Adverse Event Profile of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel Combination Therapy Based on JADER.

BACKGROUND/AIM: There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The combination of bevacizumab, carboplatin, and paclitaxel with atezolizumab, an anti-programmed death ligand 1 antibody (ABCP therapy), has been reported to be effective for treating non-small cell lung cancer. However, reports on its adverse events are limited. In this study, a survey and disproportionality analysis based on the Japanese Adverse Drug Event Report (JADER) database was conducted to elucidate the adverse event profile of ABCP therapy. MATERIALS AND METHODS: The reporting odds ratio (ROR) and information component were used as indicators for the disproportionality analysis. The ROR was also used to assess the changes in the reporting intensity with combination therapy, and the mutual exclusivity of the 95% confidence interval between the compared groups was considered. RESULTS: The reported adverse events of ABCP therapy mirrored those of the individual drugs that constituted it. ABCP therapy enhanced the reporting intensity of adverse events related to leukocytes and the skin, while decreased those related to interstitial lung disease and hepatic function abnormality as immune-related adverse events caused by atezolizumab, and gastrointestinal perforation caused by bevacizumab. CONCLUSION: Our analysis of data from the JADER database has revealed the adverse event profile of ABCP therapy. Our findings emphasize the importance of effectively managing febrile neutropenia and skin-related adverse events in ABCP therapy.

The Potential Antinociceptive Effect and Mechanism of Cannabis sativa L. Extract on Paclitaxel-Induced Neuropathic Pain in Rats Uncovered by Multi-Omics Analysis.

Cannabis sativa L. (hemp) is a herbaceous plant rich in cannabinoids with a long history of use in pain treatment. The most well-characterized cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), garnered much attention in chemotherapy-induced peripheral neuropathy (CIPN) treatment. However, few studies have investigated the biological benefits and mechanism of hemp extract on CIPN. In the present study, hemp extract (JG) rich in cannabinoids was extracted by supercritical fluid carbon dioxide extraction (SFCE). The antinociceptive efficacy was evaluated using a paclitaxel-induced peripheral neuropathy (PIPN) rat model based on behavioral tests. Further omics-based approaches were applied to explore the potential mechanisms. The results showed that JG decreased mechanical allodynia, thermal hyperalgesia, and inflammatory cytokines in PIPN rats significantly. Transcriptome analysis identified seven key genes significantly regulated by JG in PIPN model rats, mainly related to the neuroactive ligand-receptor interaction pathway, PPAR signaling pathway, and cAMP signaling pathway. In metabolomic analysis, a total of 39 significantly altered metabolites were identified, mainly correlated with pentose and glucuronate interconversions and the glycerophospholipid metabolism pathway. Gut microbiota analysis suggested that increased community Lachnoclostridium and Lachnospiraceae_UCG-006 in PIPN rats can be reversed significantly by JG. In conclusion, hemp extract exhibited antinociceptive effects on PIPN. The analgesic mechanism was probably related to the regulation of inflammation, neuroactive ligand-receptor interaction pathway, sphingolipid metabolism, etc. This study provides novel insights into the functional interactions of Cannabis sativa L. extract on PIPN.

Efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in the treatment of locally advanced cervical cancer.

BACKGROUND: Evaluate the efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in treating locally advanced cervical cancer (LACC). METHODS: Retrospective data was collected from LACC patients who were treated at our institution. These patients were categorized into three groups: the single-agent cisplatin (DDP) chemoradiotherapy group, the paclitaxel plus cisplatin (TP) chemoradiotherapy group, and the nanoparticle albumin-bound (nab-) paclitaxel combined with cisplatin (nPP) chemoradiotherapy group. The primary endpoints were overall survival (OS) and progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR) and incidence of adverse events (AEs). RESULTS: A total of 124 patients were enrolled (32 in the DDP group, 41 in the TP group, and 51 in the nPP group). There were differences in OS (P = 0.041, HR 0.527, 95% CI 0.314-0.884) and PFS (P = 0.003, HR 0.517, 95% CI 0.343-0.779) between the three groups. Notably, the 2-year OS rate was significantly higher in the nPP group compared to the DDP group (92.2% vs. 85.4%, P = 0.012). The 2-year PFS rates showed a marked increase in the TP group (78.0% vs. 59.4%, P = 0.048) and the nPP group (88.2% vs. 59.4%, P = 0.001) relative to the DPP group, with multiple comparisons indicating that the 2-year PFS rate was significantly superior in the nPP group versus the DDP group (88.2% vs. 59.4%, P = 0.001). Moreover, the ORR was also significantly higher in the nPP group than in the DDP group (P = 0.013); and no statistically significant differences were found in the incidence of AEs among the groups (P > 0.05). CONCLUSIONS: In LACC treatment, the two cisplatin-based doublet chemotherapy regimens are associated with better outcomes, with the nab-paclitaxel plus cisplatin regimen showing better efficacy than the paclitaxel plus cisplatin regimen. Furthermore, the AEs associated with these regimens were deemed tolerable. These findings could provide a reference for the clinical treatment of LACC. However, further prospective studies are needed to verify it.

Influence of (C1236T and C3435T) Polymorphisms of ABCB1 Gene on Chemotherapy Treatment Outcome and Toxicity in Breast Cancer Patients.

BACKGROUND: ATP Binding Cassette Transporters (ABCB1) gene plays an important role in transport of different metabolites and anticancer drugs across the cell membrane. There is lack of knowledge on ABCB1 gene polymorphism and its correlation with Adriamycin or paclitaxel based chemotherapy induced toxicity in breast cancer patients. Therefore in this study, we explored the correlation of ABCB1 polymorphisms gene on response and toxicity in adriamycin and paclitaxel based chemotherapy in breast cancer patients from Indian population. METHODS: Two hundred BC patients receiving Adriamycin and paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms in ABCB1 gene (C1236T, C3435T) were studied by PCR and RFLP analysis. RESULTS: The univariate logistic regression analysis showed statistically significant negative association with protective effects of ABCB1 (C3435T) polymorphism with heterozygous genotype (OR=0.34, 95% CI: 0.13-0.89; p=0.027), homozygous variant genotype (OR=0.31, 95% CI: 0.10-0.99; p=0.049) and combined C/T+T/T genotypes (OR=0.33, 95% CI: 0.13-0.79; p=0.013) in relation with severe toxicity of chemotherapy induced nausea and vomiting in breast cancer patients treated with Adriamycin chemotherapy. The 3435 C>T polymorphism of ABCB1 gene with heterozygous C/T genotype showed significantly negative association (OR=0.37, 95% CI: 0.14-0.96; p=0.042) with peripheral neuropathy in patients treated primarily with paclitaxel thereafter Adriamycin. CONCLUSION: The findings obtained from this study revealed significant association of ABCB1 3435 C>T polymorphisms with non-hematological toxicity in response to adriamycin and paclitaxel based chemotherapy.

Evaluating the clinical efficacy and safety of concurrent chemoradiotherapy with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer.

OBJECTIVE: A preclinical study showed that nab-paclitaxel acted as a radiosensitizer and improved tumor radiotherapy in a supra-additive manner. In this study, we aimed to evaluate the clinical efficacy and safety of concurrent chemoradiotherapy (CCRT) with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer with an unfavorable prognosis. METHODS: Eligible patients with stage IB1-IIA2 (FIGO 2009) cervical carcinoma were recruited retrospectively between August 2018 to May 2021. Patients in both the cisplatin and nab-paclitaxel groups received postoperative radiotherapy and weekly intravenous cisplatin 40 mg/m2 or nab-paclitaxel 100 mg concurrently. An analysis of overall survival, progression-free survival, and adverse reactions was conducted. RESULTS: A total of 105 early-stage cervical cancer patients were included into our study. The median follow-up time was 38.7 months. The 3-year overall survival and progression-free survival in both group was similar. The cycles of chemotherapy in the cisplatin group were less than those in the nab-paclitaxel group (4.5 vs. 5.0; p = 0.001). Patients in the cisplatin group had a significantly higher frequency of hematological adverse events than patients in the nab-paclitaxel group (P < 0.05). Patients in the cisplatin group had a significantly higher frequency of grade 3-4 leukopenia (46.1% vs. 18.9%; P = 0.03), grade 1-2 thrombocytopenia (32.7% vs. 9.5%; P = 0.014) than patients in the nab-paclitaxel group. Gastrointestinal reactions, such as vomiting, nausea, and anorexia were significantly reduced in the nab-paclitaxel group compared with those in the cisplatin group. Regarding the effects on alopecia, the incidence rate of the nab-paclitaxel group was higher than that of the cisplatin group (P = 0.001). There were no differences between the groups in terms of other adverse reactions. CONCLUSION: The results of this study indicate that nab-paclitaxel-based concurrent radiotherapy is tolerable and effective, and can be considered an alternative to cisplatin chemotherapy.

NT-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons.

Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), and the therapeutic options for managing CINP are limited. Here, we show that systemic paclitaxel administration upregulates the expression of neurotrophin-3 (Nt3) mRNA and NT3 protein in the neurons of dorsal root ganglia (DRG), but not in the spinal cord. Blocking NT3 upregulation attenuates paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in male and female mice. Conversely, mimicking this increase produces enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naive male and female mice. Mechanistically, NT3 triggers tropomyosin receptor kinase C (TrkC) activation and participates in the paclitaxel-induced increases of C-C chemokine ligand 2 (Ccl2) mRNA and CCL2 protein in the DRG. Given that CCL2 is an endogenous initiator of CINP and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNAs in DRG neurons, NT3 likely contributes to CINP through TrkC-mediated activation of the Ccl2 gene in DRG neurons. NT3 may be thus a potential target for CINP treatment.

CYP2C8 rs11572080 and CYP3A4 rs2740574 risk genotypes in paclitaxel-treated premenopausal breast cancer patients.

Breast cancer (BC) is the most prevalent malignancy in women globally. At time of diagnosis, premenopausal BC is considered more aggressive and harder to treat than postmenopausal cases. Cytochrome P450 (CYP) enzymes are responsible for phase I of estrogen metabolism and thus, they are prominently involved in the pathogenesis of BC. Moreover, CYP subfamily 2C and 3A play a pivotal role in the metabolism of taxane anticancer agents. To understand genetic risk factors that may have a role in pre-menopausal BC we studied the genotypic variants of CYP2C8, rs11572080 and CYP3A4, rs2740574 in female BC patients on taxane-based therapy and their association with menopausal status. Our study comprised 105 female patients with histologically proven BC on paclitaxel-therapy. They were stratified into pre-menopausal (n = 52, 49.5%) and post-menopausal (n = 53, 50.5%) groups. Genotyping was done using TaqMan assays and employed on Quantstudio 12 K flex real-time platform. Significant increased frequencies of rs11572080 heterozygous CT genotype and variant T allele were established in pre-menopausal group compared to post-menopausal group (p = 0.023, 0.01, respectively). Moreover, logistic regression analysis revealed a significant association between rs11572080 CT genotype and premenopausal BC. However, regarding rs2740574, no significant differences in genotypes and allele frequencies between both groups were detected. We reported a significant association between CYP2C8 genotypic variants and premenopausal BC risk in Egyptian females. Further studies on larger sample sizes are still needed to evaluate its importance in early prediction of BC in young women and its effect on treatment outcome.

Paclitaxel-Associated Mechanical Sensitivity and Neuroinflammation Are Sex-, Time-, and Site-Specific and Prevented through Cannabigerol Administration in C57Bl/6 Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients. One identified mechanism underlying CIPN is neuroinflammation. Most of this research has been conducted in only male or female rodent models, making direct comparisons regarding the role of sex differences in the neuroimmune underpinnings of CIPN limited. Moreover, most measurements have focused on the dorsal root ganglia (DRG) and/or spinal cord, while relatively few studies have been aimed at characterizing neuroinflammation in the brain, for example the periaqueductal grey (PAG). The overall goals of the present study were to determine (1) paclitaxel-associated changes in markers of inflammation in the PAG and DRG in male and female C57Bl6 mice and (2) determine the effect of prophylactic administration of an anti-inflammatory cannabinoid, cannabigerol (CBG). In Experiment 1, male and female mice were treated with paclitaxel (8-32 mg/kg/injection, Days 1, 3, 5, and 7) and mechanical sensitivity was measured using Von Frey filaments on Day 7 (Cohort 1) and Day 14 (Cohort 2). Cohorts were euthanized on Day 8 or 15, respectively, and DRG and PAG were harvested for qPCR analysis of the gene expression of markers of pain and inflammation Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. In Experiment 2, male and female mice were treated with vehicle or 10 mg/kg CBG i.p. 30 min prior to each paclitaxel injection. Mechanical sensitivity was measured on Day 14. Mice were euthanized on Day 15, and PAG were harvested for qPCR analysis of the gene expression of Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. Paclitaxel produced a transient increase in potency to produce mechanical sensitivity in male versus female mice. Regarding neuroinflammation, more gene expression changes were apparent earlier in the DRG and at a later time point in the PAG. Also, more changes were observed in females in the PAG than males. Overall, sex differences were observed for most markers at both time points and regions. Importantly, in both the DRG and PAG, most increases in markers of neuroinflammation and pain occurred at paclitaxel doses higher than those associated with significant changes in the mechanical threshold. Two analytes that demonstrated the most compelling sexual dimorphism and that changed more in males were Cxcl9 and Ccl2, and Tlr4 in females. Lastly, prophylactic administration of CBG protected the male and female mice from increased mechanical sensitivity and female mice from neuroinflammation in the PAG. Future studies are warranted to explore how these sex differences may shed light on the mechanisms of CIPN and how non-psychoactive cannabinoids such as CBG may engage these targets to prevent or attenuate the effects of paclitaxel and other chemotherapeutic agents on the nervous system.

Is a low dose of dexamethasone sufficient to prevent paclitaxel-related hypersensitivity reactions? A retrospective study in patients with gynecologic malignancy.

BACKGROUND: Paclitaxel hypersensitivity reactions (HSRs) are prevalent, especially in females. The common paclitaxel pretreatment, dexamethasone, may inhibit chemotherapy efficacy and accelerate tumor progression. We aimed to balance paclitaxel HSRs and the lowest dexamethasone dose for gynecologic malignancies. METHODS: We retrospectively examined 1,074 cycles of 3-weekly paclitaxel-containing treatment for 231 gynecologic malignancies at Xiangya Hospital. HSR incidence with different dexamethasone regimens was the primary outcome. Risk factors were examined in all cycles using univariate and multivariate models with generalized estimating equations. A subgroup analysis of initial exposure to paclitaxel was also conducted. RESULTS: HSR occurred in 33 patients (14.29%) and 49 cycles (4.56%), including 69.39% in cycles 1-2. There were no severe HSRs (grade ≥3). Different premedication regimens, including dexamethasone dosage and route, ranitidine presence or absence, didn't affect HSR incidence in univariate and multivariate analyzes (p > 0.05). Premenopausal women exerted fewer HSRs (ORadj 0.22, 95%CI 0.08-0.58; p = 0.002). At the first exposure to paclitaxel, more than 10 mg of dexamethasone didn't diminish HSRs (OR 0.83, 95%CI 0.27-2.59; p = 0.753). CONCLUSIONS: In gynecologic malignancies, 10 mg dexamethasone along with 20 mg diphenhydramine may be adequate to prevent paclitaxel HSRs without ranitidine. It is necessary to reevaluate paclitaxel premedication regimens.

Rates of paclitaxel hypersensitivity reactions using a modified Markman's infusion protocol as primary prophylaxis.

PURPOSE: Markman's desensitisation protocol allows successful retreatment of patients who have had significant paclitaxel hypersensitivity reactions. We aimed to reduce the risk and severity of paclitaxel hypersensitivity reactions by introducing this protocol as primary prophylaxis. METHODS: We evaluated all patients with a gynaecological malignancy receiving paclitaxel before (December 2018 to September 2019) and after (October 2019 to July 2020) the implementation of a modified Markman's desensitisation protocol. The pre-implementation group received paclitaxel over a gradually up-titrated rate from 60 to 180 ml/h. The post-implementation group received paclitaxel via 3 fixed-dose infusion bags in the first 2 cycles. Rates and severity of paclitaxel hypersensitivity reactions were compared. RESULTS: A total of 426 paclitaxel infusions were administered to 78 patients. The median age was 64 years (range 34-81), and the most common diagnosis was ovarian, fallopian tube and primary peritoneal cancer (67%, n = 52/78). Paclitaxel hypersensitivity reaction rates were similar in the pre-implementation (8%, n = 16/195) and post-implementation groups (9%, n = 20/231; p = 0.87). Most paclitaxel hypersensitivity reactions occurred within 30 min (pre- vs. post-implementation, 88% [n = 14/16] vs. 75% [n = 15/20]; p = 0.45) and were grade 2 in severity (pre- vs. post-implementation, 81% [n = 13/16] vs. 75% [n = 15/20]; p = 0.37). There was one grade 3 paclitaxel hypersensitivity reaction in the pre-implementation group. All patients were successfully rechallenged in the post-implementation group compared to 81% (n = 13/16) in the pre-implementation group (p = 0.43). CONCLUSION: The modified Markman's desensitisation protocol as primary prophylaxis did not reduce the rate or severity of paclitaxel hypersensitivity reactions, although all patients could be successfully rechallenged.

Real-World Effectiveness and Safety of Ramucirumab as a Second-Line Treatment for Patients with Unresectable Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma in Japan and South Korea: A Systematic Literature Review.

INTRODUCTION: Gastric cancer has the highest incidence and mortality in Eastern Asia. The efficacy and safety of ramucirumab (RAM) monotherapy or in combination with paclitaxel (PTX) for patients with unresectable advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (G/GEA) have been established in clinical trials. To assess the effectiveness and safety of RAM or RAM-based therapy as a second-line treatment in real-world clinical practice in Eastern Asia and to pave the way for future research, a systematic literature review (SLR) was conducted. METHODS: Studies published between January 2014 and December 2021 were identified in PubMed, Embase, Cochrane Library, CNKI, Wanfang, and CBM databases. RESULTS: This SLR included 23 studies from Japan and South Korea, of which 22 were retrospective and 11 were full-text articles. Most studies investigated RAM + PTX (range of median overall survival [mOS] 7.4-12.2 months; median progression-free survival [mPFS] 3.35-7.0 months). Data were limited for RAM, RAM + albumin-bound paclitaxel, and RAM + taxane. RAM + PTX was associated with longer survival (mOS 9.3-12.2 months vs. 5.2-9.7 months; mPFS 4.1-5.1 months vs. 3.0-4.1 months) than PTX. Patients with prior anti-programmed cell death 1 (anti-PD-1) exposure experienced longer mPFS (4.8 vs. 3.4 months) from RAM + taxane than those without prior anti-PD-1 exposure. Few patients (3.3-6.3%) discontinued RAM or RAM-based therapy because of adverse events (AEs). Hematological toxicities were most frequently occurring AEs and no new safety signals were identified compared to clinical trials. CONCLUSION: RAM + PTX as a second-line treatment is effective and associated with an acceptable toxicity profile in patients with advanced or metastatic G/GEA in real-world settings of Japan and South Korea. More studies are recommended to further evaluate effectiveness and safety of RAM or RAM-based therapy, especially after anti-PD-1 therapy, in a wider Eastern Asian population. TRIAL REGISTRATION: INPLASY registration number INPLASY2022120023.

Genetic determinants of taxane-induced peripheral neuropathy.

The efficacy of taxane­containing regimens has been demonstrated for various cancers, particularly ovarian, endometrial, breast, lung, and prostate cancers. However, extensive taxane-induced toxicities limit their use. Prediction and management of many toxic complications in cancer patients have evolved significantly over the last decade. Peripheral neuropathy is the most typical non-hematological taxane-related complication, and it has a multifactorial pathogenesis. It is often dose-dependent and progressive during therapy and sometimes even after treatment. Unfortunately, the prediction of these common adverse events remains unclear. In the past few years, several polymorphisms of candidate genes with a possible role in the development of this consequence were studied. This minireview aims to highlight the critical yet underappreciated roles of genetic predictors that may increase susceptibility to taxane-induced peripheral neuropathy in cancer patients (Ref. 40). Keywords: taxanes, paclitaxel, docetaxel, peripheral neuropathy, risk factors, genetic polymorphisms.

The Serotonin-Mediated Anti-Allodynic Effect of Yokukansan on Paclitaxel-Induced Neuropathic Pain.

Refractory peripheral neuropathy can occur as a side effect in 60-70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain.

ONYCHOLYSIS AS A COMPLICATION OF TAXANE-BASED CHEMOTHERAPY WITH CONCOMITANT CRYOTHERAPY IN BREAST CANCER PATIENTS: TWO CASE REPORTS.

Nail changes are a common side effect of taxane chemotherapy, although onycholysis is quite a rare complication the correct management of which is poorly standardized. These case reports provide a description and analysis of onycholysis, a rare but noteworthy complication observed during taxane-based chemotherapy with concomitant cryotherapy in two patients with breast cancer. Despite prophylactic measures, both cases experienced nail complications during Paclitaxel treatment, underlining the complex nature of onycholysis during taxane therapy and highlighting the critical role of nail assessment and infection screening.

Paclitaxel-induced acute myocardial infarction: a case report and literature review.

BACKGROUND: Paclitaxel is a chemotherapeutic agent commonly used for ovarian, lung, breast carcinoma, and Kaposi's sarcoma. Its common side effects include hypersensitivity reaction, bone marrow suppression, and peripheral neuropathy. However, a rare and life-threatening side effect is paclitaxel-induced myocardial infarction. CASE PRESENTATION: A 71-year-old man with type 2 diabetes mellitus, hypertension, heavy smoking history, previous coronary artery disease with percutaneous coronary intervention (PCI) in left anterior descending artery (LAD), and non-small lung cancer presented with non-ST elevation myocardial infarction during infusion of paclitaxel infusion. Coronary angiogram showed de novo three vessel disease with 70% stenosis in ostial to distal left main artery (LM) and 80% in-stent re-stenosis in proximal to mid left anterior descending artery. CONCLUSIONS: Physicians should be keeping this in mind when dealing with patients on paclitaxel, especially if they have previous risk factors for coronary artery disease.

Spinal microglial M1 polarization contributes paclitaxel-induced neuropathic pain by triggering cells necroptosis.

Paclitaxel (PTX) is a chemotherapeutic agent that is widely used for the treatment of several types of tumors. However, PTX-induced peripheral neuropathy (PIPN) is an adverse effect generally induced by long-term PTX use that significantly impairs the quality of life. Necroptosis has been implicated in various neurodegenerative disorders. Necroptosis of dorsal root ganglion neurons triggers the pathogenesis of PIPN. Therefore, the present study aims to investigate the role of spinal neuronal necroptosis in PIPN. It also explores the potential role of microglial polarization in necroptosis. We established rat models of PIPN via quartic PTX administration on alternate days (accumulated dose: 8 mg/kg). PTX induced obvious neuronal necroptosis and upregulated the expression of receptor-interacting protein kinase (RIP3) and mixed lineage kinase domain-like protein (MLKL) in the spinal dorsal horn. These effects were inhibited with a necroptosis pathway inhibitor, necrostatin-1 (Nec-1). The effect of microglial polarization on the regulation of spinal necroptosis was elucidated by administering minocycline to inhibit PTX-induced M1 polarization of spinal microglia caused by PTX. We observed a significant inhibitory effect of minocycline on PTX-induced necroptosis in spinal cord cells, based on the downregulation of RIP3 and MLKL expression, and suppression of tumor necrosis factor-α and IL-ß synthesis. Additionally, minocycline improved hyperalgesia symptoms in PIPN rats. Overall, this study suggests that PTX-induced polarization of spinal microglia leads to RIP3/MLKL-regulated necroptosis, resulting in PIPN. These findings suggest a potential target for the prevention and treatment of neuropathic pain.

A prospective comparison study utilizing patient-reported outcomes of taxane-related peripheral neuropathy between nab-paclitaxel and standard paclitaxel in patients with breast cancer.

BACKGROUND: Characteristics of taxane-induced peripheral neuropathy (PN) could be different between paclitaxel and nab-paclitaxel. The purpose of this prospective observational multicenter cohort study was to compare tri-weekly nab-paclitaxel to weekly standard paclitaxel regarding the severity, onset and recovery of sensory and motor PN in patients with breast cancer. METHODS: Patients with histologically confirmed breast cancer who were scheduled to receive standard weekly paclitaxel (80 mg/m2) or tri-weekly nab-paclitaxel (260 mg/m2) at institutions in our multicenter group were eligible for this study. Sensory and motor PN were evaluated every 3 weeks until PN improved for up to one year using patient-reported outcome. RESULTS: Between February 2011 and April 2013, 115 patients were enrolled, including 57 and 58 in the paclitaxel and nab-paclitaxel groups, respectively. The incidence of moderate or severe sensory PN was not significantly different between the two groups (p = 0.40). The incidence of moderate or higher motor PN was more frequent in the nab-paclitaxel group than in the paclitaxel group (p = 0.048). The median period for demonstrating PN were shorter in the nab-paclitaxel group than in the paclitaxel group (sensory, p = 0.003; motor, p = 0.001). The recovery of motor PN was slower in the nab-paclitaxel group than in the paclitaxel group (p = 0.035), while the recovery period of sensory PN was not statistically different. CONCLUSION: Nab-paclitaxel induced sensory PN sooner than paclitaxel, and no difference was observed in the severity and recovery duration between the two agents. Motor PN was more severe, started sooner, and improved over a longer period in the nab-paclitaxel-treated patients than in the paclitaxel-treated patients.

A three-arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel in metastatic uveal melanoma.

AIMS: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel. PATIENTS AND METHODS: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level. RESULTS: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved. CONCLUSIONS: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing.

Blocking Pannexin 1 Channels Alleviates Peripheral Inflammatory Pain but not Paclitaxel-Induced Neuropathy.

BACKGROUND: Pannexin1 (Panx1) is a membrane channel expressed in different cells of the nervous system and is involved in several pathological conditions, including pain and inflammation. At the central nervous system, the role of Panx1 is already well-established. However, in the periphery, there is a lack of information regarding the participation of Panx1 in neuronal sensitization. The dorsal root ganglion (DRG) is a critical structure for pain processing and modulation. For this reason, understanding the molecular mechanism in the DRG associated with neuronal hypersensitivity has become highly relevant to discovering new possibilities for pain treatment. Here, we aimed to investigate the role of Panx1 in acute nociception and peripheral inflammatory and neuropathic pain by using two different approaches. METHODS: Rats were treated with a selective Panx1 blocker peptide (10Panx) into L5-DRG, followed by ipsilateral intraplantar injection of carrageenan, formalin, or capsaicin. DRG neuronal cells were pre-treated with 10Panx and stimulated by capsaicin to evaluate calcium influx. Panx1 knockout mice (Panx1-KO) received carrageenan or capsaicin into the paw and paclitaxel intraperitoneally. The von Frey test was performed to measure the mechanical threshold of rats' and mice's paws before and after each treatment. RESULTS: Pharmacological blockade of Panx1 in the DRG of rats resulted in a dose-dependent decrease of mechanical allodynia triggered by carrageenan, and nociception decreased in the second phase of formalin. Nociceptive behavior response induced by capsaicin was significantly lower in rats treated with Panx1 blockade into DRG. Neuronal cells with Panx1 blockage showed lower intracellular calcium response than untreated cells after capsaicin administration. Accordingly, Panx1-KO mice showed a robust reduction in mechanical allodynia after carrageenan and a lower nociceptive response to capsaicin. A single dose of paclitaxel promoted acute mechanical pain in wildtype (WT) but not in Panx1-KO mice. Four doses of chemotherapy promoted chronic mechanical allodynia in both genotypes, although Panx1-KO mice had significant ablation in the first eight days. CONCLUSION: Our findings suggest that Panx1 is critical for developing peripheral inflammatory pain and acute nociception involving transient receptor potential vanilloid subtype 1 (TRPV1) but is not essential for neuropathic pain chronicity.