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.

BACKGROUND: Locally 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. METHODS: The 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. RESULTS: After 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. CONCLUSIONS: These 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).

Effort myocardial ischemia during chemotherapy with 5-fluorouracil: an underestimated risk.

BACKGROUND: Effort-induced myocardial ischemia (EMI) has been seldom described. Aims of our study were (A) to evaluate the prevalence of EMI during long-lasting 5-FU infusion; (B) to identify possible risk factors of EMI during 5-FU infusion. PATIENTS AND METHODS: For the purpose (A), we prospectively evaluated a group of patients undergoing in-hospital continuous infusion (c.i.) of 5-FU. Patients with rest ischemia were excluded. Among 358 consecutive patients, 21 (5.9%) had rest ischemia; 109 could not perform a stress test. The remaining 228 patients underwent a treadmill stress test (TST) after >46 h of 5-FU infusion. For the purpose (B), we compared the characteristics of patients with EMI (including 3 previously described in a 2001 paper) with those without EMI. RESULTS: Among 228 patients, 16 (6.9%) had EMI. These 16 had a second TST after stopping 5-FU: in 14, it was negative, 2 patients with coronary artery disease had milder ischemia. The whole group of 231 (including 3 described in a previous paper) patients undergoing TST included 148 males and 83 females, with mean age of 57.5. Cardiovascular risk factors were present in 178 of them. Eight patients had ischemic heart disease. Among 19 patients with EMI, 7 had angina, 12 silent ischemia. ST segment at ECG was elevated in 10 patients, depressed in 9. Comparing the group with toxicity and the one without, the only significant difference was the complaint of atypical symptoms at rest before the TST. No difference was observed as regards: chemotherapy schedule (chronic c.i. in 49, 5 days in 178, FOLFOX type in 12), coronary risk factors or heart disease. CONCLUSIONS: EMI is as frequent as rest ischemia during 5-FU infusion. Patients undergoing 5-FU continuous infusions should be adviced to avoid unusual efforts, to refer any cardiac symptom, and should be investigated for EMI.

Evaluation of pemetrexed (Alimta, LY231514) as second-line chemotherapy in persistent or recurrent carcinoma of the cervix: the CERVIX 1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group.

BACKGROUND: The objective of the study was to estimate the antitumor activity of pemetrexed in patients with advanced/recurrent carcinoma of the cervix and to determine the nature and degree of toxicity. METHODS: A multicenter phase II trial was conducted by the Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO) Group. Patients with advanced/recurrent measurable carcinoma of the cervix that had failed one prior chemotherapy regimen in association or not with radiotherapy were treated with pemetrexed at a dose of 500 mg/m(2) every 21 days. All the patients had a measurable lesion according to RECIST criteria in a not previously irradiated field. RESULTS: From November 2006 to September 2008, 43 patients were entered by seven member institutions of the MITO-Group. A total of 164 cycles (median 2, range 1-9) were administered. The treatment was well tolerated. More serious toxic effects (grades 3 and 4) included leukopenia in 27.9% and neutropenia in 30.2% of patients. No treatment-related deaths were reported. Six patients (13.9%) had partial responses (at least a 30% decrease in the sum of longest diameter of target lesions taking as reference the baseline sum longest diameter) with a median response of 7 weeks (range 3-27). Twenty-three patients (53.4%) had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) and fourteen (32.5%) patients had progressive disease. Median progression-free survival was 10 weeks and overall survival was 35 weeks. CONCLUSION: Pemetrexed showed moderate activity against advanced/recurrent cervical cancer that had failed prior chemotherapy.

Biology, prognosis and response to therapy of breast carcinomas according to HER2 score.

BACKGROUND: The standardization of the HER2 score and recent changes in therapeutic modalities points to the need for a reevaluation of the role of HER2 in recently diagnosed breast carcinoma. PATIENTS AND METHODS: A multicenter, retrospective study of 1794 primary breast carcinomas diagnosed in Italy in 2000/2001 and scored in HER2 four categories according to immunohistochemistry was conducted. RESULTS: Ductal histotype, vascular invasion, grade, MIB1 positivity, estrogen and progesterone receptor expression differed significantly in HER2 3+ tumors compared with the other categories. HER2 2+ tumors almost showed values intermediate between those of the negative and the 3+ subgroups. The characteristics of HER2 1+ tumors were found to be in between those of HER2 0 and 2+ tumors. With a median follow-up of 54 months, HER2 3+ status was associated with higher relapse rates in node-positive and node-negative subgroups, while HER2 2+ only in node positive. Analysis of relapses according to type of therapy provided evidence of responsiveness of HER2-positive tumors to chemotherapy, especially taxanes. CONCLUSIONS: The present prognostic significance of HER2 is correlated to receptor expression level and points to the need to consider HER2 2+ and HER2 3+ tumors as distinct diseases with different outcomes and specific features.

Simplified gemcitabine and platin regimen in patients with advanced or metastatic non-small cell lung cancer (NSCLC) to be proposed as neoadjuvant therapy.

BACKGROUND: Chemotherapy of non-small-cell lung cancer (NSCLC) has been improved by the use of cis-platin (P) and the pyrimidine antimetabolite gemcitabine (G) (2',2'-difluorodeoxycytidine). GP regimens currently used in Italy for NSCLC were and are mainly based on G day 1, 8 and 15; P on day 2, every 28 days (4 Day-Hospital admissions per cycle). However, the third G dose is frequently omitted because of myelo-toxicity, with a consistent dose decrease of both G and P in comparison with the intended dose. The 24-h lag time from 1(st) G and P has not reasonable clinical pharmacology base. AIM OF THE STUDY: To have a simplified GP regimen based on two Day-Hospital admissions per cycle, with G on day 1 and 8, P after G on day 8; every 21 days, with the goal to use it in the neoadjuvant setting. MATERIAL AND METHODS: The study was designed as a controlled, prospective, multicentre investigation, based on G (1500 mg/m(2)) on day 1 and 8, and P (100 mg/m(2)) on day 8 immediately following G, administered on a 3-week cycle. Quality of life (EORTC) was valuated in 46 patients out of 95 valuable patients. Restaging procedures were repeated after the 3rd and the 6th cycle. RESULTS: Enrolled patients were 105 (stage IV: 63: IIIB: 29; IIIA: 13). GP cycles were 488 (1 to 6 per patient) 95 patients had at least 3 cycles and 59 of them had further 3 cycles. Myelotoxicity >or= g3 was mainly neutropenia, easily amenable with symptomatic and GCSF therapies (12.6% neutropenic fever); PNS toxicity occurred in 17.9% of patients. QoL was ameliorated (P < 0.05). Therapy was tolerable and gave a Response Rate (RR) of 52.3% after 3 cycles (Intention-to-treat analysis) and of 57.9% in 95 valuable patients who received at least 3 therapy cycles. CONCLUSION: Present results confirm a good efficacy and/or synergism of G to P, with G on day 1 and 8 and P on day 8. This two day-hospital admissions regimen is at least as good as more complex GP regimens, and may be proposed in the neoadjuvant setting.

Treatment of older breast cancer patients with high recurrence risk.

Adjuvant treatment of elderly women affected by breast cancer who have a high risk of recurrence is one of the most questionable issues in clinical oncology. The use of tamoxifen in women with hormone receptor-positive tumors is a relatively simple therapeutic option considering the favourable toxicity profile, whereas the administration of adjuvant chemotherapy is more complicated and a variety of aspects need to be considered. The estimated life expectancy, the presence and degree of comorbid conditions, the geriatric assessment and estimated benefit from treatment should be taken into account. Due to the lack of data from clinical trials in women over the age of 70, the approach is still experimental. Clinical trials evaluating the role of adjuvant chemotherapy in high risk patients are currently being developed and hopefully in the near future, more convincing data on the best drugs, regimens and benefits for the treatment of elderly breast cancer patients will become available.

Catheter-related bacteremia due to Kocuria kristinae in a patient with ovarian cancer.

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.

Occult small cell lung cancer associated with paraneoplastic neurologic syndrome: case report.

Cancer is often associated with paraneoplastic syndromes, which may be misinterpreted. We report a case of a patient with occult small cell lung cancer that was initially compounded by clinical features of a paraneoplastic neurologic syndrome. The presence of antineuronal antibodies and positron emission tomography scan guided the search for the underlying tumor. Following chemo-radiotherapy the patient showed no evidence of disease for the next 18 months, whereas only a slight improvement in the neurologic disorders was observed. The course of the small cell lung cancer was very indolent and the paraneoplastic neurologic syndrome did not worsen with the use of cisplatin.

Image-guided core breast biopsy: a suitable method for preoperative biological characterization of small (pT1) breast carcinomas.

Multiple prognostic indicators, namely histological grade and immunostaining for estrogen (ER) and progesterone receptors (PgR), MIB 1, bc1-2, and p53, were retrospectively determined on preoperative core biopsies from 75 patients with pT 1 breast carcinoma. The association of the preoperatively evaluated factors with those on the corresponding resected tumors (i.e. nodal status, histological grade, presence or absence of vascular invasion and necrosis) was assessed. In univariate analysis, histological grade on resected tumors was significantly associated with histological grade on core biopsy, p53 expression, MIB1 immunostaining. An inverse association was found between postoperative histologic grade and ER, PgR, and bc1-2. Necrosis was significantly associated with grade, p53, MIB1, and inversely with ER, PgR, and bc1-2. Nodal involvement and vascular invasion were significantly associated with MIB1. In multivariate analysis, histological grade and ER were the only independent core biopsy variables associated with postoperative histological grade and necrosis, respectively. This study showed that image-guided core biopsy is a suitable method that can be used to reveal some characteristics of the tumor biology in a preoperative stage.