Cancer treatment-related neuropathic pain: proof of concept study with menthol--a TRPM8 agonist.

PURPOSE: Effective treatment of neuropathic pain without unacceptable side effects is challenging. Cancer sufferers increasingly live with long-term treatment-related neuropathic pain, resulting from chemotherapy-induced peripheral neuropathy (CIPN) or surgical scars. This proof-of-concept study aimed to determine whether preclinical evidence for TRPM8 ion channels in sensory neurons as a novel analgesic target could be translated to clinical benefit in patients with neuropathic pain, using the TRPM8 activator menthol. PATIENTS AND METHODS: Patients with problematic treatment-related neuropathic pain underwent a baseline assessment using validated questionnaires, psychophysical testing, and objective functional measures. The painful area was treated with topical 1 % menthol cream twice daily. Assessments were repeated at 4-6 weeks. The primary outcome was the change in Brief Pain Inventory total scores at 4-6 weeks. Secondary outcomes included changes in function, mood and skin sensation. RESULTS: Fifty-one patients (female/male, 32/19) were recruited with a median age of 61 (ranging from 20 to 89). The commonest aetiology was CIPN (35/51), followed by scar pain (10/51). Thirty-eight were evaluable on the primary outcome. Eighty-two per cent (31/38) had an improvement in total Brief Pain Inventory scores (median, 47 (interquartile range, 30 to 64) to 34 (6 to 59), P < 0.001). Improvements in mood (P = 0.0004), catastrophising (P = 0.001), walking ability (P = 0.008) and sensation (P < 0.01) were also observed. CONCLUSION: This proof-of-concept study indicates that topical menthol has potential as a novel analgesic therapy for cancer treatment-related neuropathic pain. Improvements in patient-rated measures are supported by changes in objective measures of physical function and sensation. Further systematic evaluation of efficacy is required.

Clinically relevant fatigue in recurrence-free prostate cancer survivors.

BACKGROUND: Little is known about the prevalence and associations of clinically relevant fatigue (CRF) in recurrence-free prostate cancer survivors. PATIENTS AND METHODS: Four hundred and sixteen recurrence-free prostate cancer survivors who were >1 year post-radiotherapy or radical prostatectomy were surveyed. The prevalence of CRF (defined as Brief Fatigue Inventory >3) was determined and compared with a noncancer control group. Other measures included the Hospital Anxiety and Depression Scale, International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Relationships between these factors and CRF were explored in univariate and multivariate analyses. RESULTS: Analyzable data were obtained from 91% (377/416) of patients. The prevalence of CRF was 29% (108/377) versus 16% (10/63) in the controls (P=0.031). CRF was more common in post-radiotherapy than in post-prostatectomy 33% (79/240) versus 22% (29/133), P=0.024. However, when other factors (current depression, anxiety, urinary symptoms, medical comorbidities, pain and insomnia) were controlled for, previous treatment did not predict CRF. Current depression [Hospital Anxiety and Depression Scale≥8 was by far the strongest association [odds ratio 9.9, 95% confidence interval 4.2-23.5)]. CONCLUSIONS: Almost one-third of recurrence-free prostate cancer survivors report CRF. Depression, anxiety, urinary symptoms, pain and insomnia measured at outcome are more strongly associated than type of cancer treatment previously received.

Clinically relevant fatigue in men with hormone-sensitive prostate cancer on long-term androgen deprivation therapy.

BACKGROUND: The purpose of the study was to determine the prevalence and associations of clinically relevant fatigue (CRF) in men with biochemically controlled prostate cancer on long-term androgen deprivation therapy (ADT). PATIENTS AND METHODS: One hundred and ninety-eight men were surveyed and the prevalence of CRF (Brief Fatigue Inventory score >3) determined. Associations with other measures (Hospital Anxiety and Depression Scale; International Prostate Symptom Score; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; Brief Pain Inventory worst pain; clinical and demographic information) were explored in univariate and multivariate analyses. RESULTS: Eight-one per cent (160 of 198) of questionnaires were analysable. CRF prevalence was 43% (68 of 160). CRF associations included moderate/severe urinary symptoms, anxiety and medical co-morbidities; the strongest associations were depression [odds ratio (OR) 9.8, 95% confidence interval (CI) 4.3-22.8] and pain (OR 9.2, 95% CI 4.0-21.5). After controlling for other factors, the independent associations were depression (OR 4.7, 95% CI 1.6-14.0) and pain (OR 3.1, 95% CI 1.0-8.9). There was no association with age, disease burden or treatment duration. CONCLUSIONS: Two-fifths of men with biochemically controlled prostate cancer on long-term ADT report CRF that interferes with function. Management aimed at improving CRF should address depression and pain.

Capecitabine combined with oxaliplatin (CapOx) in clinical practice: how significant is peripheral neuropathy?

BACKGROUND: There is speculation that peripheral neuropathy (PN) with capecitabine and oxaliplatin (CapOx; 130 mg/m(2), day 1, every 21 days) may be more common than with FOLFOX4 (5-fluorouracil and oxaliplatin 85 mg/m(2), day 1, every 14 days). We aimed to determine PN incidence and associations during CapOx, and 6 and 12 months after CapOx. PATIENTS AND METHODS: Retrospective audit of 188 oxaliplatin-naive colorectal cancer patients (87 adjuvant, 101 palliative) who received at least one cycle of CapOx. Neurosensory Common Toxicity Criteria Adverse Events version 3 were applied. RESULTS: Overall, 94% experienced acute PN. Worst severities for adjuvant and palliative patients, respectively, were grade 1, 44% and 54%; grade 2, 35% and 32%; grade 3, 16% and 3%; grade 4, 0% and 1% and grade unclear 1% and 1%. Two patients developed PN after CapOx completion despite no symptoms during treatment. Chronic PN at 6 months affected 57% and 18% of adjuvant and palliative patients, respectively. At 12 months, 35% and 16% were affected. Chronic PN at 12 months was associated with cumulative oxaliplatin dose but not age, gender, acute myotonia, pseudolaryngospasm or grade 2 or more PN during treatment. CONCLUSION: Incidence of acute PN during CapOx appears similar to FOLFOX4 but chronic PN in adjuvant patients may be more common with CapOx.

Clinically relevant fatigue in cancer outpatients: the Edinburgh Cancer Centre symptom study.

BACKGROUND: Fatigue is associated with cancer and its treatment but we know little about how many and which patients suffer fatigue of clinical severity. We aimed to determine the prevalence of clinically relevant fatigue (CRF) and its associations in outpatients with various cancer diagnoses. PATIENTS AND METHODS: A survey of outpatients with colorectal, breast, gynaecological, genitourinary, sarcoma, melanoma and miscellaneous tumours at a regional cancer centre. Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) fatigue subscale and the Hospital Anxiety and Depression Scale (HADS). These self-report data were linked to demographic and clinical variables. Data were available on 2867 outpatients. RESULTS: The prevalence of CRF (EORTC fatigue subscale > or =40) was 32% (95% confidence interval 31-34%). The variables independently associated with CRF were primary cancer site, having disease present, type of cancer treatment and emotional distress (total HADS score > or =15). Emotional distress had the strongest association with fatigue but half the cases of CRF were not distressed. CONCLUSION: CRF is common in cancer outpatients and is associated with type of disease and treatment, as well as with emotional distress. The association between CRF and emotional distress is strong but they are not equivalent conditions.

Dephosphorylation of 1D-myo-inositol 1,4-bisphosphate in rat liver.

Dephosphorylation of 1D-myo-inositol 1,4-bisphosphate [Ins(1,4)P2] in rat liver is catalysed by a cytosolic phosphatase that removes the 1-phosphate group. The Km for Ins(1,4)P2 is approx. 17 microM. Li+ (100 mM) causes 50% inhibition of Ins(1,4)P2 phosphatase activity when activity is measured at the very low substrate concentration of 10 nM, but on raising the substrate concentration to 100 microM there is a greater than 10-fold increase in sensitivity to Li+, suggesting that Li+ acts mainly, but not entirely, as an uncompetitive inhibitor of Ins(1,4)P2 phosphatase. In addition, rat liver cytosol shows Li+-sensitive phosphatase activity against 1D-myo-inositol 1-,3- and 4-monophosphates. The Ins(1,4)P2 1-phosphatase and inositol monophosphatase activities all share an apparent Mr of 47 x 10(3), as determined by gel-filtration chromatography. However, the Ins(1,4)P2 1-phosphatase is more sensitive to inactivation by heat, and can be separated from inositol monophosphatase activity by anion-exchange chromatography. We conclude that rat liver cytosol contains an Ins(1,4)P2 1-phosphatase that is distinct from, but in many ways similar to, inositol monophosphatase.

Dephosphorylation of myo-inositol 1,4,5-trisphosphate and myo-inositol 1,3,4-triphosphate.

We have augmented our previous studies [Storey, Shears, Kirk & Michell (1984) Nature (London) 312, 374-376] on the subcellular location and properties of Ins(1,4,5)P3 (inositol 1,4,5-trisphosphate) phosphatases in rat liver and human erythrocytes. We also investigate Ins(1,3,4)P3 (inositol 1,3,4-trisphosphate) metabolism by rat liver. Membrane-bound and cytosolic Ins(1,4,5)P3 phosphatases both attack the 5-phosphate. The membrane-bound enzyme is located on the inner face of the plasma membrane, and there is little or no activity associated with Golgi apparatus. Cytosolic Ins(1,4,5)P3 5-phosphatase (Mr 77,000) was separated by gel filtration from Ins(1,4)P2 (inositol 1,4-bisphosphate) and inositol 1-phosphate phosphatases (Mr 54,000). Ins(1,4,5)P3 5-phosphatase activity in hepatocytes was unaffected by treatment of the cells with insulin, vasopressin, glucagon or dibutyryl cyclic AMP. Ins(1,4,5)P3 5-phosphatase activity in cell homogenates was unaffected by changes in [Ca2+] from 0.1 to 2 microM. After centrifugation of a liver homogenate at 100,000 g, Ins(1,3,4)P3 phosphatase activity was largely confined to the supernatant. The sum of the activities in the supernatant and the pellet exceeded that in the original homogenate. When these fractions were recombined, Ins(1,3,4)P3 phosphatase activity was restored to that observed in unfractionated homogenate. Ins(1,3,4)P3 was produced from Ins(1,3,4,5)P4 (inositol 1,3,4,5-tetrakisphosphate) and was metabolized to a novel InsP2 that was the 3,4-isomer. Ins(1,3,4)P3 phosphatase activity was not changed by 50 mM-Li+ or 0.07 mM-Ins(1,4)P2 alone, but when added together these agents inhibited Ins(1,3,4)P3 metabolism. In Li+-treated and vasopressin-stimulated hepatocytes, Ins(1,4)P2 may reach concentrations sufficient to inhibit Ins(1,3,4)P3 metabolism, with little effect on Ins(1,4,5)P3 hydrolysis.

Infarction of the greater omentum. Elusive cause of acute abdominal pain.

Omental infarction may be much more common than the number of cases reported in the literature would imply. The condition should be considered in the differential diagnosis of acute abdominal pain. A thorough search for it should be made in patients whose findings at laparotomy are not consistent with the preoperative diagnosis (usually acute appendicitis), especially when serosanguineous fluid is found in the peritoneal cavity. Treatment is excision of infarcted omentum to prevent formation of adhesions with obstructive and septic complications.

Stepwise enzymatic dephosphorylation of inositol 1,4,5-trisphosphate to inositol in liver.

Many receptors for hormones, neurotransmitters and other signals cause hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and effect a rise in cytosolic Ca2+ concentration. The inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) liberated during PtdIns(4,5)P2 breakdown seems to serve as a second messenger that activates the release of Ca2+ from a nonmitochondrial intracellular compartment. As expected if it is an important intracellular messenger, Ins(1,4,5)P3 is relatively rapidly degraded, both within stimulated cells and when added to homogenates of blowfly salivary gland or to permeabilized, but not intact, hepatocytes. Here we report that the dephosphorylation reactions responsible for the conversion of Ins(1,4,5)P3 to free inositol in rat liver are catalysed by two or more enzymes, and that these reactions are distributed between the plasma membrane and cytosol. The Ins(1,4,5)P3 5-phosphatase and inositol 1-phosphate (Ins(1)P) phosphatase of liver appear similar to enzymes described previously in erythrocytes and brain.