Publications by authors named "Christina Cox"

28 Publications

  • Page 1 of 1

Evaluation of Time to Resolution of Medical Necrotizing Enterocolitis Using Severity-Guided Management in a Neonatal Intensive Care Unit.

J Pediatr Pharmacol Ther 2021 15;26(2):179-186. Epub 2021 Feb 15.

Objective: No studies, to our knowledge, have determined the relationship between symptom resolution and timing of antimicrobial discontinuation in necrotizing enterocolitis (NEC). Our study seeks to determine the period to NEC resolution by using severity-guided management, based on surrogate markers used in the diagnosis of NEC.

Methods: This retrospective, observational review included patients in our NICU with NEC from June 1, 2012, to June 1, 2018. Patients were excluded for surgical NEC, a positive blood culture or transfer from an outside institution at the time of NEC, presence of a peritoneal drain, or death prior to NEC resolution. The primary outcome was time to resolution of NEC, measured by return to baseline of surrogate markers used in the diagnosis of NEC.

Results: The median times to resolution in days, based on our institution's NEC severity group, were as follows: mild 3 (range, 1-4); moderate 4 (range, 1-17); severe 9 (range, 5-21). No difference in NEC recurrence was found based on antibiotic duration (OR 0.803; 95% CI, 0.142-4.225).

Conclusions: Time to resolution of NEC differs by severity group, suggesting a need for different treatment durations. Recurrence of NEC did not differ between groups, suggesting that shorter antibiotic durations do not lead to an increased incidence of NEC recurrence. Further exploration of the optimal antimicrobial treatment duration for NEC is warranted.
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http://dx.doi.org/10.5863/1551-6776-26.2.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887889PMC
February 2021

Joint Statement on Pediatric Education at Schools of Pharmacy.

Am J Pharm Educ 2020 08;84(8):ajpe7892

Roseman University of Health Sciences, College of Pharmacy, South Jordan, Utah.

Providing health care for children is a unique specialty, and pediatric patients represent approximately 25% of the population. Education of pharmacy students on patients across the lifespan is required by current Accreditation Council for Pharmacy Education standards and outcomes; thus, it is essential that pharmacy students gain a proficiency in caring for children. A collaborative panel of pediatric faculty members from schools and colleges of pharmacy was established to review the current literature regarding pediatric education in Doctor of Pharmacy curricula and establish updated recommendations for the provision of pediatric pharmacy education. This statement outlines five recommendations supporting inclusion of pediatric content and skills in Doctor of Pharmacy curricula.
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http://dx.doi.org/10.5688/ajpe7892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473221PMC
August 2020

Nonpeghylated liposomal doxorubicin combination regimen (R-COMP) for the treatment of lymphoma patients with advanced age or cardiac comorbidity.

Hematol Oncol 2020 Oct 9;38(4):478-486. Epub 2020 Jul 9.

Ematologia e Trapianto Midollo Osseo, Ospedale Santa Maria della Misericordia, Azienda Ospedaliera Perugia, Perugia, Italy.

Doxorubicin is the most effective single agent in the treatment of non-Hodgkin's lymphoma (NHL). Its use is limited because of the cardiac toxicity primarily in elderly patients (pts) and in pts with history of cardiac disease. Liposomal doxorubicin has been proven to reduce cardiotoxicity. The aim of this retrospective study was the use of nonpeghylated liposomal doxorubicin (NPLD) in term of efficacy, response rate and incidence of cardiac events. We retrospectively collected the experience of 33 Hematological Italian Centers in using NPLD. Nine hundred and forty-six consecutive pts treated with R-COMP (doxorubicin was substituted with NPLD, Myocet) were collected. Median age was 74 years, the reasons for use of NPLD were: age (466 pts), cardiac disease (298 pts), uncontrolled hypertension (126 pts), other reasons (56 pts). According to clinicians' evaluation, 49.9% of pts would not have used standard doxorubicin for different situations (age, cardiomyopathy, previous use of doxorubicin, and uncontrolled hypertension). Overall 687 pts (72.6%) obtained a complete remission (CR). About 5% (n = 51) of subjects developed major cardiotoxic events including heart failure (N = 31), ischemic heart disease (N = 16), acute heart attack (N = 3), and acute pulmonary oedema (N = 1). After a median follow-up of 32 months, 651 pts were alive and the overall survival (OS) was 72%. After a median observation period of 23 months disease free survival (DFS) was 58%. Either in univariate or in multivariate analysis OS and DFS were not significantly affected by age or cardiac disease. Our findings strongly support that including R-COMP is effective and safe when the population is at high risk of cardiac events and negatively selected. Moreover, the use of this NPLD permitted that about half of our population had the opportunity to receive the best available treatment.
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http://dx.doi.org/10.1002/hon.2764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689940PMC
October 2020

Standardized image quality for Ga-DOTA-TATE PET/CT.

EJNMMI Res 2020 Mar 23;10(1):27. Epub 2020 Mar 23.

Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands.

Background: Positron emission tomography (PET) imaging with Gallium labeled somatostatin analogues (Ga-DOTA-SSA) plays a key role in neuroendocrine tumor management. The impact of patient size on PET image quality is not well known for PET imaging with Ga-DOTA-SSA. The aim of this study is to propose a dose regimen based on patient size that optimizes image quality and yields sufficient image quality for diagnosis.

Methods: Twenty-one patients (12 males, 9 females) were prospectively included for Gallium-DOTA-Tyr3-Octreotate (Ga-DOTA-TATE) PET/CT, which was acquired in whole body list mode using 6 min per bed position (mbp). The list-mode events were randomly sampled to obtain 1 to 6 mbp PET reconstructions. For semi-quantitative assessment of image quality, the signal-to-noise ratio (SNR) was measured in the liver. The SNR normalized (SNRnorm) for administered activity and mbp was correlated with body mass, length, body mass index, body mass/length, and lean body mass. Three experienced nuclear medicine physicians visually graded image quality using a 4-point scale, and categorically scored the number of somatostatin-receptor positive lesions for each reconstruction. To investigate the impact of image quality on lesion quantification, the mean, maximum, and peak standardized uptake values (SUVs) of one abdominal lesion were measured in the 1 to 6 mbp PET reconstructions.

Results: Of all patient-dependent parameters, body mass showed the strongest correlation (R = 0.6) with SNRnorm. Lesion detectability analysis showed no significant difference for 3-5 mbp compared with the complete 6 mbp PET reconstruction. The SUV measurements showed no significant (p > 0.05) differences across the reconstructions. Visual assessment revealed that an SNR of 6.2 results in PET scans with moderate to good image quality. A non-linear expression was derived to calculate the required (dose × acquisition time) product (DTP) for the chosen SNR level of 6.2 that would yield a more constant image quality.

Conclusion: Body mass can be used to predict Ga-DOTA-TATE PET image quality. The proposed non-linear dose regimen based on body mass standardizes the image quality while maintaining sufficient image quality for diagnosis.
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http://dx.doi.org/10.1186/s13550-020-0601-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085989PMC
March 2020

Clinical and Antitumor Immune Responses in Relapsed/Refractory Follicular Lymphoma Patients after Intranodal Injections of IFNα-Dendritic Cells and Rituximab: a Phase I Clinical Trial.

Clin Cancer Res 2019 09 6;25(17):5231-5241. Epub 2019 Jun 6.

Institute of Translational Pharmacology, CNR, Rome, Italy.

Purpose: This study was aimed at evaluating the feasibility, safety, immunologic and clinical responses in patients with follicular lymphoma treated with monocyte-derived dendritic cells generated in the presence of IFNα and GM-CSF (IFN-DC) in combination with low doses of rituximab.

Patients And Methods: Firstly, we analyzed and the immunologic properties of IFN-DC against follicular lymphoma. Thus, we performed a phase I trial in 8 patients with refractory and relapsed follicular lymphoma based on sequential intranodal injections of low-dose of rituximab and unloaded IFN-DC and report the safety, clinical, and immunologic results of the enrolled patients.

Results: Preclinical studies indicated that IFN-DC can synergize with rituximab leading to increased cytotoxicity and T-cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37%, and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11-47). Notably, following the combined therapy all patients showed induction/enhancement of T-cell responses by CD107 degranulation or IFNγ ELISPOT assay against patient-specific tumor IGHV sequences.

Conclusions: These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor-specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in patients with cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0709DOI Listing
September 2019

The metronomic all-oral DEVEC is an effective schedule in elderly patients with diffuse large b-cell lymphoma.

Invest New Drugs 2019 06 26;37(3):548-558. Epub 2019 Apr 26.

Hematology Unit, IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.

Metronomic-chemotherapy (M-CHT) has been rarely assessed in non-Hodgkin-lymphoma (NHL). Therefore, in 2011 we started experimenting a new all-oral M-CHT schedule termed DEVEC (Deltacortene®, etoposide, vinorelbine, cyclophosphamide, +/-Rituximab) in diffuse-large-B-cell lymphoma (DLBCL) patients. Methods Patients with stage Ib-IV were enrolled as follows: 1) treatment-naïve, frail ≥65y, or unfit ≥85y; and 2) relapsed/refractory (R/R) ≥55y. Data were prospectively collected from six Italian centres and compared for efficacy to two reference groups, treated with established iv Rituximab-CHT in 1 and 2 line respectively. Results from April-2011 to March-2018, 17/51(33%) naïve, 21/51(41%) refractory and 13/51(25.5%) relapsed patients started DEVEC; 39/51(76.5%) were de-novo DLBCL; 10/51(19.6%) transformed-DLBCL and 2/51(3.9%) unclassifiable-DLBCL/classical-Hodgkin-lymphoma. The median age was 85y (range=77-93) and 78y (range=57-91) in naïve and R/R respectively and overall the DEVEC patients had very poor features compared to the reference. The rate of grade≥3 haematological-AEs was 43%(95CI=29-58%): G3-neutropenia was the most frequent; grade≥3 extra-haematological-AEs was 13.7% (95%CI=5.4-25.9%), the most frequent was infection. One-year OS and PFS were 67% and 61% for naive, 60% and 50% for reference-naïve respectively; Cox proportional hazard ratio (Cox-PH-ratio) for OS and PFS were 0.69 (95%CI=0.27-1.76;p=.441) and 0.68 (95%CI=0.28-1.62;p=.381) respectively. One-year OS and PFS were 48% and 39% in the R/R, 36% and 17% in the reference-R/R respectively; Cox-PH-ratio for OS and PFS, were 0.76 (95%CI=0.42-1.40; p=.386) and 0.48 (95%CI=0.28-0.82; p=.007) respectively. Conclusion The favourable activity of DEVEC compared to a real-life series and the convenience of an oral administration, may possibly lay the groundwork for a paradigm-shift in the treatment of elderly DLBCL.
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http://dx.doi.org/10.1007/s10637-019-00769-5DOI Listing
June 2019

Antibiotic Exposure and the Risk of Food Allergy: Evidence in the US Medicaid Pediatric Population.

J Allergy Clin Immunol Pract 2019 02 20;7(2):492-499. Epub 2018 Nov 20.

Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC. Electronic address:

Background: Food allergy is a significant public health concern in the United States, especially in the pediatric population. It places substantial clinical and economic burdens on the health care system. Exposure to antibiotics in early childhood is thought to increase the risk of subsequent food allergy.

Objective: To examine the impact of exposure to antibiotics early in life on time to development of food allergy.

Methods: We conducted a population-based matched cohort study using Medicaid data from 28 states. Antibiotic nonusers were matched 1:1 to antibiotic users on date of birth, sex, race, and state. A Cox proportional hazards regression model was used to evaluate the effect of antibiotic exposure on time to development of food allergy. Sensitivity analyses were performed to assess the robustness of study findings.

Results: We matched 500,647 antibiotic nonusers to 500,647 antibiotic users in the Medicaid pediatric population. In the adjusted Cox proportional hazards regression analysis, antibiotic exposure was significantly associated with faster development of food allergy (hazard ratio, 1.40; 95% CI, 1.34-1.45). The magnitude and significance of the association between antibiotic exposure and food allergy did not change in the sensitivity analyses. A significant association between antibiotic exposure and faster development of food allergy was found in 17 of 28 states.

Conclusion: Compared with antibiotic nonusers, children with antibiotic prescription had an increased risk of food allergy.
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http://dx.doi.org/10.1016/j.jaip.2018.09.036DOI Listing
February 2019

The significance of serum immunoglobulin paraprotein in diffuse large B-cell lymphoma.

Br J Haematol 2018 09 17;182(5):741-742. Epub 2017 Aug 17.

Department of Clinical and Molecular Medicine, Pathology Unit, La Sapienza University, Azienda ospedaliera universitaria Sant'Andrea, Rome, Italy.

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http://dx.doi.org/10.1111/bjh.14873DOI Listing
September 2018

Peripheral blood T cell alterations in newly diagnosed diffuse large B cell lymphoma patients and their long-term dynamics upon rituximab-based chemoimmunotherapy.

Cancer Immunol Immunother 2017 Oct 29;66(10):1295-1306. Epub 2017 May 29.

Department of Experimental Medicine, University La Sapienza, Viale Regina Elena 324, 00161, Rome, Italy.

The importance of T cell-dependent immune responses in achieving long-term cure of chemoimmunotherapy-treated cancer patients is underscored by the recently described "vaccinal effect" exerted by therapeutic mAbs. In accordance, pre- and post-therapy peripheral blood lymphopenia represents a well-established negative prognostic factor in DLBCL. We analyzed the phenotypic and functional (IFNγ production, and Granzyme B (GrzB) cytotoxic granule marker expression) profile of peripheral blood T lymphocyte subsets ("conventional" CD4 and CD8, FOXP3CD25 Treg, and "innate-like" CD56) in DLBCL patients at diagnosis, and assessed the long-term impact of R-CHOP chemoimmunotherapy, in a prospective study. At diagnosis, DLBCL patients showed lower lymphocyte counts, due to selective decrement of CD4 T (including Treg) and B lymphocytes. While all T cell subsets transiently decreased during therapy, CD4 T cell and Treg remained significantly lower than controls, up to 1 year after R-CHOP. Phenotypically skewed profile of CD4 and CD8 T cell subsets associated with higher frequencies of IFNγ and GrzB cells at diagnosis, that transiently decreased during therapy, and re-attained persistently elevated levels, till up to 1 year after therapy. Differently, the pre-therapy elevated levels of circulating monocytes, and of plasma IL-6 and IL-10 rapidly normalized upon R-CHOP. In sum, we describe a quantitatively and functionally altered status of the peripheral blood T cell compartment in DLBCL patients at diagnosis, that persists long-term after tumor eradication, and it is only transiently perturbed by R-CHOP chemoimmunotherapy. Moreover, data suggest the association of selected T cell functional features with DLBCL phenotype, and with therapy outcome.
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http://dx.doi.org/10.1007/s00262-017-2026-7DOI Listing
October 2017

Antibiotic prescription and food allergy in young children.

Allergy Asthma Clin Immunol 2016 17;12:41. Epub 2016 Aug 17.

Department of Internal Medicine; Division of Allergy, Asthma and Immunology, University of South Carolina School of Medicine, Columbia, SC USA.

Background: To assess the relationship between any systemic antibiotic prescription within the first year of life and the presence of an ICD-9-CM diagnosis code for food allergy (FA).

Methods: This was a matched case-control study conducted using South Carolina Medicaid administrative data. FA cases born between 2007 and 2009 were matched to controls without FA on birth month/year, sex, race/ethnicity. Conditional logistic regression was used to model the adjusted odds ratio (aOR) of FA diagnosis. All models were adjusted for presence of asthma, wheeze, or atopic dermatitis.

Results: A total of 1504 cases and 5995 controls were identified. Receipt of an antibiotic prescription within the initial 12 months of life was associated with FA diagnosis in unadjusted and adjusted models (aOR 1.21; 95 % CI 1.06-1.39). Compared to children with no antibiotic prescriptions, a linear increase in the aOR was seen with increasing antibiotic prescriptions. Children receiving five or more (aOR 1.64; 95 % CI 1.31-2.05) antibiotic prescriptions were significantly associated with FA diagnosis. The strongest association was noted among recipients of cephalosporin and sulfonamide antibiotics in both unadjusted and adjusted models.

Conclusions: Receipt of antibiotic prescription in the first year of life is associated with FA diagnosis code in young children after controlling for common covariates. Multiple antibiotic prescriptions are more strongly associated with increases in the odds of FA diagnosis.
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http://dx.doi.org/10.1186/s13223-016-0148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988015PMC
August 2016

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients.

Oncoimmunology 2015 Mar 7;4(3):e990773. Epub 2015 Jan 7.

Department of Experimental Medicine; Sapienza University ; Rome, Italy.

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56 and CD16 NK cells, and a higher frequency of GrzB cells in CD56, CD56, and CD16 NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon γ (IFNγ) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower "natural" cytotoxicity. A marked and prolonged therapy-induced reduction of both "natural" and CD16-dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56 subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNγ production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies.
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http://dx.doi.org/10.4161/2162402X.2014.990773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404844PMC
March 2015

The immunoglobulin isotype matters in diffuse-large-B-cell lymphoma with serum paraproteinaemia.

Ann Hematol 2015 Apr 6;94(4):681-2. Epub 2014 Sep 6.

Hematology Unit, Sant'Andrea Hospital, Department of Clinical and Molecular Medicine La Sapienza University, Rome, Italy,

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http://dx.doi.org/10.1007/s00277-014-2201-2DOI Listing
April 2015

Clinicopathologic characterization of diffuse-large-B-cell lymphoma with an associated serum monoclonal IgM component.

PLoS One 2014 4;9(4):e93903. Epub 2014 Apr 4.

Pathology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, La Sapienza University, Rome, Italy.

Recently, diffuse-large-B-cell lymphoma (DLBCL) associated with serum IgM monoclonal component (MC) has been shown to be a very poor prognostic subset although, detailed pathological and molecular data are still lacking. In the present study, the clinicopathological features and survival of IgM-secreting DLBCL were analyzed and compared to non-secreting cases in a series of 151 conventional DLBCL treated with R-CHOP. IgM MC was detected in 19 (12.5%) out of 151 patients at disease onset. In 17 of these cases secretion was likely due to the neoplastic clone, as suggested by the expression of heavy chain IgM protein in the cytoplasm of tumor cells. In IgM-secreting cases immunoblastic features (p<.0001), non-GCB-type (p = .002) stage III-IV(p = .003), ≥ 2 extra nodal sites (p<.0001), bone-marrow (p = .002), central-nervous-system (CNS) involvement at disease onset or relapse (p<.0001), IPI-score 3-5 (p = .009) and failure to achieve complete remission (p = .005), were significantly more frequent. FISH analyses for BCL2, BCL6 and MYC gene rearrangements detected only two cases harboring BCL2 gene translocation and in one case a concomitant BCL6 gene translocation was also observed. None of the IgM-secreting DLBCL was found to have L265P mutation of MYD88 gene. Thirty-six month event-free (11.8% vs 66.4% p<.0001), progression-free (23.5% vs 75.7%, p<.0001) and overall (47.1% vs 74.8%, p<.0001) survivals were significantly worse in the IgM-secreting group. In multivariate analysis IgM-secreting (p = .005, expB = 0.339, CI = 0.160-0.716) and IPI-score 3-5 (p = .010, expB = 0.274, CI = 0.102-0.737) were the only significant factors for progression-free-survival. Notably, four relapsed patients, who were treated with salvage immunochemotherapy combined with bortezomib or lenalidomide, achieved lasting remission. Our data suggests that IgM-secreting cases are a distinct subset of DLBCL, originating from activated-B-cells with terminally differentiated features, prevalent extra nodal dissemination and at high risk of CNS involvement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093903PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976325PMC
January 2015

Metronomic chemotherapy for cancer treatment: a decade of clinical studies.

Cancer Chemother Pharmacol 2013 Jul 9;72(1):13-33. Epub 2013 Mar 9.

Department of Oncology, Faculty of Medicine and Psychology, Sapienza University, Sant' Andrea Hospital, Via di Grottarossa 1035-1039, 00189, Rome, Italy.

Purpose: Over the past few years, more and more new selective molecules directed against specific cellular targets have become available for cancer therapy, leading to impressive improvements. In this evolving scenario, a new way of delivering older cytotoxic drugs has also been developing. Many studies demonstrated that several cytotoxic drugs have antiangiogenic properties if administered frequently and at lower doses compared with standard schedules containing maximal tolerated doses (MTD). Such a new strategy, named metronomic chemotherapy, focuses on a different target: the slowly proliferating tumour endothelial cells. About 10 years ago, metronomic chemotherapy was firstly enunciated and hereafter many clinical experiences were published related to almost any cancer disease. This review analyses available studies dealing with metronomic chemotherapy and its combination with several targeted agents in solid tumours.

Methods: A computerized literature search of MEDLINE was performed using the following search terms: metronomic OR "continuous low dose" AND chemotherapy AND cancer OR solid tumours.

Results: Satisfactory results have been achieved in diverse tumour types, such as breast and prostate cancer or paediatric sarcomas. Moreover, many studies have reported that metronomic chemotherapy determined minimal toxicity compared to MTD chemotherapy. Overall, published series on metronomic schedules are very heterogeneous often reporting on retrospective data, while only very few studies were randomized trials. These limitations still prevent to draw definitive conclusions in diverse tumour types.

Conclusions: Large well-designed studies are eagerly awaited for confirming the promises of metronomic schedules and their combinations with targeted molecules.
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http://dx.doi.org/10.1007/s00280-013-2125-xDOI Listing
July 2013

'Les liaisons dangereuses': Hepatitis C, Rituximab and B-cell non-Hodgkin's lymphomas.

World J Gastrointest Pharmacol Ther 2012 Apr;3(2):21-8

Massimo Marignani, Michela di Fonzo, Paola Begini, Elia Gigante, Ilaria Deli, Sara Gallina, Emanuela de Santis, Gianfranco Delle Fave, Department of Digestive and Liver Disease, School of Medicine and Psychology University "Sapienza", Azienda Ospedaliera S. Andrea, Via Grottarossa, 1035-1039, 00189 Rome, Italy.

Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin's lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with Rituximab-containing regimens. In this paper we review the recent data regarding the effects of Rituximab in NHL patients with HCV infection. We also added a section devoted to improving communication between oncohaematologists and hepatologists. Furthermore, we propose a common methodological ground to study hepatic toxicity emerging during chemotherapy.
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http://dx.doi.org/10.4292/wjgpt.v3.i2.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348959PMC
April 2012

Use of interim [18F]fluorodeoxyglucose-positron emission tomography is not justified in diffuse large B-cell lymphoma during first-line immunochemotherapy.

Leuk Lymphoma 2012 Feb 23;53(2):263-9. Epub 2011 Sep 23.

Department of Hematology, AO Sant'Andrea, La Sapienza University, Rome, Italy.

In diffuse large B-cell lymphoma (DLBCL), the response to first-line immunochemotherapy remains somewhat unpredictable. Interim [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET) (PET-int) analysis could be an important tool in the prompt shift to intensified regimens. We prospectively evaluated the effectiveness of PET-int carried out at mid-treatment with standard immunochemotherapy in predicting relapse in a series of 85 consecutive patients with DLBCL. PET-int results were dichotomized as positive or negative using the recently validated five-point scale scoring system. This examination was also compared with interim computed tomography (CT-int) and final PET (PET-fin). End-points were: complete remission (CR), positive predictive value (PPV) of refractoriness and relapse, negative predictive value (NPV), overall survival (OS) and progression-free survival (PFS). Observation time was fixed to 24 months unless preceded by a DLBCL-related event. The PPV of PET-int was 58% and the NPV was 77%. CR was correlated with both PET-int and CT-int (p < 0.0001), but in multivariate analysis only CT-int was correlated with CR (p = 0.002). CT-int and PET-fin were predictive of both OS and PFS, whereas PET-int was predictive only of OS (p = 0.013). In Cox regression only PET-fin was predictive for both OS (p = 0.004) and PFS (p = 0.005). PET-int was unable to discriminate those chemosensitive patients who would later relapse. We therefore believe that the use of this expensive radioactive tool is not justified as an interim analysis.
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http://dx.doi.org/10.3109/10428194.2011.614704DOI Listing
February 2012

Specific effects exerted by B-lymphoproliferative diseases on peripheral T-lymphocyte protein expression.

Br J Haematol 2010 Aug 6;150(4):463-72. Epub 2010 Jul 6.

2nd Faculty of Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Italy.

A proteomic approach was applied to study the protein expression profile of peripheral T-cells derived from patients at the onset of different B-lymphoproliferative diseases, because a rising interest in specific actions played by T-cells in such pathologies has emerged. Decreased levels of profilin-1 and cofilin-1 and increased levels of coronin1A and prohibitin were found in patients, compared with healthy controls. The protein-protein interaction network of these proteins was studied using a web-based bioinformatics tool, highlighting the actin cytoskeleton regulation as the main biological process involved in peripheral T-cells of such patients. Unsupervised cluster analysis of protein expression data shows that the recorded alteration of T-cell proteome was specifically induced by B-cell pathologies.
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http://dx.doi.org/10.1111/j.1365-2141.2010.08285.xDOI Listing
August 2010

HCV-positive status and hepatitis flares in patients with B-cell non-Hodgkin's lymphoma treated with rituximab-containing regimens.

Dig Liver Dis 2011 Feb 15;43(2):139-42. Epub 2010 Jun 15.

Digestive and Liver Disease Dpt, Azienda Ospedaliera S Andrea, Via Grottarossa 1035-1039, 00189 Rome, Italy.

Background: Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin's lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with rituximab-containing regimens.

Aim: to evaluate the liver-related effects of rituximab-containing regimens on HCV-positive CD20-positive B-cell NHL patients.

Patients And Methods: Retrospective analysis of 104 consecutive patients. HCV status was determined, and development of hepatitis flares analysed.

Results: Nine patients (8.6%) were HCV-positive. No correlation was shown between viral load and alanine transaminase levels. Three of the 9 HCV-positive, and none of the 95 HCV-negative developed hepatitis flares (p<0.001). At the 12-month follow-up hepatitis flare patients were alive and in remission for their haematological disease and no hepatitis flares, liver-related death had developed.

Conclusions: HCV-positive status may represent a risk factor for the development of hepatic flares in B-cell NHL patients receiving rituximab-containing regimens. Despite the increase in liver function tests, there were no major clinical events.
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http://dx.doi.org/10.1016/j.dld.2010.05.010DOI Listing
February 2011

Hepatitis B virus infection.

N Engl J Med 2009 Jan;360(3):304-5; author reply 305-6

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January 2009

Combined analysis of bcl-2 and MDR1 proteins in 256 cases of acute myeloid leukemia.

Haematologica 2004 Aug;89(8):934-9

Cattedra di Ematologia, Università di Roma Tor Vergata, Divisione di Ematologia, Osp.S.Eugenio, p.le dell'Umanesimo 10, 00144 Rome, Italy.

Background And Objectives: The objective of this study was to investigate the expression of MDR1 and bcl-2 proteins in de novo acute myeloid leukemia (AML).

Design And Methods: The expression of MDR1 and bcl-2 was analyzed by flow cytometry in a large series of 256 consecutive cases of AML. The results were recorded as percentage of positivity and relative mean fluorescence intensity (rMFI). To determine individual protein levels, an index which equals the product of the percentage of positive cells and rMFI was generated.

Results: Using cut-offs of >or=800 and 300 of the index value for bcl-2 and MDR1 expression, respectively, we identified 4 different classes of AML: 1) double negative; 2) single positive bcl-2+/MDR1-; 3) single positive bcl-2-/MDR1+; 4) double positive. The highest incidence of double negative cases was observed in the M2 class whereas double positive cases occurred more frequently in the M4, M5 and M6 subgroups. Seventy-eight percent and 71% of M0 and M1, respectively, showed single positive bcl-2+/MDR1- expression (p = 0.00001). Twenty-eight percent of patients belonging to the double positive category achieved complete remission, whereas for double negative, single positive bcl-2+MDR1- and single positive bcl-2-/MDR1+ category, the complete remission rate was 69%, 52% and 56%, respectively (p = 0.00038). In multivariate analysis, the double positive status independently affected frequency of complete remission (p = 0.008).

Interpretation And Conclusions: Bcl-2 is over-expressed in CD34+ AML; conversely, MDR1 is over-expressed in CD34- AML. However, the combined expression of the two proteins defines a subset of AML with a very poor prognosis.
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August 2004

Chromosomal aberration of the 11q23 locus in acute leukemia and frequency of MLL gene translocation: results in 378 adult patients.

Am J Clin Pathol 2004 Aug;122(2):298-306

Department of Hematology, S'Eugenio Hospital, University of Tor Vergata, Rome, Italy.

Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chromosome change observed in 3% to 7% of acute lymphoblastic leukemias and in 3% to 4% of acute myeloblastic leukemias. The resolution of conventional cytogenetics (CC) in detecting 11q23 rearrangement is limited when the translocative partner has a telomeric location; furthermore, CC can barely discriminate between true 11q23+/MLL+ and rearrangements clustering within the 11q22 to approximately 25 region without MLL involvement (MLL-). We characterized a series of 378 consecutive patients with adult acute leukemia by using CC, fluorescence in situ hybridization (FISH), and multiplex karyotyping (M-FISH) analysis. Our aim was to define the frequency of cryptic MLL+ cases and the frequency of MLL+ within 11q22 to approximately 25+ cases. As expected, FISH was more sensitive than CC in detecting MLL+ cases, but rather unexpectedly, 9 (45%) of 20 patients with 11q22 to approximately 25+ were MLL-. A better characterization of 11q22 to approximately 25+/MLL- leukemias is relevant for the identification of new, recurrent translocations. Moreover, these cases should be readily distinguishable from 11q23+/MLL+ cases. We recommend that karyotypic analysis always be complemented by molecular or FISH methods to unravel MLL rearrangements.
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http://dx.doi.org/10.1309/RX27-R8GJ-QM33-0C22DOI Listing
August 2004

Clinical relevance of minimal residual disease detection in adult acute myeloid leukemia.

J Hematother Stem Cell Res 2002 Apr;11(2):349-57

Cattedra di Ematologia, Università di Roma "Tor Vergata," Divisione di Ematologia, Osp.S.Eugenio, P.le dell'Umanesimo 10-00144, Rome, Italy.

We have used flow cytometry to quantify minimal residual disease (MRD) in 63 patients with acute myeloid leukemia (AML). No significant correlation was found between the level of MRD after induction and disease outcome. After consolidation, a threshold of 3.5 x 10(-4) residual leukemic cells divided the 57 evaluable patients into two distinct groups: the MRDCons(+) and the MRDCons(-) group, with a relapse rate of 81% (22/27) and 27% (8/30), respectively (p = 0.000035). Although not correlated with prognosis, the level of MRD after induction course affected the degree of cytoreduction achieved with consolidation. In fact, the patients who entered a MRDCons(-) status had a median number of leukemic residual cells of 1.8 x 10(-4) after induction; at the same stage, the bone marrow of patients who were in a MRDCons(+) condition harbored a median level of 1.7 x 10(-3) malignant residual cells (p = 0.00073). The MRDCons(+) status also correlated significantly with poor/intermediate risk cytogenetics, MDR1 phenotype, short duration of overall survival, and relapse-free survival (p = 0.024, 0.021, 0.00001, and 0.00001, respectively). In multivariate analysis, the MRDCons(+) status was associated with a high probability of relapse (p < 0.00026) and short duration of relapse free survival (p = 0.008). Stem cell transplantation did not seem to alter the prognostic impact of high levels of MRD after consolidation: within the MRDCons(+) group, the relapse rate after transplant was 78%. Thus, a MRD > or = 3.5 x 10(-4) leukemic cells at the end of consolidation strongly predicts relapse, and is significantly associated with MDR1-positive phenotype and intermediate/unfavorable cytogenetics.
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http://dx.doi.org/10.1089/152581602753658538DOI Listing
April 2002