Myositis/Myasthenia after Pembrolizumab in a Bladder Cancer Patient with an Autoimmunity-Associated HLA: Immune-Biological Evaluation and Case Report.

Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe immune-related (ir) adverse events (AEs). Here, we report the clinical and immune-biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.

Effectiveness of abiraterone acetate plus prednisone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer in a large prospective real-world cohort: the ABItude study.

BACKGROUND: Real-world data on chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone plus prednisone are limited, largely deriving from small retrospective studies. METHODS: ABitude is an Italian, observational, prospective, multicenter study of mCRPC patients receiving abiraterone plus prednisone in clinical practice. Chemotherapy-naïve mCRPC patients were consecutively enrolled at abiraterone start (February 2016 to June 2017) and are being followed for 3 years, with evaluation approximately every 6 months. Several clinical and patients reported outcomes were examined. RESULTS: In this second interim analysis, among 481 enrolled patients, 453 were evaluable for analyses. At baseline, the median age was 77 years and ~69% of patients had comorbidities (mainly cardiovascular diseases). Metastases were located mainly at bones and lymph nodes; 8.4% of patients had visceral metastases. During a median follow-up of 18 months, 1- and 2-year probability of radiographic progression-free survival were 73.9% and 56.2%, respectively; the corresponding rates for overall survival were 87.3% and 70.4%. In multivariable analyses, the number of bone metastases significantly affected radiographic progression-free survival and overall survival. During abiraterone plus prednisone treatment, 65% of patients had a ⩾50% prostate-specific antigen decline, and quality of life remained appreciably high. Among symptomatic patients according to the Brief Pain Inventory) (32%), scores significantly declined after 6 months of treatment. Overall, eight patients (1.7%) had serious adverse reactions to abiraterone. CONCLUSIONS: Abiraterone plus prednisone is effective and safe for chemotherapy-naïve mCRPC patients in clinical practice.

Mucinous histology of colon cancer predicts poor outcomes with FOLFOX regimen in metastatic colon cancer.

Mucinous adenocarcinoma (MA) of colorectal cancer seems associated with reduced responsiveness to chemotherapy. The overexpression of markers of resistance to fluorouracil and oxaliplatin has recently been demonstrated. We revised the outcomes of metastatic MA of the colon treated with FOLFOX. From January 2002 to December 2009, we treated 198 patients with metastatic colon cancer, of which 21 (10.6%) had diagnosis of MA and were compared with 42 control patients with non-mucinous adenocarcinoma (NMA). In MA group, three patients [14%; inhibitory concentration 95: ± 7.5%] reached partial response, and in NMA group, two patients obtained complete response and 16 obtained partial response with an overall response rate of 43% (inhibitory concentration 95: ± 7.6%) with a significant statistical difference (P = 0.027). Median progression-free survival for MA group was 4 months with respect to 8 months for NMA (P = 0.0001); regarding overall survival, we registered a median of 8 months with respect to 18 months for MA and NMA (P = 0.001). In multivariate analysis, MA histology, Eastern Cooperative Oncology Group performance status 2, more than two metastatic sites, and peritoneal metastatic involvement resulted in negative independent prognostic factors. Also in our study, MA is connected to poor prognosis and reduced activity of chemotherapy. In the absence of randomised studies, it may be convenient to analyse this subgroup of patients within the large trials carried out on colorectal cancer.

Critical issues on high-dose chemotherapy with autologous hematopoietic progenitor cell transplantation in breast cancer patients.

INTRODUCTION: High-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell transplantation (AHPCT) for high-risk (HR) or metastatic breast cancer (MBC) is no longer an option. AREAS COVERED: An expert panel including medical oncologists and hematologists produce an opinion paper on the use of HDC and AHPCT in BC patients and they explain why they believe that; despite inconclusive results thus far, this treatment should have an ongoing role in breast cancer management under clinical trials. EXPERT OPINION: HDC with AHPCT has become a safe treatment modality and an advantage in disease-free survival has been observed in most of the studies with HDC, with the caveat that today, even a limited relapse-free survival and progression-free survival benefit is sufficient for the approval of new antineoplastic agents. Moreover, in HRBC, an overall survival benefit by HDC could be achieved in the HER2-ve and triple-negative populations and, in this setting, HDC with AHPCT represents a therapeutic option that can be proposed to well-informed patients. In MBC, the HDC approach should be investigated further in selected patients with HER2-ve, chemosensitive disease. This paper is not intended to give any conclusion, but rather to open a debate on the value of HDC in HR and MBC.

Alkaline phosphatase levels as a prognostic factor in metastatic colorectal cancer treated with the FOLFOX 4 regimen: a monoinstitutional retrospective study.

AIMS AND BACKGROUND: Metastatic colorectal cancer has a heterogeneous behavior, and a set of patients will have minimal response and rapid disease progression. To understand this heterogeneity, studies have evaluated biological and clinical prognostic factors. Alkaline phosphatase seems to be a key prognostic factor, so we have reviewed the outcomes of our patients with respect to alkaline phosphatase levels. METHODS AND STUDY DESIGN: Between January 2003 and December 2008, we treated with the FOLFOX 4 regimen 103 consecutive patients with metastatic colorectal cancer. Thirty-two patients had alkaline phosphatase > or =300 U/l. RESULTS: Median time to progression was 4 months for patients with high alkaline phosphatase levels and 8 months for those with low alkaline phosphatase levels. Median overall survival was 8 and 17.5 months, respectively. Only 3 patients in the high alkaline phosphatase group obtained partial response (9.4%) compared to 3 complete responses and 24 partial responses (41.5%) in low alkaline phosphatase group. Toxicity was substantially different, with more grade 3-4 neutropenia, diarrhea and oral mucositis in the high than low alkaline phosphatase group. CONCLUSIONS: Alkaline phosphatase is an uncomplicated and potent prognostic factor. Patients with high alkaline phosphatase levels had a poor prognosis.

Current knowledge and future directions on bisphosphonate-related osteonecrosis of the jaw in cancer patients.

BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe adverse event of long-term use of bisphosphonates that heavily affects the quality of life of cancer patients. OBJECTIVE: To review epidemiologic data, pathobiology, risk factors, diagnosis and management of BRONJ. METHODS: Articles were identified by searching the PubMed and MEDLINE databases and recent meetings abstracts. RESULTS/CONCLUSION: BRONJ pathobiology is thought to be related to bisphosphonate-induced suppression of normal bone remodeling and impairment of bone blood flow. Dental extractions, daily masticatory traumas, oral infections, chemotherapy and antiangiogenic drugs can also play an active role. Collaboration between oncologists and dentists is essential to prevent BRONJ. A conservative approach based on pain control, oral rinses, antibiotics and limited debridement represents the current management. Optimization of therapy based on reduction of bisphosphonate doses or exposure time, newer bisphosphonates and biomolecular agents could favorably impact on BRONJ incidence.

Mitomycin C plus capecitabine (mixe) in anthracycline- and taxane-pretreated metastatic breast cancer. A multicenter phase II study.

BACKGROUND: Capecitabine is considered the treatment of choice for anthracycline- and taxane-pretreated metastatic breast cancer. Mitomycin C seems to improve the activity of capecitabine by up-regulation of thymidine phosphorylase. PATIENTS AND METHODS: Fifty-five women with metastatic breast cancer previously treated with anthracyclinetaxane were treated with mitomycin C 10 mg/m2 on day 1 every six weeks and capecitabine 1000 mg/m2 on days 2-15 every three weeks. RESULTS: An overall response rate of 38% was found, consisting of 3 (5%) complete responses (CR) and 18 (33%) partial responses (PR); 8 patients (14%) had a stable disease (SD) for more than 4 months. The combination was well-tolerated, with the main toxicities being neutropenia, diarrhea and fatigue; other toxicities were of mild to moderate intensity without impairment in the quality of life of the patients. CONCLUSION: Capecitabine is confirmed as the drug of choice in the treatment of anthracycline- and taxane-pretreated metastatic breast cancer and its combination with mitomycin appears to improve its efficacy.

Prospective multicenter study of combined treatment with chemotherapy and radiotherapy in breast cancer women with the rare clinical scenario of ipsilateral supraclavicular node recurrence without distant metastases.

PURPOSE: To evaluate the role of chemotherapy combined with curative radiotherapy in breast cancer patients who presented with recurrent ipsilateral supraclavicular lymph node metastases (ISLM) without "nonregional disease," we designed an observational study performed prospectively. PATIENTS AND METHODS: Forty-four consecutive patients with ISLM from breast cancer as part of recurrent regional disease without distant metastases were included in this study. All patients received chemotherapy with doxorubicin-based schema or paclitaxel for six courses and curative radiotherapy (60 Gy/30 fractions of 2 Gy/5 days a week). An "involved field" radiation was delivered during the interval between the third and fourth chemotherapy course; hormonal therapy was given based on receptor status. RESULTS: The rate of overall clinical response after chemotherapy and radiotherapy was 94.9%. Median time to progression and overall survival were 28 and 40 months, respectively; the 5-year actuarial overall survival and disease-free survival rates were 35% (95% confidence interval, 19-51) and 20% (95% confidence interval, 6-34), respectively. CONCLUSION: A curative course of intravenous chemotherapy and radical irradiation is feasible in patients with ISLM. All patients presenting recurrence in supraclavicular nodes should be treated with definitive locoregional treatments and systemic therapy because the outcomes are better than might be historically assumed.

Mitomycin C and capecitabine combination (MiXe) in heavily pretreated metastatic breast cancer patients. A dose-finding study.

BACKGROUND: No standard chemotherapy has been defined for metastatic breast cancer patients pretreated with anthracyclines and taxanes. In preclinical studies, mitomycin C (MMC) and capecitabine showed a synergistic effect by up-regulation of thymidine phosphorylase, and both drugs were active against breast cancer with a lack of overlapping toxicity, making their combination a well-tolerated regimen. PATIENTS AND METHODS: A dose-finding study was carried out in order to determine the maximum tolerable dose of MMC combined with fixed-dose capecitabine and to describe the dose-limiting toxicities. RESULTS: Twenty-one patients were enrolled, with metastatic breast cancer pretreated at least with anthracyclines and taxanes (3 at dose level I, 15 at dose level II, 3 at dose level III). At dose level III (MMC 12 mg/m2 and capecitabine 1000 mg/m2 days 2-15) dose-limiting toxicities were recorded in 2 patients (G4 thrombocytopenia, neutropenic fever, G4 neutropenia); dose level II (MMC 10 mg/m2 and capecitabine 1000 mg/m2 days 2-15) was extended for a better safety evaluation. No severe toxicity was noted at this dose level, and therefore this dose was recommend for the phase II study. With regard to activity, 4 partial responses and 2 stable diseases (28%) were recorded. CONCLUSION: Our data show that the combination is feasible, well tolerated and active in this set of patients.

Is weekly docetaxel an active and gentle chemotherapy in the treatment of metastatic breast cancer?

BACKGROUND: Docetaxel is a very active drug against breast cancer, but at the standard dose causes severe myelosuppression. In order to reduce the toxicity while maintaining the activity, weekly docetaxel administration was tested. PATIENTS AND METHODS: We enrolled 30 patients with metastatic breast cancer, who had been treated with intravenous infusion of weekly docetaxel 35 mg/m2 in 100 ml of normal saline over 30 minutes for six weeks, followed by two weeks' rest from docetaxel therapy (one cycle). RESULTS: The overall response rate was 33% (95% CI +/- 16.8%) and the estimated time to progression was 8 months. Acute toxicity was mild. Nail loss, excessive tearing and dysgeusia worsened the quality of life of the patients. CONCLUSION: Weekly docetaxel is an active schedule for treating metastatic breast cancer patients, particularly the elderly and those unsuited to anthracycline-based regimens.

The role of ultrasound-guided aspiration biopsy of peripheral pulmonary nodules: our experience.

BACKGROUND: Peripheral lung lesions are difficult to diagnose with conventional methods: ultrasound-guided aspiration biopsy is an interesting prospect having been reported to have good sensitivity and specificity. PATIENTS AND METHODS: From January 1991 to August 2001 we investigated, in 268 patients, the role of ultrasound-guided transthoracic fine needle aspiration for cytological diagnosis of peripheral lung lesions. Nodule sizes ranged from 1 to 10 cm. RESULTS: From 268 patients, we obtained 174 positive specimens for malignancy, of which 155 were positive for primary lung tumors and 19 for metastasis; 76 negative; 9 inadequate; and 9 aspecific. One patient developed pneumothorax after needle aspiration and one patient emophtoe. The nodule size did not affect complication rate and diagnostic outcome. CONCLUSION: This diagnostic procedure appears to be effective, safe and feasible, even in bedridden patients. The cost is low (70Euro), the examination is fast (5-6 minutes) and well-tolerated and, if the specimen is inadequate or non-specific, it is possible to repeat the examination. Ultrasound-guided aspiration biopsy can replace the TC-guided biopsy in patients with peripheral lung nodules.