medical factors associated with chronic pain by comparing breast cancer survivors with chronic pain with survivors without chronic pain. In addition, we investigated the prevalence, intensity, and body location of chronic pain after breast cancer treatment nationwide. METHODS: A nationwide postal survey of 1332 women who received surgery and adjuvant therapy for breast cancer in Norway two to six years before the onset of this study. RESULTS: A total of 832 women (63%) returned the questionnaires, and 41% reported pain, of which 51% had mild, 41% moderate, and 8% severe pain. Among the women who experienced pain, 33.8% reported symptoms and signs of neuropathic pain. Young age (odds ratio [OR], 0.95; 95% CI, 0.93-0.98; P < 0.0001), axillary lymph node dissection with subsequent chemotherapy and radiotherapy (OR, 1.69; 95% CI, 1.07-2.67; P = 0.02), other illness that caused pain (OR, 2.37; 95% CI, 1.72-3.26; P < 0.0001), depression (OR, 2.07; 95% CI, 1.25-3.40; P = 0.004), and anxiety (OR, 1.83; 95% CI, 1.26-2.66; P = 0.002) were associated with chronic pain. CONCLUSION: Young age, previous comorbidities (such as back pain, arthritis, arthrosis, and fibromyalgia), and combined treatment with axillary lymph node dissection, chemotherapy, and radiotherapy were risk factors for chronic pain. Whether depression or anxiety is a risk factor for chronic pain remains unclear.

[Small-fibre neuropathy]. / Tynnfibernevropati.

BACKGROUND: Small-fibre neuropathy is a neuropathy that mainly affects the small nerve fibres. Owing to doctors' inadequate knowledge of the condition and limited diagnostic methods, this type of neuropathy is probably under-diagnosed. Small-fibre neuropathy has many causes, but the symptoms are often relatively similar. This review article is intended to give doctors insight into the clinical expressions and diagnosis of the condition. METHOD: The article is based on literature searches in PubMed and the authors' clinical and scientific experience of the subject. RESULTS: Small-fibre neuropathy generates a characteristic distribution of symptoms, particularly pain, and is associated with a number of common illnesses. Specific tests for small fibre neuropathy, such as skin biopsy and thermal testing, can be used to confirm the diagnosis. The treatment targets the symptoms, but complete pain relief is often difficult to achieve. INTERPRETATION: The clinical neurological examination will not generally be able to detect small-fibre neuropathy, but will contribute primarily to excluding a more general polyneuropathy. Supplementary tests are often necessary to make a final diagnosis.

Preinjury treatment with morphine or ketamine inhibits the development of experimentally induced secondary hyperalgesia in man.

We examine the effect of morphine or ketamine (N-methyl-D-aspartate receptor antagonist; NMDA) treatment on secondary hyperalgesia. Drug treatment started preinjury and continued into the early postinjury period. Hyperalgesia was induced by a local 1 degrees burn injury covering 12.5 cm(2) on the medial side of the calf. In this double-blind, cross-over study, 12 healthy volunteers received, on 3 separate days and in randomized order: (1) placebo; (2) morphine, bolus 150 microg/kg + infusion 1 microg/kg per min and 0.5 microg/kg per min; and (3) ketamine, bolus 60 microg/kg + infusion 6 microg/kg per min and 3 microg/kg per min. Bolus + infusion started 30 min before injury and ended 50 min after it. The area of secondary hyperalgesia was quantitated using punctate (von Frey filaments) and brush stimuli (electric brush). On the day of placebo, all subjects developed an area of hyperalgesia to punctate and brush stimuli outside the thermal injury (secondary hyperalgesia). We show that ketamine or morphine treatment starting preinjury significantly reduces this development (P<0.01, both). In a previous study, we found that postinjury treatment alone with morphine did not affect secondary hyperalgesia, whereas ketamine did so significantly. The differential response to morphine administered pre- or postinjury may be relevant to the recently shown NMDA receptor mediated interaction of central hyperexcitability and morphine antinociception. The effect of ketamine supports the hypothesis of the role of NMDA receptor mediation in central hyperexcitability.

Treatment of cancer pain in Norway. A questionnaire study.

A questionnaire study was performed in order to clarify knowledge and practice of cancer pain treatment in Norway: a 10% random sample of Norwegian physicians received a questionnaire. Of 800 correctly addressed questionnaires, 549 were returned and 306 were analyzed after exclusion of those doctors who never treated cancer patients. Their knowledge of the principles and methods of cancer pain treatment were evaluated with 8 multiple-choice and 13 open questions. Their ability to apply their knowledge in practice was evaluated by analyzing their suggested treatment of 3 illustrative case histories. The results show that only 25% of Norwegian physicians treating cancer patients appear to have knowledge of the principles of the World Health Organization analgesic ladder strategy. However, the majority (86%) of the physicians were prepared to prescribe strong opioid analgesics, but in the illustrative cases where strong opioids were appropriate, 44% prescribed too small doses and often preferred neuroleptic drugs instead of increasing the analgesic to a sufficiently large dose. Patients needing step two on the analgesic ladder, in Norway often (49%) are treated with a standard combination of paracetamol and codeine. However, when a strong opioid is required, 50% of Norwegian physicians forget to continue the paracetamol or NSAID component. Two hundred seventy-four (97%) of the physicians said they experienced problems when treating cancer pain, ranging from inefficient pain relief (52%) to side effects of opioid analgesics (32%), most often sedation, in combination with nausea and constipation. Only 13% of the physicians had a correct understanding of opioid drug dependence. As many as 72% of Norwegian physicians thought their education in cancer pain treatment was insufficient.