Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

BACKGROUND: Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS: Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS: During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS: Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Cognitive Retraining and Functional Treatment (CRAFT) for adults with cancer related cognitive impairment: a preliminary efficacy study.

PURPOSE: To examine the preliminary efficacy of Cognitive Retraining and Functional Treatment (CRAFT) combining remote computerized cognitive training (CCT) and occupation-based treatment in adults with cancer-related cognitive impairment (CRCI). METHODS: Three-armed randomized controlled trial including 74 individuals with CRCI, randomized into 12 weeks of either CRAFT, CCT alone, or treatment-as-usual. Assessments evaluating participation in daily life, perceived cognition, cognitive performance, quality-of-life, and treatment satisfaction were administered at baseline, post-intervention, and 3-month follow-up. RESULTS: Significant time × group interactions in favor of the CRAFT and CCT groups were found for participation in daily life (F2,34 = 5.31, p = .01, eta = .238), perceived cognition (F2,34 = 4.897, p = .014, eta = .224), and cognitive performance on speed of processing test (F = 5.678, p = .009, eta = .289). The CRAFT group demonstrated significantly larger clinically meaningful gains on participation in daily life (chi-square = 6.91, p = .032) and significantly higher treatment satisfaction. All treatment gains were maintained at a 3-month follow-up (n = 32). CONCLUSIONS: CCT and CRAFT were found to have a positive impact on participation and cognitive outcomes among individuals with CRCI. The CRAFT showed an additional advantage in improving self-chosen occupation-based goals suggesting that a combination of cognitive training with occupation-based intervention has a positive synergistic effect resulting in "real world" health benefits. IMPLICATIONS FOR CANCER SURVIVORS: A combination of cognitive training with occupation-based intervention has a positive effect resulting in clinically meaningful improvements in participation in daily life, objective cognitive performance, and subjective cognitive impairment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04210778, December 26, 2019, retrospectively registered.

Predictors of quality of life among adults with self-reported cancer related cognitive impairment.

OBJECTIVE: The purpose of the current study was to examine the unique contribution of personal and medical factors, objective and subjective cognition, and self-efficacy to the explained variance of quality of life (QoL) among survivors with self-reported cancer related cognitive impairment (CRCI). METHOD: Seventy-three cancer survivors (non-central nervous system) with CRCI (mean age: 50.85 ± 10.82 years old, mean years post-treatment: 3 ± 2.7) participated in this cross-sectional study. QoL was assessed using the Functional Assessment of Cancer Therapy (FACT)-GP, while the cognitive function was assessed both objectively using tests of attentional control, speed of processing and sustained attention, and subjectively using the FACT-Cognition perceived cognitive impairments (FACTcog-PCI) subscale. Self-efficacy was assessed using the New General Self-Efficacy Scale (NGSE). RESULTS: A hierarchical multiple linear regression analysis revealed that sustained attention, perceived cognitive impairment and self-efficacy, accounted for 54% of the variance of QoL (R2 = 0.543, p < 0.000), each providing a unique contribution to the explained variance (15-20% each) after controlling for age and gender. CONCLUSIONS: Considering that these variables may be amenable to change, this model can serve as a conceptual framework for designing effective cognitive treatment options for CRCI. Clinical Trial Registration: ClinicalTrials.gov NCTImplication for rehabilitationCancer related cognitive impairment is characterized by difficulties in the speed of processing performance, severe perceived cognitive impairments, and relatively low general self-efficacy.Multi-dimensional assessments including subjective and objective cognition as well as self-efficacy should be administered to cancer survivors with cognitive complaints to understand the underlying mechanisms of their QoL.Integrative cognitive rehabilitation interventions that aim to improve QoL among people with cancer-related cognitive impairment should target sustained attention, perceived cognitive impairment, and self-efficacy.

Rituximab, methotrexate, procarbazine and lomustine (R-MPL) for the treatment of primary Central nervous system lymphoma.

The optimal high-dose methotrexate (HDMTX)-based combination therapy for primary central nervous system lymphoma is unknown. We report our experience with rituximab, HDMTX, procarbazine and lomustine (R-MPL) given as first-line treatment in our center. Fifty-two patients between 2006 and 2019 were included. Eighteen patients proceeded to autologous transplant or two cycles of intermediate-dose cytarabine. The median age was 62 y (range 28-94) and the Eastern Cooperative Oncology Group performance status (ECOG-PS) was ≥2 in 62% (32/52). The overall/complete response rates were 79% (41/52) and 52% (27/52), respectively. The median progression-free/overall survival was 19 m/84m, respectively. Grade 3-4 adverse events included infections (17%) and kidney injury (13%). Ten patients (19%) discontinued therapy for toxicity. There were no treatment-related deaths. In summary, in a cohort enriched in frail patients, R-MPL achieved good responses and OS and was safe for all ages. The PFS was sub-optimal, possibly explained by a low proportion of consolidation. This regimen should be evaluated prospectively.

Liquid biopsy reveals collateral tissue damage in cancer.

Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases. In addition, patients with localized pancreatic or colon cancer showed elevated hepatocyte cfDNA, suggesting liver damage inflicted by micrometastatic disease, by primary pancreatic tumor pressing the bile duct, or by a systemic response to the primary tumor. We also identified elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA in a subpopulation of patients with brain metastases compared with cancer patients without brain metastasis. Cell type-specific cfDNA methylation markers enabled the identification of collateral tissue damage in cancer, revealing the presence of metastases in specific locations and potentially assisting in early cancer detection.

Venous Thromboembolism Prophylaxis with Low-Molecular-Weight Heparin in Primary Central Nervous System Lymphoma.

BACKGROUND: Venous thromboembolism (VTE) is a frequent, potentially lethal complication in individuals with cancer. Patients with brain tumors are at particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B cell lymphoma, involving the craniospinal axis. The incidence of VTE in patients with PCNSL was reported as very high, occurring mostly in the early period of therapy. OBJECTIVES: We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (LMWH) throughout the treatment of PCNSL. PATIENTS: All patients >18 years of age diagnosed and treated for PCNSL at our institution in 2005-2017 were included. RESULTS: There were 44 patients; mean age at diagnosis was 61.5 years. Three patients (6.8%) had a personal history of thrombosis, 11 (25%) had a history of diabetes or smoking, and 32 (72%) had an Eastern Cooperative Oncology Group performance status of 0-1 at diagnosis. During treatment with LMWH, no VTE events were recorded; 2 (4.5%) patients experienced a minor bleeding event and 1 (2.3%) a major bleeding event. CONCLUSIONS: Among our 44 patients with PCNSL treated with prophylactic LMWH, no VTE events were recorded, and only 1 (asymptomatic) intracranial bleed was recorded. Within the limitations of a retrospective nonrandomized study, our findings suggest that VTE prophylaxis may be beneficial for individuals with PCNSL.

Neurological misdiagnoses of lymphoma.

BACKGROUND: Lymphoma of the nervous system is rare and usually involves the brain, spinal cord, or peripheral nerves. Hence, it has varied clinical presentations, and correct diagnosis is often challenging. Incorrect diagnosis delays the appropriate treatment and affects prognosis. We report 5 patients with delayed diagnosis of lymphoma involving the central and/or peripheral nervous system, initially evaluated for other neurological diagnoses. We also discuss the challenge of diagnosis and appropriate testing. METHODS: Retrospective review of 2011-2019 records of patients with confirmed nervous system lymphoma diagnosed in a tertiary care medical center. RESULTS: We present 5 adult patients initially evaluated for inflammatory myelopathy, inflammatory lumbosacral plexopathy, atypical parkinsonism, and demyelinating disease of the CNS. Final diagnosis of the nervous system lymphoma was delayed by 4 to 18 months and was based on tissue biopsy in 4, and on CSF and bone marrow examination in 1 patient. CONCLUSIONS: Lymphoma may imitate various central and peripheral nervous system disorders. We suggest several red flags that indicate the need to consider lymphoma, including subacute but progressive symptomatic evolution, painful neurological deficit, unclear clinical diagnosis, and transient steroid responsiveness. Correct diagnosis often requires a combination of diagnostic tests, while pathology testing is crucial for early diagnosis and is strongly recommended in the appropriate clinical setting.

Physiological Differences Between Heat Tolerant and Heat Intolerant Young Healthy Women.

Purpose: Heat intolerance (HI) is determined in the Israel Defense Force according to a heat tolerance test (HTT) before returning to duty after an exertional heat stroke (EHS) event. Recently, increased numbers of female combatants resulted in an increased number of EHS cases among women and a higher percentage of heat intolerance (HI) individuals. We aimed to evaluate the differences between tolerance to heat among women performing an HTT in relation to their menstrual cycle phase. Method: Thirty-three female participants were sorted into two groups: HI and heat tolerant (HT) according to two HTTs performed during both the luteal and follicular phases of the menstrual cycle or while consuming and during a break from consuming contraceptives. Results: HT women had an 18% higher maximal oxygen uptake (p < .005, 95% CI [2.6,9.8]) and 1.2% lower skin temperature in the HTT at the during and follicular phases (p < .01, 95% CI [0.12,0.77]) and 1.7% lower at the off and luteal phases (p < .001, 95% CI [0.34,0.92]). The mean sweat rate was 14% lower among the HI group only at the HTT at the during and follicular phases (p < .05, 95% CI (3,88)]). Conclusion: We found that HT can be predicted using aerobic capacity and core body temperature. Moreover, during the luteal phase, women presented altered thermoregulation that decreased the probability of being HT. This emphasizes the importance of considering the HT/HI criteria in the HTT for women, according to their aerobic ability and menstrual-cycle phase.

Neurological variability in chemotherapy-induced posterior reversible encephalopathy syndrome associated with thrombotic microangiopathy: Case reports and literature review.

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by headaches, seizures, a confusional state and visual disturbances associated with transient predominantly bilateral posterior white mater magnetic resonance imaging lesions. It is primarily reported in the setting of hypertension, acute renal failure, peripartum eclampsia, autoimmune disease, immunosuppression and chemotherapy. Thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) has also been reported as potential PRES inducer. The present study reviews two cases of patients with PRES, associated with TMA caused by chemotherapy. Their clinical and imaging data, and the relevant literature were reviewed. Patient 1 presented with TMA-induced PRES following mitomycin-C for metastatic colon adenocarcinoma. Treatment with steroids, plasma exchange, intravenous immunoglobulins, aspirin, antihypertensive drugs, and diuretics resulted in resolution of the neurological and imaging deficits. Patient 2 presented with TMA-induced PRES following gemcitabine for metastatic breast carcinoma. Treatment was ineffective and the patient deteriorated despite verapamil, dexamethasone, and plasma exchange. In this report, the relevant literature regarding pathogenesis, treatment and prognosis of chemotherapy-induced PRES associated with TMA was reviewed. We conclude that several chemotherapy agents may cause PRES through various pathogenic mechanisms, leading to clinical variability and divergent response to therapy.

Neurologic complications of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days-19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Sandfly virus seroconversion associated with neurologic presentation.

OBJECTIVE: To describe the clinical presentation and unique neurologic manifestations of sandfly viruses (SFVs) in the Jerusalem area. METHODS: We identified all patients with acute seroconversion to SFV at the Hadassah-Hebrew University Medical Centers during the years 2008-2013 and retrospectively collected and analyzed the clinical and imaging data. RESULTS: Nine patients (ranging from 1.5 to 85 years old) were identified. Presentation included acute neurologic disease, mostly with fever, change in consciousness and behavior, seizures, headache, meningitis, limb paresis, or myelitis. Eight patients had clinical signs of meningitis, meningoencephalitis, or encephalitis alone. Four patients had myelitis. MRI identified pathologic symmetrical changes in the basal ganglia, thalami, and other deep structures in 5 patients, and additional myelitis of the spine was noted on imaging in 3 patients. Seven patients had long-term follow-up: 4 completely recovered and 3 had remaining neurologic sequelae, among them 1 with permanent severe brain damage. CONCLUSION: Neurologic involvement associated with acute SFV infections is considered to be benign. However, in this series, all 9 patients presented with significant neurologic pathology associated with a unique finding of myelitis and symmetrical basal ganglia, thalami, or white matter involvement. Thus, acute SFV infection should be included in the differential diagnosis in febrile onset of neurologic manifestations and neuroradiologic changes.

[Fluid and sodium balance during exercise--standpoint].

During exercise certain metabolic and physiological processes influence fluid and electrolyte balance. Fluid loss, mostly through sweating, that is not properly compensated for by drinking, may result in dehydration. Clinical manifestations of dehydration depend on the amount of fluid lost. The more severe the level of dehydration is, the greater the reduction in physical and cognitive performance. It is recommended to drink water frequently and in small amounts. In order to encourage drinking, the fluid should be cool, palatable, readily available, and not carbonated. During exercise the ability of the kidney to excrete water is restricted, and therefore, there is a risk of hyperhydration and hyponatremia, mainly under conditions of overdrinking. Sodium loss through sweating and the development of hyponatremia will primarily occur during strenuous exercise lasting more than 4 hours. Symptoms of hyponatremia will generally appear at sodium concentrations below 130 mmol/l. In order to avoid hyponatremia one must avoid overdrinking, and during prolonged physical activity (> 4 hours) sodium intake must match the amount lost by sweating. Proper electrolyte and carbohydrate consumption through a normal diet is preferable to sport beverages or exogenous sodium supplements. In order to avoid dehydration, on one hand, and hyponatremia due to hyperhydration, on the other hand, the amount of fluid consumed should complement the amount of fluid lost during exercise. Given that there is intra- (depending on the type of activity and environmental conditions) and interindividual variability in the rate of fluid and salt loss, fluid and salt intake should be determined on an individual basis, as outlined in this standpoint.

Heat tolerance in women--reconsidering the criteria.

INTRODUCTION: Exertional heat stroke (EHS) is the most dangerous heat-related injury. EHS may be followed by a state of heat intolerance. The Israeli Defense Forces (IDF) performs heat tolerance tests (HTT) to all heat injury victims 6-8 wk following injury as part of the "return to duty" process. The HTT protocol and normal values are based on vast experience with young healthy men. Over the last several years an increasing number of female soldiers have been joining combat units. Heat injuries and, thus, HTT among women have become more frequent. Due to potential gender-related physiological and thermoregulatory differences, we examined the necessity for validating the HTT protocol for women. METHODS: Retrospective physiological data from our database on heat injuries and HTT between the years 2008-2010 was compared between 9 female subjects and 170 male subjects who had similar background characteristics. RESULTS: Defining heat intolerance as peak rectal temperature > 38.5 degrees C, peak heart rate > 150 bpm, or the inability to reach equilibrium in these values, we diagnosed 67% of the female subjects as heat intolerant. In the male subjects, only 26% were diagnosed as heat intolerant using the same criteria. CONCLUSIONS: Using the standard HTT criteria, women are more frequently diagnosed as heat intolerant than men. Further studies should be performed in order to re-evaluate the normal values for a "female HTT" in order to optimize the process of safe return to duty of female heat injury victims and to minimize false positive results among female soldiers.

Hypothermia following exertional heat stroke treatment.

Exertional heat stroke (EHS) is a life-threatening condition, which deteriorates rapidly. Immediate cooling treatment can, therefore, be life saving. Over the past two winters, we witnessed three cases of hypothermia resulting from treatment of suspected EHS. Since no such cases were described in the literature before, we, therefore, in this study present one of those cases. In addition, recommended approaches for proper management of similar situations are discussed. We suggest that in order to avoid hypothermia following aggressive cooling, core temperature (T (core)) should be continuously monitored. Upon reaching 38°C, cooling must be discontinued, and the patient should be dried and covered.

Non-PKC DAG/phorbol-ester receptor(s) inhibit complement receptor-3 and nPKC inhibit scavenger receptor-AI/II-mediated myelin phagocytosis but cPKC, PI3k, and PLCgamma activate myelin phagocytosis by both.

Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/II (SRAI/II), and Fcgamma-receptor (FcgammaR) can mediate myelin phagocytosis in macrophages and microglia. Paradoxically, after injury to CNS axons these receptors are expressed but myelin is not phagocytosed, suggesting that phagocytosis is subject to regulation between efficient and inefficient states. In the present work, we focus on CR3/MAC-1 and SRAI/II-mediated myelin phagocytosis. Phagocytosis by CR3/MAC-1 and SRAI/II was inhibited by cPKC inhibitor Go-6976, general-PKC inhibitors Ro-318220 and calphostin-C, and BAPTA/AM, which chelates intracellular Ca2+ required for cPKC activation. Signaling/activation by cPKC are thus suggested. PMA, which mimics diacylglycerol (DAG) as an activator of cPKC, novel-PKC (nPKC), and non-PKC DAG-driven molecule(s), produced a dose-dependent dual effect on phagocytosis by CR3/MAC-1 and SRAI/II, i.e., augmentation at low concentrations and inhibition at high concentrations. Inhibition of phagocytosis by CR3/MAC-1 was enhanced by combining inhibiting concentrations of PMA with PKC inhibitors Go-6976 or Ro-318220, suggesting inhibition by PMA/DAG-driven non-PKC molecule(s). In contrast, inhibition of phagocytosis by SRAI/II was enhanced by combining inhibiting concentrations of PMA with cPKC inhibitor Go-6976 but not with general-PKC inhibitor Ro-318220, suggesting inhibition by nPKC. Phagocytosis by CR3/MAC-1 and SRAI/II was further inhibited by PI3K inhibitors wortmannin and LY-294002 and PLCgamma inhibitor U-73122. Altogether, our observations suggest that CR3/MAC-1 and SRAI/II-mediated myelin phagocytosis share activation by PI3K, PLCgamma and cPKC. The two differ, however, in that non-PKC DAG-driven molecule(s) inhibit CR3/MAC-1-mediated phagocytosis, whereas nPKC inhibit SRAI/II-mediated phagocytosis. Each of these signaling steps may be targeted for regulating CR3/MAC-1 and/or SRAI/II-mediated phagocytosis between efficient and inefficient states.

cAMP cascade (PKA, Epac, adenylyl cyclase, Gi, and phosphodiesterases) regulates myelin phagocytosis mediated by complement receptor-3 and scavenger receptor-AI/II in microglia and macrophages.

The removal by phagocytosis of degenerated myelin is central for repair in Wallerian degeneration that follows traumatic injury to axons and in autoimmune demyelinating diseases (e.g., multiple sclerosis). We tested for roles played by the cAMP cascade in the regulation of myelin phagocytosis mediated by complement receptor-3 (CR3/MAC-1) and scavenger receptor-AI/II (SRAI/II) separately and combined in mouse microglia and macrophages. Components of the cAMP cascade tested are cAMP, adenylyl cyclase (AC), Gi, protein kinase A (PKA), exchange protein directly activated by cAMP (Epac), and phosphodiesterases (PDE). PKA inhibitors H-89 and PKI(14-22) amide inhibited phagocytosis at normal operating cAMP levels (i.e., those occurring in the absence of reagents that alter cAMP levels), suggesting activation of phagocytosis through PKA at normal cAMP levels. Phagocytosis was inhibited by reagents that elevate endogenous cAMP levels to above normal: Gi-inhibitor Pertussis toxin (PTX), AC activator Forskolin, and PDE inhibitors IBMX and Rolipram. Phagocytosis was inhibited also by cAMP analogues whose addition mimics abnormal elevations in endogenous cAMP levels: nonselective 8-bromo-cAMP, PKA-specific 6-Benz-cAMP, and Epac-specific 8-CPT-2'-O-Me-cAMP, suggesting that abnormal high cAMP levels inhibit phagocytosis through PKA and Epac. Altogether, observations suggest a dual role for cAMP and PKA in phagocytosis: activation at normal cAMP levels and inhibition at higher. Furthermore, a balance between Gi-controlled cAMP production by AC and cAMP degradation by PDE maintains normal operating cAMP levels that enable efficient phagocytosis.

Phosphatidylinositol 3-kinase, phosphoinositide-specific phospholipase-Cgamma and protein kinase-C signal myelin phagocytosis mediated by complement receptor-3 alone and combined with scavenger receptor-AI/II in macrophages.

Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/II (SRAI/II) and Fcgamma-receptor (FcgammaR) can mediate phagocytosis of degenerated myelin in macrophages and microglia. However, CR3/MAC-1 and SRAI/II, but not FcgammaR, mediate phagocytosis after axonal injury. We tested for phosphatidylinositol 3-kinase (PI3K), phosphoinositide-specific phospholipase-Cgamma (PLCgamma) and protein kinase-C (PKC) signaling in myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II. Phagocytosis was inhibited by PI3K inhibitors wortmannin and LY-294002, PLCgamma inhibitor U-73122, classical PKC (cPKC) inhibitor Go-6976, general PKC inhibitors Ro-318220 and calphostin-C, and BAPTA/AM which chelates intracellular Ca(2+) required for cPKC activation. PKC activator PMA augmented phagocytosis and further alleviated inhibitions induced by PI3K and PLCgamma inhibitors. Overall, altering PKC activity modulated phagocytosis 4- to 6-fold between inhibition and augmentation. PLCgamma activation did not require tyrosine phosphorylation. Thus, signaling of myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II involves PI3K, PLCgamma and cPKC, the cascade PI3K-->PLCgamma-->cPKC, and wide-range modulation by PKC. This pathway may thus be targeted for in vivo modulation, which may explain differences in the efficiency of CR3/MAC-1-mediated myelin phagocytosis in different pathological conditions.