Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis

2016 ◽  
Vol 34 (3) ◽  
pp. 227-234 ◽  
Author(s):  
Maarten J. Deenen ◽  
Didier Meulendijks ◽  
Annemieke Cats ◽  
Marjolein K. Sechterberger ◽  
Johan L. Severens ◽  
...  
Keyword(s):  
Cost Analysis ◽  
Drug Exposure ◽  
Standard Dose ◽  
Variant Allele ◽  
Dose Titration ◽  
Wild Type ◽  
Adequate Treatment ◽  
Life Threatening ◽  
Grade 3 ◽  
Historical Controls

Purpose Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype–guided dosing. Patients and Methods Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses. Results A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs. Conclusion DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype–guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving.

The potential clinical impact of pre-emptive screening of multiple polymorphisms in gene-encoding DPD on patients candidate for fluoropyrimidine based-chemotherapy: An experience of the Northern Italy Cancer Centre.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2567-2567
Author(s):  
Francesco Iachetta ◽  
Angela Damato ◽  
Candida Bonelli ◽  
Alessandra Romagnani ◽  
Maria Banzi ◽  
...  
Keyword(s):  
Standard Dose ◽  
Dihydropyrimidine Dehydrogenase ◽  
The Other ◽  
Severe Toxicity ◽  
Wild Type ◽  
Gene Encoding ◽  
Mutational Status ◽  
Key Enzyme ◽  
Life Threatening ◽  
Potential Clinical Impact

2567 Background: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluorouracil. Deleterious polymorphisms in gene-encoding DPD ( DPYD) results in a DPD deficiency that causes life-threatening toxicities when the standard dose of fluorouracil is used. DPYD*2A (IVS14+1G > A) is the most common single-nucleotide polymorphism (SNP) associated with critical DPD deficiency. At present, most of the evidence supports screening for at least 3 SNPs (DPYD*2A, c.2846 A > T, c.1679T > G). The aim of this study is to confirm that the detection of additional polymorphisms of DPYD could enhance prevention of fluoropyrimidine toxicity. Methods: In 2011, we began to screen DPYD*2A in patients candidate for fluoropyrimidine based-chemotherapy. As the first step of the evaluation, we selected all cases of DPYD*2A wild type, from 2011 to 2012, who developed CTC-NCI-V.3 toxicity ≥ G3. In these patients, we researched the other 3 SNPs (c.2846 A > T, c.1679T > G, c.2194C > A). Mutational status was analyzed with real Time PCR. Results: From 2011 to 2016 we pre-emptively screened DPD deficiency in 1,863 patients and 32 subjects (1.6%), with results mutated for DPYD*2A. As the first step of the evaluation, 548 subjects were assessed from 2011 to 2012. We found 7 patients who were carriers of the DPYD*2A mutation (1.27%). Of the 541 wild type cases, 114 presented toxicities ≥ G3. In this subgroup, 22 patients (19%) proved to be mutated for the other SNPs of DPYP, as reported in the table below. Conclusions: Preliminary data show that in 22 (19%) of 114 patients who presented severe toxicity which was not correlated with DPYD*2A, we found other polymorphisms of gene encoding DPD. Out of the 3 SNPs evaluated, c.2194 C > A proved to be the most frequent, although it is the polymorphism that is least known and least studied. Such results suggest that the evaluation of additional polymorphisms could enhance the prevention of fluoropyrimidine toxicity. The results are expected to be clarified further in the second step, which is ongoing. [Table: see text]

Inosine-Triphosphate-Pyrophosphatase Genotype Is a Determinant of Severe Fever with Neutropenia Following Treatment of Acute Lymphoblastic Leukemia with Combination Chemotherapy That Includes Mercaptopurine Adjusted for Thiopurine-S-Methyltransferase Genotype.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2827-2827
Author(s):  
Gabriele Stocco ◽  
Meyling Cheok ◽  
Wenjian Yang ◽  
Thierry Dervieux ◽  
Kristine Crews ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Variant Allele ◽  
Inosine Triphosphate Pyrophosphatase ◽  
Life Threatening ◽  
Variant Alleles ◽  
Grade 3 ◽  
Tpmt Gene

Abstract Germline polymorphisms can be significant determinants of toxicity to anti-leukemic therapy. For mercaptopurine (6MP) it is established that variant alleles of the thiopurine-S-methyl-transferase (TPMT) gene, resulting in low enzymatic activity, are associated with an increase in the concentration of thioguanine-nucleotide metabolites (TGN) and in the risk of hematotoxicity. Polymorphisms of genes encoding other enzymes involved in 6MP metabolism could also influence its pharmacokinetics and consequently its efficacy and toxicity. Among possible candidate genes, inosine-triphosphate-pyrophosphatase (ITPA) has been related to adverse events to thiopurine treatment of inflammatory bowel disease, but it has not been fully investigated for leukemia therapy. The aim of this study was to assess the association between severe life-threatening toxicities (Grade 3–4) during the continuation treatment of acute lymphoblastic leukemia (ALL) and the variant alleles of TPMT and ITPA genes, and the influence of these variant alleles on the concentration of 6MP metabolites, TGN and methylated nucleotides (MMPN). Patients with ALL on the St. Jude Total 13B protocol were assessed for toxicity according to NCI criteria. Relevant variant alleles of TPMT (SNPs rs1142345, rs1800462, rs1800660) and ITPA (SNP rs41320251) were determined using PCR assays. The association between the variant alleles and the development of adverse events during the continuation phase of treatment was assessed using weighted logistic regression. Concentrations of the two main metabolites of 6MP were measured in erythrocytes by HPLC; the association between genotypes and the concentrations of 6MP metabolites was evaluated using mixed linear effects models. TPMT and ITPA genotypes were determined for 233 patients; 13 (5.2%) were heterozygous for variant alleles of the TPMT gene and 31 (13.3%) for the ITPA gene; no patient had two variant alleles of either gene and 1 patient (0.4%) had a variant allele for both TPMT and ITPA. Since 6MP dose was individualized based on the TPMT variant allele among patients treated in the protocol, genetic polymorphisms of TPMT, not surprisingly, were not associated with toxicity. On the other hand, the presence of an ITPA variant allele was significantly associated with the incidence of Grade 3–4 fever with neutropenia in the univariate and in the multiple weighted logistic regression (odds ratio 3.0, 95% C.I. 1.2–7.8, p = 0.021). 6MP metabolites were measured in 257 samples from 108 patients, and the results revealed that variant alleles of both candidate genes were associated with changes in the concentration of the MMPN metabolites: TPMT with a reduction (p = 0.048) and ITPA with an increase (p = 0.047). Genetic polymorphism of ITPA rs41230251 is a significant determinant of severe and life-threatening fever with neutropenia and of 6MP metabolism in patients with ALL who are treated with 6MP doses individualized based on TPMT genotype.

A phase II trial of high-dose cetuximab (cmab) plus irinotecan in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (MCRC) who progressed on standard-dose cmab plus irinotecan.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 598-598
Author(s):  
A. M. Patta ◽  
J. A. McMahon ◽  
C. Samborski ◽  
M. Fakih
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Standard Dose ◽  
Performance Status ◽  
Dose Schedule ◽  
High Dose ◽  
Wild Type ◽  
Ecog Performance Status ◽  
Grade 3 ◽  
Higher Doses

598 Background: Prior clinical data suggest a dose-related response to cmab when combined with irinotecan in pts with KRAS WT tumors who do not develop grade 2 and above rash with standard cmab dosing. However, the investigation of higher doses of cmab in the setting of acquired or innate resistance to standard dose cmab has not been previously investigated. We conducted a phase II clinical trial of high-dose cmab plus irinotecan in KRAS WT pts with standard-dose cmab plus irinotecan – refractory disease to address this question. Methods: Pts with KRAS WT MCRC progressing on standard dose of cmab with irinotecan were eligible for study. Pts should have received a minimum of 6 weeks of prior standard dose cmab plus irinotecan and progressed within 4 weeks from the last dose. Cmab was administered at 500 mg/m2/week and irinotecan was administered at the same dose/schedule on which the patient previously progressed. 12-week PFS rate was the primary endpoint. Results: 8 pts were treated on study: median age 68 yrs (45-85), 5 pts were males, ECOG performance status was 1 in all 8 pts. Grade ≥ 3 toxicities consisted of hypomagnesaemia (4 pts), anemia (1 pt), leucopenia (1 pt), fatigue (1 pt), and diarrhea (1 pt). 6 pts achieved stable disease (with regression in target lesions noted in 3 pts). 12 week PFS rate is 5/8 and 18 week PFS is 4/8. 3 pts remain on study at 4.5, 5, and 8 months from enrollment. Conclusions: High-dose cmab/irinotecan is well tolerated except for hypomagnesemia. Encouraging prolonged disease stabilizations warrant further investigation of this approach in pts in KRAS WT population. Accrual is ongoing. [Table: see text]

Overview of Lamotrigine and the New Antiepileptic Drugs: The Challenge

1997 ◽  
Vol 12 (1_suppl) ◽  
pp. S48-S52 ◽  
Author(s):  
John M. Pellock
Keyword(s):  
Adverse Effect ◽  
Adverse Effects ◽  
Antiepileptic Drugs ◽  
Adjunctive Therapy ◽  
Dose Titration ◽  
Childhood Epilepsy ◽  
Major Advance ◽  
New Antiepileptic Drugs ◽  
Life Threatening ◽  
Titration Schedule

Lamotrigine, like all antiepileptic drugs, can be effective when used as monotherapy or adjunctive therapy. In general, adverse effects are reduced when monotherapy is employed. The most frequent adverse effect prompting withdrawal of lamotrigine is rash. This potentially life-threatening adverse effect occurs more frequently in children, is increased when a rapid dose titration schedule is employed, and is greater when lamotrigine is prescribed in combination with valproate. The availability of lamotrigine and other antiepileptic drugs represents a major advance for the treatment of childhood epilepsy. The challenge in using all of the new antiepileptic drugs, including lamotrigine, is to balance the expected improved efficacy with the potentially serious adverse effects. (J Child Neurol 1997;12(Suppl 1):S48-S52).

scholarly journals Ehrlichia chaffeensis and Its Invasin EtpE Block Reactive Oxygen Species Generation by Macrophages in a DNase X-Dependent Manner

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Omid Teymournejad ◽  
Mingqun Lin ◽  
Yasuko Rikihisa
Keyword(s):  
Host Cell ◽  
Cell Receptor ◽  
Ros Generation ◽  
Ehrlichia Chaffeensis ◽  
Biological Processes ◽  
Wild Type ◽  
New Approach ◽  
Host Cell Receptor ◽  
Life Threatening ◽  
Human Monocytic Ehrlichiosis

ABSTRACT The obligatory intracellular pathogen Ehrlichia chaffeensis lacks most genes that confer resistance to oxidative stress but can block reactive oxygen species (ROS) generation by host monocytes-macrophages. Bacterial and host molecules responsible for this inhibition have not been identified. To infect host cells, Ehrlichia uses the C terminus of its surface invasin, entry-triggering protein of Ehrlichia (EtpE; EtpE-C), which directly binds the mammalian cell surface receptor glycosylphosphatidylinositol-anchored protein DNase X. We investigated whether EtpE-C binding to DNase X blocks ROS production by mouse bone marrow-derived macrophages (BMDMs). On the basis of a luminol-dependent chemiluminescence assay, E. chaffeensis inhibited phorbol myristate acetate (PMA)-induced ROS generation by BMDMs from wild-type, but not DNase X−/−, mice. EtpE-C is critical for inhibition, as recombinant EtpE-C (rEtpE-C)-coated latex beads, but not recombinant N-terminal EtpE-coated or uncoated beads, inhibited PMA-induced ROS generation by BMDMs from wild-type mice. DNase X is required for this inhibition, as none of these beads inhibited PMA-induced ROS generation by BMDMs from DNase X−/− mice. Previous studies showed that E. chaffeensis does not block ROS generation in neutrophils, a cell type that is a potent ROS generator but is not infected by E. chaffeensis. Human and mouse peripheral blood neutrophils did not express DNase X. Our findings point to a unique survival mechanism of ROS-sensitive obligate intramonocytic bacteria that involves invasin EtpE binding to DNase X on the host cell surface. This is the first report of bacterial invasin having such a subversive activity on ROS generation. IMPORTANCE Ehrlichia chaffeensis preferentially infects monocytes-macrophages and causes a life-threatening emerging tick-transmitted infectious disease called human monocytic ehrlichiosis. Ehrlichial infection, and hence the disease, depends on the ability of this bacterium to avoid or overcome powerful microbicidal mechanisms of host monocytes-macrophages, one of which is the generation of ROS. Our findings reveal that an ehrlichial surface invasin, EtpE, not only triggers bacterial entry but also blocks ROS generation by host macrophages through its host cell receptor, DNase X. As ROS sensitivity is an Achilles’ heel of this group of pathogens, understanding the mechanism by which E. chaffeensis rapidly blocks ROS generation suggests a new approach for developing effective anti-infective measures. The discovery of a ROS-blocking pathway is also important, as modulation of ROS generation is important in a variety of ailments and biological processes. IMPORTANCE Ehrlichia chaffeensis preferentially infects monocytes-macrophages and causes a life-threatening emerging tick-transmitted infectious disease called human monocytic ehrlichiosis. Ehrlichial infection, and hence the disease, depends on the ability of this bacterium to avoid or overcome powerful microbicidal mechanisms of host monocytes-macrophages, one of which is the generation of ROS. Our findings reveal that an ehrlichial surface invasin, EtpE, not only triggers bacterial entry but also blocks ROS generation by host macrophages through its host cell receptor, DNase X. As ROS sensitivity is an Achilles’ heel of this group of pathogens, understanding the mechanism by which E. chaffeensis rapidly blocks ROS generation suggests a new approach for developing effective anti-infective measures. The discovery of a ROS-blocking pathway is also important, as modulation of ROS generation is important in a variety of ailments and biological processes.

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 57-57
Author(s):  
Hideaki Bando ◽  
Daisuke Kotani ◽  
Masahito Kotaka ◽  
Akihito Kawazoe ◽  
Toshiki Masuishi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Braf V600e ◽  
Phase Iii ◽  
Fixed Dose ◽  
Wild Type ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.

scholarly journals A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2976-2983 ◽  
Author(s):  
Heyu Ni ◽  
Pingguo Chen ◽  
Christopher M. Spring ◽  
Ebrahim Sayeh ◽  
John W. Semple ◽  
...  
Keyword(s):  
High Titer ◽  
Maternal Antibodies ◽  
Platelet Glycoprotein ◽  
Wild Type ◽  
Wild Type Male ◽  
Glycoprotein Iiia ◽  
Life Threatening ◽  
Β3 Integrin ◽  
Pathogenic Antibodies ◽  
Alloimmune Thrombocytopenia

AbstractFetal and neonatal alloimmune thrombo cytopenia (FNAITP) is a life-threatening bleeding disorder caused by maternal antibodies directed against fetal platelet antigens. The immunoreactive epitopes in FNAITP are primarily located in the extracellular regions of the platelet glycoprotein IIIa (β3 integrin). Here we have established a novel animal model of FNAITP using β3 integrin–deficient (β3-/-) mice. We demonstrated first that these mice are immunoresponsive to β3 integrin; β3-/- mice transfused with wild-type platelets generated specific anti–β3 antibodies which were able to induce thrombocytopenia in wild-type mice. Subsequently, β3-/- female mice (both naive and immunized) were bred with wild-type male mice to recapitulate the features of FNAITP. The titer of generated maternal antibodies correlated with the severity of FNAITP. High titer maternal anti–β3 anti-bodies caused severe fetal thrombocytopenia, intracranial hemorrhage, and even miscarriage. Furthermore, maternal administration of intravenous immunoglobulin G (IgG) ameliorated FNAITP and down-regulated pathogenic antibodies in both the maternal and fetal circulations.

Combined evaluation of genotype and phenotype of thiopurine S-methyltransferase (TPMT) in the clinical management of patients in chronic therapy with azathioprine

2019 ◽  
Vol 34 (1) ◽  
Author(s):  
Francesco Rucci ◽  
Maria Sole Cigoli ◽  
Valeria Marini ◽  
Carmen Fucile ◽  
Francesca Mattioli ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Adverse Events ◽  
High Performance ◽  
Clinical Information ◽  
Variant Allele ◽  
Clinical Settings ◽  
Wild Type ◽  
Chronic Therapy ◽  
Significant Difference ◽  
Combined Evaluation

Abstract Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.

scholarly journals The Meningococcal ABC-Type l-Glutamate Transporter GltT Is Necessary for the Development of Experimental Meningitis in Mice

2009 ◽  
Vol 77 (9) ◽  
pp. 3578-3587 ◽  
Author(s):  
Roberta Colicchio ◽  
Susanna Ricci ◽  
Florentia Lamberti ◽  
Caterina Pagliarulo ◽  
Chiara Pagliuca ◽  
...  
Keyword(s):  
Histological Analysis ◽  
Glutamate Uptake ◽  
Glutamate Transporter ◽  
Systemic Infection ◽  
Fold Increase ◽  
Wild Type ◽  
Nutrient Source ◽  
Infectious Dose ◽  
Life Threatening ◽  
The Brain

ABSTRACT Experimental animal models of bacterial meningitis are useful to study the host-pathogen interactions occurring at the cerebral level and to analyze the pathogenetic mechanisms behind this life-threatening disease. In this study, we have developed a mouse model of meningococcal meningitis based on the intracisternal inoculation of bacteria. Experiments were performed with mouse-passaged serogroup C Neisseria meningitidis. Survival and clinical parameters of infected mice and microbiological and histological analysis of the brain demonstrated the establishment of meningitis with features comparable to those of the disease in humans. When using low bacterial inocula, meningococcal replication in the brain was very efficient, with a 1,000-fold increase of viable counts in 18 h. Meningococci were also found in the blood, spleens, and livers of infected mice, and bacterial loads in different organs were dependent on the infectious dose. As glutamate uptake from the host has been implicated in meningococcal virulence, mice were infected intracisternally with an isogenic strain deficient in the ABC-type l-glutamate transporter GltT. Noticeably, the mutant was attenuated in virulence in mixed infections, indicating that wild-type bacteria outcompeted the GltT-deficient meningococci. The data show that the GltT transporter plays a role in meningitis and concomitant systemic infection, suggesting that meningococci may use l-glutamate as a nutrient source and as a precursor to synthesize the antioxidant glutathione.

Does the primary tumour location affect the prognosis of patients with colorectal cancer peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy?

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Haipeng Chen ◽  
Sicheng Zhou ◽  
Jianjun Bi ◽  
Qiang Feng ◽  
Zheng Jiang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Intraperitoneal Chemotherapy ◽  
Cytoreductive Surgery ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Primary Tumour ◽  
Cancer Center ◽  
Tumour Location ◽  
Life Threatening ◽  
Grade 3 ◽  
The Impact

Abstract Background The impact of primary tumour location on the prognosis of patients with peritoneal metastasis (PM) arising from colorectal cancer (CRC) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is rarely discussed, and the evidence is still limited. Methods Patients with PM arising from CRC treated with CRS and HIPEC at the China National Cancer Center and Huanxing Cancer Hospital between June 2017 and June 2019 were systematically reviewed. Clinical characteristics, pathological features, perioperative parameters, and prognostic data were collected and analysed. Results A total of 70 patients were divided into two groups according to either colonic or rectal origin (18 patients in the rectum group and 52 patients in the colon group). Patients with PM of a colonic origin were more likely to develop grade 3–4 postoperative complications after CRS+HIPEC (38.9% vs 19.2%, P = 0.094), but this difference was not statistically significant. Patients with colon cancer had a longer median overall survival (OS) than patients with rectal cancer (27.0 vs 15.0 months, P = 0.011). In the multivariate analysis, the independent prognostic factors of reduced OS were a rectal origin (HR 2.15, 95% CI 1.15–4.93, P = 0.035) and incomplete cytoreduction (HR 1.99, 95% CI 1.06–4.17, P = 0.047). Conclusion CRS is a complex and potentially life-threatening procedure, and we suggest that the indications for CRS+HIPEC in patients with PM of rectal origin be more restrictive and that clinicians approach these cases with caution.

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