Simona Scalone

Catheter-Related Bacteremia Due to Kocuria kristinae in a Patient with Ovarian Cancer

ABSTRACT We report on the first case of a catheter-related recurrent bacteremia caused by Kocuria kristinae, a gram-positive microorganism belonging to the family Micrococcaceae, in a 51-year-old woman with ovarian cancer. This unusual pathogen may cause opportunistic infections in patients with severe underlying diseases.

Long-term, weekly one-hour infusion of paclitaxel in patients with metastatic breast cancer: A phase II monoinstitutional study

Aims and background A dose-dense therapy with weekly paclitaxel given as a 1-hr infusion yielded a 53% overall response rate in breast cancer patients resistant to anthracyclines, with a remarkable lack of neutropenia (Seidman, 1998). We performed a monoinstitutional phase II trial in order to confirm these interesting results. Patients and methods Eligibility criteria included advanced breast cancer and no taxane pretreatment. Paclitaxel was administered weekly at the dose of 90 mg/m2 (60 mg/m2 in patients at high risk of toxicity) by 1-hr iv infusion. Fifty-eight patients entered the trial. Median age was 54 years (range, 38-72). Performance status was good (median 1; range, 0-2). Fifty-two patients were pretreated with anthracyclines. Results A total of 1,004 weekly paclitaxel infusions were administered (median, 19 per patient; range, 4-43). The median delivered dose intensity was 67.4 mg/m2/week (range, 43-86). Twenty-eight of the 58 assessable patients obtained an objective response (48%), 15 had stable disease (26%) and 15 progressed (26%). The overall response rate was 48% (95% confidence interval, 35-61%) with 5 complete responses (8%). In anthracycline-pretreated patients, 23/52 (44%) responses were observed. Median duration of response was 5 months (range, 3-27). Toxicity was acceptable apart from a case of pulmonary embolism in a 70-year-old patient, 1 case of congestive heart failure in an anthracycline-pretreated patient aged 64, and 9 cases of G3 neutropenia. Peripheral neuropathy was observed in 38 patients (64%), usually of a mild grade; alopecia in 45 patients (78%) and onychopathy in 16 (28%), usually of a mild grade apart from 2 cases requiring treatment interruption. Tachycardia and atrial fibrillation occurred in a 55-year-old woman. Conclusions Our data seem to confirm the activity and safety of this approach even in a heavily pretreated population of patients. Its combination with other active drugs needs to be further investigated in clinical trials.

Clinical validity of a DPYD-based pharmacogenetic test to predict severe toxicity to fluoropyrimidines.

Pre‐therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL)‐related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD‐rs3918290, DPYD‐rs55886062, DPYD‐rs67376798, DPYD‐rs2297595, DPYD‐rs1801160, DPYD‐rs1801158, DPYD‐rs1801159, DPYD‐rs17376848) for association with Grade ≥3 toxicity, developed within the first three cycles of therapy. DPYD‐rs3918290 and DPYD‐rs67376798 were associated to Grade ≥3 toxicity after bootstrap validation and Bonferroni correction (p = 0.003, p = 0.048). DPYD‐rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD‐rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD‐rs3918290, DPYD‐rs55886062 and DPYD‐rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD‐rs3918290, DPYD‐rs55886062 or DPYD‐rs67376798 allele, not developing Grade ≥3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade ≥3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD‐rs3918290, DPYD‐rs55886062, DPYD‐rs67376798 genotyping test to prevent FL‐related Grade ≥3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.

A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies

IntroductionThe clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy.MethodsBlood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Students t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data.ResultsThe proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1β, IL-8, IL-6, IL-10).ConclusionsCompared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset of patients with the use of drugs acting through, but also promoting, immune-mediated effects.

A phase II study of liposomal doxorubicin in recurrent epithelial ovarian carcinoma

Background We conducted a phase II trial to evaluate the efficacy and safety of liposomal formulation of doxorubicin in recurrent ovarian carcinoma patients. Methods Thirty patients were included in the study after having obtained an informed consent. Their main characteristics were: median age, 64 years (range, 45-80), ECOG performance status 0 in 17 patients (56%), 1 in 11 patients (36%) and 2 in 2 patients (6.6%). Eighteen patients had metastatic disease and 12 locally advanced disease. All patients were pretreated with a platinum-based chemotherapy: 3 were considered refractory to platinum (progression or stable disease), 2 were platinum resistant (relapse <12 months), and 7 were platinum sensitive (relapse ≥12 months). Treatment consisted of liposomal doxorubicin, 50 mg/m2 every 4 weeks. Results The overall response rate was 26.6%, with 2 complete responses and 6 partial responses lasting 3.5 months. The incidence of grade 3-4 toxicity was 23.3% for neutropenia, 10% for mucositis and 10% for plantar-palmar erythrodysesthesia. Median survival was 12+ months (range, 2-26+). Conclusions Liposomal doxorubicin appears to be a moderately active drug in pretreated patients, and its activity seems to be similar to that reported for other active regimens in terms of response rate. The toxicological profile of liposomal doxorubicin suggests that it may be combined with other drugs in the treatment of patients with ovarian cancer.

Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy.

BackgroundLocally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction.MethodsThe immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8+ T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-γ ELISPOT and IFN-γ/IL-2 DualSpot assays.ResultsAfter NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti-tumor T cell responses highlighted sustained levels of CD8+ T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response.ConclusionsThese results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients.Trail registration: Trial registration number: NCT02307227, registered on ClinicalTrials.gov (http://www.clinicaltrials.gov, November 26, 2014).

Therapeutic management of breast cancer in the elderly

Introduction: Over the last few decades, the population of developed countries has aged. Breast cancer is the most common cancer among the increased numbers of older women. The choice of adjuvant treatment is particularly difficult in older women because the oncologist has to balance reduction of the risk of recurrence with patient-related comorbidities that may increase the risk of treatment-related toxicity and influence patient survival. Areas covered: This article describes the concept of a comprehensive geriatric assessment and reviews the current literature on biological and pathological characteristics of breast cancer in the elderly, including genomic assays recently available in the clinic. Endocrine, targeted and chemotherapy treatments both in adjuvant and metastatic setting are also covered. Expert opinion: A new generation of studies aimed to re-evaluate treatments in the various subtypes of breast cancer is needed. Whether this will be possible through prospective studies (especially in the adjuvant setting) is unknown. An alternative direction for further research in the elderly could be a reappraisal of old studies with carefully planned subtype analyses. Whatever the direction, the management of elderly breast-cancer patients is inherently multidisciplinary: the contribution of medical and allied health professionals is essential to the provision of optimal care.

Prognostic Role of Serum Antibody Immunity to p53 Oncogenic Protein in Ovarian Cancer: A Systematic Review and a Meta-Analysis

Objective Serum p53 autoantibodies (p53-AAbs) are the product of an endogenous immune response against p53 overexpression driven by the ovarian tumour. The p53-AAbs are detectable only in a subset of patients. To date, the evidence of an association between the presence of p53-AAbs and ovarian cancer outcomes has been poorly investigated. Methods A systematic literature search was performed to identify eligible studies investigating the association of serum p53-AAbs and overall survival (OS) and disease free survival (DFS). Associations between presence of serum p53-AAbs and baseline tumour characteristics were also evaluated. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were computed to estimate the prognostic impact of serum p53-AAbs. Heterogeneity between studies was assessed. Results A total of 583 patients (7 studies) for OS and 356 patients (4 studies) for DFS were included in the meta-analysis. Presence of p53-AAbs was not associated to OS (pooled uni- multivariate HR = 1.09; 95% CI: 0.55–2.16), and a large heterogeneity was found. When only multivariate HRs were pooled together (4 studies), presence of p53-AAbs was significantly associated to a better OS (pooled HR = 0.57; 95% CI: 0.40–0.81), and no significant heterogeneity was observed. A reduced DFS was associated to p53-AAbs (pooled uni- multivariate HR = 1.37; 95% CI: 0.83–2.25), though not significantly and with a moderate heterogeneity. Conclusions The prognostic significance of serum p53-AAbs in ovarian cancer was diverging according to uni or multivariate models used. Since the results of this work were based on only few investigations, large prospective studies are needed to better define the role of antibody immunity against p53.

Vinorelbine-induced acute reversible peripheral neuropathy in a patient with ovarian carcinoma pretreated with carboplatin and paclitaxel

Vinorelbine is a semisynthetic derivative of vinblastine commonly used for the treatment of advanced breast cancer and non-small cell lung cancer. It has also been tested in other malignancies including ovarian and prostatic carcinoma as well as lymphoma (1). Its antitumoral activity is dependent on the high affinity for mitotic tubulin, which results in the inhibition of both microtubule formation and metaphase cell division. Vinorelbine differs from other vinca alkaloids with regard to its toxicity profile: it seems to be less neurotoxic because of its lower affinity for axonal microtubules. Mild to moderate peripheral neuropathy, principally characterized by sensory effects such as loss of deep tendon reflexes, paresthesia and hypoesthesia, occurs in 6% to 31% of patients; other frequently observed neurotoxic effects include constipation observed in about 30% of subjects, whereas severe toxicity occurs in 2 /3% (1). Vinorelbine-associated neuropathy has also been shown to increase with cumulative doses and in patients with pre-existing peripheral neurological impairment; for example, in the case of diabetes mellitus, elevated alcohol consumption and inherited neuropathy. Moreover, concomitant or previous treatment with other potentially neurotoxic drugs such as cisplatin and paclitaxel is associated with a moderate increase in the incidence of acute, severe neurotoxicity. In this report, we describe a case of vinorelbine-related severe neuropathy following first-line carboplatin and second-line paclitaxel chemotherapy. Moreover, we provide a general review of chemotherapy-induced neurotoxicity, focusing on cisplatin compounds, taxanes and vinca alkaloids. Case report . An 82-year-old woman without any relevant past medical history was diagnosed with inoperable serous-papillary ovarian carcinoma in January 2002. She received four cycles of carboplatin (AUC 4) up to April 2002. Restaging evaluation with abdominal CT scan revealed disease stabilization. In May 2002, a bilateral salpingo-oophorectomy, total abdominal hysterectomy and omentectomy were performed. The pathological examination revealed a stage III bilateral poorly differentiated ovarian carcinoma. Thereafter, four further courses of chemotherapy with carboplatin were given with a decrease in the CA 125 level from 165 IU/ml to 65 IU/ml. In October 2002, treatment with weekly paclitaxel at a dosage of 80 mg/m was started because of an increase in the CA 125 level up to 125 IU/ml, even though an abdominal gynecological examination and abdominal CT scan were both negative. After the 15th administration of paclitaxel, treatment was discontinued because of progressive elevation of the CA 125 level and evidence of disease progression on CT scan. The patient did not complain of any symptoms of neuropathy at the time of paclitaxel discontinuation. Four weeks later, a third-line course of chemotherapy with vinorelbine was started. After the second infusion of vinorelbine, the patient developed a sudden, grade 3 sensory-motor neuropathy characterized by hypoestesia and mild paresthesia of the lower extremities associated with relevant neuromuscular impairment. The diagnostic work-up included a neurological examination, electromyography, a dorsolumbar spinal cord MRI and an abdominal CT scan. The clinical, electrophysiological and radiological findings strongly suggested an iatrogenic pathogenesis of the neuropathological manifestations. In fact, the MRI did not show any abnormal signal intensity and abnormal mass effect, whereas the neurological and electromyographic studies revealed a bilateral loss of the deep Achilles tendon reflexes, weakness of the lower limbs and a moderate grade paresis of the distal muscles. Vinorelbine administration was promptly stopped; treatment with vitamin B6 (900 mg/day) and gabapentin (900 mg/day) associated with physiotherapy was started. Thereafter, the dose of gabapentin was increased up to 2,400 mg/day. Gradual and progressive improvement in the signs and symptoms was noticed within a few weeks after discontinuation of vinorelbine. Up to four months from the toxic episode the neurological functions have almost completely recovered. Physiokinesis therapy is still ongoing while vitamin therapy has been stopped. Gabapentin is presently administered at the dosage of 300 mg twice daily. Discussion . Chemotherapy-induced neurotoxicity is a major clinical problem because it represents a dose-limiting side effect of a significant number of antineoplastic drugs and may lead to severe, disabling conditions, thus impairing quality of life (2 /6). Little is known about the mechanisms responsible for the development of neuropathy. For most neurotoxic agents, high-dose chemotherapy, combination chemotherapy, concomitant cranial CASE REPORT

Second-line chemotherapy in recurrent clear cell ovarian cancer: Results from the Multicenter Italian Trials in Ovarian cancer (MITO-9)

Background and Aims: Ovarian clear cell carcinoma (CCC) has a poorer prognosis than other subtypes of ovarian cancer. In this study, we evaluated the responsiveness to second-line chemotherapy in recurrent ovarian CCC. Methods: The MITO-9 project investigated a cohort of patients observed between 1991 and 2007 in 20 centers. We identified 72 out of 240 patients with recurrent disease (28% stage I-II and 72% stage III-IV at diagnosis). Results: In 56% of patients, the clear cell histology was pure. Twenty-five patients were platinum-resistant, 18 were platinum-sensitive with a platinum-free interval (PFI) of 6-12 months, and 29 had a PFI >12 months. Upon recurrence, 47% of patients were treated with platinum chemotherapy according to the PFI. The overall response rate (RR) to platinum was 80%, with 55, 100, and 80% RR in patients with PFI of 6-12, >12, and >24 months. The RR to nonplatinum agents in resistant patients was 33%. Among the nonplatinum agents used in primary and secondary resistant cases, gemcitabine, administered in 12 cases, had a higher activity (RR = 66%) compared to topotecan or liposomal doxorubicin (n = 31; RR = 33 and 10%, respectively). Conclusions: This study showed that the treatment of recurrent ovarian CCC should be based on the PFI as in the other subtypes. Data in platinum-resistant patients suggest gemcitabine as the drug with the highest activity. We recommend that gemcitabine be studied prospectively in a phase 2 trial.