Approach to fever assessment in ambulatory cancer patients receiving chemotherapy: a clinical practice guideline.

BACKGROUND: This guideline was prepared by the Fever Assessment Guideline Development Group, a group organized by the Program in Evidence-Based Care at the request of the Cancer Care Ontario Systemic Treatment Program. The mandate was to develop a standardized approach (in terms of definitions, information, and education) for the assessment of fever in cancer patients receiving chemotherapy. METHODS: The guideline development methods included a search for existing guidelines, literature searches in medline and embase for systematic reviews and primary studies, internal review by content and methodology experts, and external review by targeted experts and intended users. RESULTS: The search identified eight guidelines that had partial relevance to the topic of the present guideline and thirty-eight primary studies. The studies were mostly noncomparative prospective or retrospective studies. Few studies directly addressed the topic of fever except as one among many symptoms or adverse effects associated with chemotherapy. The recommendations concerning fever definition are supported mainly by other existing guidelines. No evidence was found that directly pertained to the assessment of fever before a diagnosis of febrile neutropenia was made. However, some studies evaluated approaches to symptom management that included fever among the symptoms. Few studies directly addressed information needs and resources for managing fever in cancer patients. CONCLUSIONS: Fever in patients with cancer who are receiving systemic therapy is a common and potentially serious symptom that requires prompt assessment, but currently, evidence to inform best practices concerning when, where, and by whom that assessment is done is very limited.

Approach to evaluation of fever in ambulatory cancer patients receiving chemotherapy: A systematic review.

PURPOSE: To define the optimal model of care for patients receiving outpatient chemotherapy who experience a fever. Fever is a common symptom in patients receiving chemotherapy, but the approach to evaluation of fever is not standardized. METHODS: We conducted a search for existing guidelines and a systematic review of the primary literature from database inception to November 2015. Full-text reports and conference abstracts were considered for inclusion. The search focused on the following topics: the relationship between temperature and poor outcome; predictors for the development of febrile neutropenia (FN); the timing, location, and personnel involved in fever assessment; and the provision of information to patients receiving chemotherapy. RESULTS: Eight guidelines and 38 studies were included. None of the guidelines were directly relevant to the target population because they dealt primarily with the management of FN after diagnosis. The primary studies tended to include fever as one of many symptoms assessed in the setting of chemotherapy. Temperature level was a weak predictor of poor outcomes. We did not find validated prediction models for identifying patients at risk of FN among patients receiving chemotherapy. Several studies presented approaches to symptom management that included fever among the symptoms, but results were not mature enough to merit widespread adoption. CONCLUSION: Despite the frequency and risks of fever in the setting of chemotherapy, there is limited evidence to define who needs urgent assessment, where the assessment should be performed, and how quickly. Future research in this area is greatly needed to inform new models of care.

Selenium depletion in burn patients.

Victims of major burns may be at risk for selenium (Se) depletion because increased postinjury nutrient needs are often met by total parental nutrition and tube feedings which contain little Se. This study compared Se status of 17 burn patients and 191 healthy control subjects. Se intake of burn patients was lower than the intake of control subjects when total parenteral nutrition or tube feedings were used as primary nutrient sources but was comparable to the control intake when burn patients consumed oral diets. Serial determinations each 10 days during recovery showed that burn patients had lower plasma Se, erythrocyte Se, and erythrocyte glutathione peroxidase levels, and lower 24-hr urine Se excretion. These results provide biochemical evidence of Se depletion despite exogenous Se intake within the range recommended for healthy adults. Further studies are indicated to determine if Se depletion in burn patients can be prevented by Se supplementation of total parenteral nutrition and tube feeding solutions.

Nocardial infection in a renal transplant recipient on tacrolimus and mycophenolate mofetil.

Infection with Nocardia spp. is an uncommon but important cause of morbidity and mortality in organ transplant recipients. Cotrimoxazole prophylaxis against urinary tract infection and Pneumocystis carinii pneumonia in these patients usually prevents nocardial infection also. We report the case of a patient on tacrolimus and mycophenolate mofetil who developed drug-induced diabetes mellitus followed by nocardial brain infection. This infection occurred despite conventional cotrimoxazole prophylaxis. Physicians should be aware that newer, more potent and more diabetogenic immunosuppressive regimens may increase the risk of opportunistic infections such as nocardiosis, even in the presence of "adequate" antimicrobial preventive measures.

Na(+)-independent Cl(-)-HCO3- exchange in sarcolemmal vesicles from vascular smooth muscle.

Intracellular pH (pHin) affects vascular smooth muscle function, but the mechanisms that control pHin in this tissue are not well understood. These studies were performed to determine whether sarcolemmal vesicles from bovine superior mesenteric artery (SMA) contain a Na(+)-independent Cl(-)-HCO3- exchanger and, if so, to determine its sensitivity to membrane voltage and inhibitors. 36Cl- was taken up by vesicles into an osmotically active intravesicular space. In Na(+)-free media, an outwardly or inwardly directed HCO3- gradient stimulated 36Cl- transport in the opposite direction. An outwardly directed unlabeled Cl- gradient stimulated 36Cl- uptake by a mechanism that was inhibited by external HCO3-. HCO3- or Cl- gradient-stimulated 36Cl- uptake was not due to voltage coupling between ions. In the nominal absence of HCO3-, a threefold outwardly directed OH- gradient did not affect 36Cl- uptake. Total 36Cl- uptake was stimulated by an inside-positive voltage, but the HCO3- gradient-stimulated component of 36Cl- uptake was insensitive to a change in membrane voltage. Finally, HCO3- gradient-stimulated 36Cl- uptake was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and furosemide, with 50% inhibitory concentration values equalling approximately 1.0 and 0.5 mM, respectively. These data indicate that sarcolemmal vesicles from bovine SMA contain a Na(+)-independent Cl(-)-HCO3- exchanger. This transport system is probably electroneutral and is inhibitable by DIDS and furosemide. A conductive pathway for Cl- is present in the vesicles, but Cl(-)-OH- exchange activity was not observed.

Acute infarction, intracoronary thrombolysis, and primary PTCA in pregnancy.

Acute myocardial infarction has an incidence in pregnancy of 1 in 10,000, with a mortality ranging from 37-50%. Mortality is increased if the infarct occurs in the third trimester, if the patient is under age 35 yr, if she delivers within 2 wk of her infarct, and if she has a cesarean section. We present a case involving all four prognostically poor factors. The patient was treated emergently in the cardiac catheterization laboratory with intracoronary thrombolysis and primary PTCA of an occluded LAD. She had an uncomplicated recovery and subsequent delivery of a healthy child with no peripartum cardiac complications. A review of myocardial infarction in pregnancy follows.

Sensitization of adenylyl cyclase by P2 purinergic and M5 muscarinic receptor agonists in L cells.

Many hormones have been shown to activate phospholipase C, which results in the hydrolysis of membrane polyphosphoinositides, such as phosphatidylinositol 4,5-bisphosphate (PIP2). Two second messengers are known to be produced by PIP2 hydrolysis, 1,2-diacylglycerol, an endogenous activator of a family of enzymes called protein kinase C (PKCs), and inositol 1,4,5-trisphosphate, which raises free levels of intracellular Ca2+. Treatment of various cells with 4 beta-phorbol 12-myristate 13-acetate (PMA), a specific exogenous activator of PKCs, causes an enhancement or sensitization of adenylyl cyclase activities. This finding prompted us to examine the effects of direct hormonal activation of PIP2 hydrolysis on the sensitization of adenylyl cyclase. Liao et al. [J. Biol. Chem. 265:11273-11284 (1990)] have shown that P2 purinergic receptor agonists such as ATP and muscarinic receptor agonists such as carbachol stimulate PIP2 hydrolysis in L cells expressing the M5 muscarinic acetylcholine receptor. We investigated the effects of these hormones on adenylyl cyclase and contrasted these effects with the sensitizing effects of PMA. We found that ATP pretreatment of two different types of L cells resulted in a rapid 50-150% sensitization of prostaglandin E1-, epinephrine-, and forskolin-stimulated adenylyl cyclase activity, with an EC50 of 3 microM ATP. This effect was qualitatively similar to that caused by 10 nM PMA. The enhancement of adenylyl cyclase activity was associated with an increase in the Vmax for hormonal stimulation and with a lack of significant effects of ATP on the EC50. The effect was completely eliminated when adenylyl cyclase was assayed in the presence of high free Mg2+ levels (10 mM). Down-regulation of PKCs with long term PMA treatment did not affect the ATP-induced sensitization of adenylyl cyclase, although the PMA-induced sensitization of adenylyl cyclase was eliminated. In contrast to the effects of ATP and PMA, treatment of the cells with carbachol alone had no effect on adenylyl cyclase; however, in combination with nanomolar concentrations of PMA, synergism of the sensitization of adenylyl cyclase was observed. These data indicate that the activation of P2 purinergic receptors by ATP, and possibly activation of M5 muscarinic receptors by carbachol, may be important in the signal transduction pathways leading to the increases in the responsiveness of hormone-stimulated adenylyl cyclase.

Na(+)-H+ and Na(+)-dependent Cl(-)-HCO3- exchange control pHi in vascular smooth muscle.

The mechanisms that control intracellular pH (pHi) in vascular smooth muscle are not fully understood. These studies were performed to determine the identity and relative importance of the sarcolemmal transport systems that mediate net acid efflux in primary cultured vascular smooth muscle cells from canine femoral artery. In HEPES- or HCO3(-)-buffered physiological salt solution (HEPES-PSS, HCO3(-)-PSS), recovery from an acute acid load was totally dependent on external Na+. 5-[N-ethyl-N-isopropyl]amiloride (EIPA, 50 microM) inhibited pHi recovery 100 and 68% in HEPES-PSS and HCO3(-)-PSS, respectively. EIPA-insensitive pHi recovery in HCO3(-)-PSS was inhibited 48% by 4,4'-diisothyocyanostilbene-2,2'-disulfonic acid (DIDS). An outwardly directed H+ gradient stimulated amiloride-sensitive 22Na+ uptake, and an inwardly directed HCO3- gradient stimulated amiloride-insensitive 22Na+ uptake. The latter was inhibited by DIDS or prior depletion of cell Cl-. In HEPES-PSS, resting pHi was 7.17 +/- 0.03, was not affected by DIDS, but was lowered by EIPA or by removing extracellular Na+. In HCO3(-)-PSS, resting pHi was 7.25 +/- 0.02 (P less than 0.05) and was not affected by EIPA. Removing extracellular Na+ in the presence of EIPA decreased pHi in HCO3(-)-PSS but not in HEPES-PSS. DIDS lowered resting pHi in HCO3(-)-PSS, after which EIPA further lowered pHi. We conclude that acid efflux from these cells is mediated by a Na(+)-H+ exchanger and a Na(+)-dependent Cl(-)-HCO3- exchanger. In HEPES-PSS, acid efflux via the Na(+)-H+ exchanger maintains resting pHi. In HCO3(-)-PSS, additional acid efflux via the Na(+)-dependent Cl(-)-HCO3- exchanger results in a higher pHi. Although the Na(+)-H+ exchanger is primarily responsible for acid efflux after an acute acid load, the Na(+)-dependent Cl(-)-HCO3- exchanger is responsible for acid efflux under physiological conditions.

The role of high levels of dietary fat in 7,12-dimethylbenzanthracene-induced mouse mammary tumorigenesis: lack of an effect on lipid peroxidation.

The effects of dietary fat on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumorigenesis were examined in BALB/c female mice. In the first experiment, BALB/c mice were treated with a total dose of 1, 3, or 6 mg DMBA to induce mammary tumors. One week after the last dose of DMBA, the mice were placed on a 5% (LF) or 20% (HF) corn oil semi-purified diet. The 20% corn oil diet resulted in a significantly decreased mean tumor latency period in each of the three groups of mice (p less than 0.05). However, the mammary tumor incidences at 11 months after DMBA treatment were the following: 6 mg DMBA (LF-14/32, HF-17/32); 3 mg DMBA (LF-13/50, HF-14/50); 1 mg (LF-2/50, HF-6/50). In the second experiment, prolonged hormonal stimulation by pituitary isografts, but not a HF diet, enhanced the incidence of mammary tumors in BALB/c mice given a threshold dose of DMBA (0.5 mg). In a further attempt to examine the mechanism of the enhancing effects of dietary fat, lipid peroxidation was measured in the microsomal-mitochondrial fractions of the mammary glands by two assays; measurements of conjugated dienes and TBA reactants (malonyldialdehyde). The high fat diet had no effect on the levels of conjugated dienes in mammary cell membrane preparations and decreased the levels of TBA reactants (malonyldialdehyde). The results indicated that a high fat diet did not lead to enhanced levels of lipid peroxidation in preparations of microsomal mitochondrial membranes from mouse mammary glands. The implications of these results are discussed with respect to the role of dietary fat as a promoter of mouse mammary tumorigenesis.