Organizing pneumonia after pancreatic cancer treatment with nab-paclitaxel and gemcitabine: a case report.

The incidence of pancreatic cancer is increasing. Most patients have advanced disease at diagnosis, and therapeutics is limited in this setting. Gemcitabine and nab-paclitaxel combination is indicated as first-line treatment in patients with metastatic cancer of pancreas. The most common adverse events of Grade 3 or higher gemcitabine and nab-paclitaxel combination are neutropenia, fatigue and neuropathy. In this report, we describe a rare case of organizing pneumonia associated with the use of nab-paclitaxel and gemcitabine in metastatic pancreatic cancer. A 68-year-old female underwent total splenopancreatectomy for ductal adenocarcinoma of the neck of the pancreas, followed by adjuvant chemoradiation therapy. Afterwards she relapsed and received first-line chemotherapy with gemcitabine plus nab-paclitaxel combination for 12 cycles. Following the administration of the 12th cycle of gemcitabine plus nab-paclitaxel, the patient experienced low-grade pyrexia, effort dyspnoea, persistent non-productive cough and malaise. High-resolution CT scan of chest revealed new-onset bilateral peripheral ground-glass opacities, smooth interlobular septal thickening and patchy subpleural consolidation areas, findings consistent with organizing pneumonia. A thorough microbiological workup was negative. Treatment with steroids resulted in prompt clinical and radiological improvement. Organizing pneumonia closely mimics infection or progressive disease and can be difficult to diagnose in the setting of malignancy. Correct diagnosis is of primary importance since delay in treatment can result in significantly adverse patient outcomes.

Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis.

Despite the genomic characterization of pancreatic cancer (PC), marked advances in the development of prognosis classification and novel therapeutic strategies have yet to come. The present study aimed to better understand the genomic alterations associated with the invasive phenotype of PC, in order to improve patient selection for treatment options. A total of 30 PC samples were analysed by either whole transcriptome (9 samples) or exome sequencing (21 samples) on an Illumina platform (75X2 or 100X2 bp), and the results were matched with normal DNA to identify somatic events. Single nucleotide variants and insertions and deletions were annotated using public databases, and the pathogenicity of the identified variants was defined according to prior knowledge and mutation-prediction tools. A total of 43 recurrently altered genes were identified, which were involved in numerous pathways, including chromatin remodelling and DNA damage repair. In addition, an analysis limited to a subgroup of early stage patients (50% of samples) demonstrated that poor prognosis was significantly associated with a higher number of known PC mutations (P=0.047). Samples from patients with a better overall survival (>25 months) harboured an average of 24 events, whereas samples from patients with an overall survival of <25 months presented an average of 40 mutations. These findings indicated that a complex genetic profile in the early stage of disease may be associated with increased aggressiveness, thus suggesting an urgent requirement for an innovative approach to classify this disease.

KRAS, BRAF and PIK3CA status in squamous cell anal carcinoma (SCAC).

Anti-EGFR therapy appears to be a potential treatment option for squamous cell anal carcinoma (SCAC). KRAS mutation is a rare event in SCAC, indicating the absence of the principal mechanism of resistance to this type of therapy. However, no information is available from the literature regarding the status of BRAF or PIK3CA in this cancer type. We analysed KRAS, BRAF and PIK3CA status in SCAC patients in relation to the clinical-pathological characteristics of patients and to the presence of the human papilloma virus (HPV). One hundred and three patients were treated with the Nigro scheme for anal cancer from March 2001 to August 2012. Fifty patients were considered for the study as there was insufficient paraffin-embedded tumour tissue to perform molecular analysis the remaining 53. DNA was extracted from paraffin-embedded sections. KRAS, BRAF and PIK3CA gene status and HPV genotype were evaluated by pyrosequencing. KRAS and BRAF genes were wild-type in all cases. Conversely, PIK3CA gene was found to be mutated in 11 (22%) cases. In particular, 8 mutations occurred in exon 9 and 3 in exon 20 of the PIK3CA gene. These findings suggest that SCAC could potentially respond to an anti-EGFR drug. PIK3CA mutation may be involved in the process of carcinogenesis in some cases of SCAC.

Acute psychological stress increases peripheral blood CD3+CD56+ natural killer T cells in healthy men: possible implications for the development and treatment of allergic and autoimmune disorders.

Acute psychological stress has primarily been investigated regarding its effects on conventional lymphocytes such as natural killer (NK) cells and CD4(+) and CD8(+) T cells. However, it might be important to focus on more "specialized" lymphocyte subsets, playing a role, for instance, in allergic conditions and autoimmunity, to identify links between stress, the immune system and somatic diseases. Using flow cytometry we determined frequencies of circulating T helper (Th)1-type (CD226(+)) and Th2-type (CRTH2(+)) T cells, γδ T cells, conventional CD56(+) natural killer T (NKT) cells and invariant NKT cells (iNKT) in healthy young males (N = 31; median age 26 years) undergoing a laboratory computer-based stressor lasting 12 min. We found that acute psychological stress induced a prolonged increase in CD4(+) and CD8(+) T cells expressing a Th2 phenotype. We also detected an acute increase in CD4(-) and CD8(-) double negative γδ T cells. Finally, we found that the well-known increase in NK cells under stressful conditions was paralleled by a significant increase in numbers of conventional CD56(+) NKT cells. In contrast, numbers of iNKT was not altered by stress. This study adds further evidence to a psychoneuroimmunological model proposing that under stressful conditions certain lymphocyte subsets, including iNKT and less mature T cells, are retained in lymphoid tissues while antigen-experienced effector-type T cells with a Th2 phenotype, γδ T cells and conventional CD56(+) NKT cells are mobilized into the peripheral blood. We suggest that in the case of frequent stress exposure, this might result in the promotion of, for example, allergic conditions.

Gemcitabine and paclitaxel combination as second-line chemotherapy in patients with small-cell lung cancer: a phase II study.

BACKGROUND: Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. PATIENTS AND METHODS: Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m(2) days 1 and 8 immediately followed by gemcitabine at 1000 mg/m(2) every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. RESULTS: Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most-frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. CONCLUSIONS: The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic.

Decrease of CD4(+)FOXP3(+) T regulatory cells in the peripheral blood of human subjects undergoing a mental stressor.

We have previously shown that acute psychological stress alerts the adaptive immune response causing an increase in antigen-experienced effector T cells in the peripheral blood. T regulatory cells (Tregs) play a central role in maintaining self-tolerance and controlling autoimmune responses. Here, we analyzed for the first time the behaviour of Tregs in the context of a stress-induced activation of the adaptive immune response. 31 healthy young males underwent a brief laboratory stressor and, in a crossover design, served as their own unstressed controls. We quantified effects of acute stress on CD4(+)FOXP3(+) T regulatory cells and other T cell subpopulations using flow cytometry. In addition, the expression of Treg-related effector molecules and stress hormone receptors were analyzed in the subjects' peripheral T cells. We confirmed our previous observation of a stress-induced decrease in CD45RA(+)CCR7(+) "naïve" and CD45RA(-)CCR7+ "central memory" T cells while CD45RA(-)-CCR7(-) "memory effector" and CD45RA(+)CCR7(-) "terminally differentiated" effector T cells remained stable or increased. Importantly, we found acute psychological stress to cause a concomitant decrease in CD4(+)FOXP3(+) Tregs and in CD4(+) T cells expressing Treg-related effector molecules cytotoxic T-lymphocyte antigen-4 (CTLA-4) and latency associated peptide (LAP). Finally, we observed beta(1)-adrenergic and glucorticoid alpha receptors to be overexpressed in Tregs, suggesting that these molecules might mediate stress-related effects on Tregs. In conclusion, inhibiting components of the adaptive immune response, like Tregs, are down-regulated during a stress-induced activation of the adaptive immune response. In situations of chronic stress, this scenario might result in an exacerbation of inflammatory conditions such as autoimmune diseases.