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New treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical cancer were treated with external beam radiation therapy (EBRT), using conventional three-dimensional or intensity modulated radiation therapy without constraints for bone marrow sparing. Serial blood sampling for immunomonitoring was performed before, midway and at 3, 6 and 9 weeks after EBRT to analyze the composition of lymphocyte and myeloid-cell populations, the expression of co-stimulatory molecules, T-cell reactivity and antigen presenting cell (APC) function. Therapy significantly decreased the absolute numbers of circulating leukocytes and lymphocytes. Furthermore, the capacity of the remaining T cells to respond to antigenic or mitogenic stimulation was impaired. During treatment the frequency of both CD4+ and CD8+ T cells dropped and CD4+ T cells displayed an increased expression of programmed cell death-1 (PD-1). In vitro blocking of PD-1 successfully increased T-cell reactivity in all five samples isolated before radiotherapy but was less successful in restoring reactivity in samples isolated at later time points. Moreover, (chemo)radiotherapy was associated with an increase in both circulating monocytes and myeloid-derived suppressor cells (MDSCs) and an impaired capacity of APCs to stimulate allogeneic T cells. T-cell reactivity was slowly restored at 6–9 weeks after cessation of therapy. We conclude that conventional (chemo)radiotherapy profoundly suppresses the immune system in cervical cancer patients, and may restrict its combination with immunotherapy.

Objective: To investigate prognostic factors in patients with recurrent cervical cancer after treatment of early-stage disease in order to identify high-risk patients who might benefit from alternative treatment strategies., Study Design: The authors retrospectively analyzed clinical and pathology data from 130 recurrent cervical cancer patients after surgical treatment for early-stage disease. Patients were compared with a recurrence-free control group matched for age, FIGO Stage, and adjuvant treatment. Univariate and multivariate Cox regression analyses were performed to determine prognostic factors for recurrence and survival., Results: Of 889 patients, 130 (14.6%) developed recurrent disease after primary treatment for early-stage cervical cancer. Local or loco-regional metastasis was observed in 45%, distant metastasis in 31%, and combined pelvic and distant metastasis in 24%. Median survival after recurrence was 12 months (range 1-107 months). Median five-year survival was 96% in the control group and 29% in the recurrence group. Tumor size ≥ 40 mm and lymph node metastasis were independent unfavorable prognostic factors for overall survival (OS) and disease-free survival (DFS). The number of positive lymph nodes (≥ one) and bilateral occurrence of pelvic lymph node metastasis were associated with adverse clinical outcome., Conclusions: Tumor size ≥ 40 mm and lymph node metastasis were independent unfavorable prognostic factors in surgically treated, early-stage cervical cancer patients. The combination of these factors was particularly associated with recurrence. Future trials should focus on the role of alternative adjuvant treatment strategies in patients at high risk of recurrent disease (e.g., by chemotherapy, immunotherapy or combinations thereof).

Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell-mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carboplatin and paclitaxel chemotherapy to improve immunity and which time point would be optimal for vaccination. This was studied in the HPV16 E6/E7-positive TC-1 mouse tumor model and in patients with advanced cervical cancer. In mice and patients, the presence of a progressing tumor was associated with abnormal frequencies of circulating myeloid cells. Treatment of TC-1-bearing mice with chemotherapy and therapeutic vaccination resulted in superior survival and was directly related to a chemotherapy-mediated altered composition of the myeloid cell population in the blood and tumor. Chemotherapy had no effect on tumor-specific T cell responses. In advanced cervical cancer patients, carboplatin-paclitaxel also normalized the abnormal numbers of circulating myeloid cells, and this was associated with increased T cell reactivity to recall antigens. The effect was most pronounced starting 2 weeks after the second cycle of chemotherapy, providing an optimal immunological window for vaccination. This was validated with a single dose of HPV16-SLP vaccine given in this time window. The resulting proliferative HPV16-specific T cell responses were unusually strong and were retained after all cycles of chemotherapy. In conclusion, carboplatin-paclitaxel therapy fosters vigorous vaccine-induced T cell responses when vaccination is given after chemotherapy and has reset the tumor-induced abnormal myeloid cell composition to normal values., (Copyright © 2016, American Association for the Advancement of Science.)

Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24-hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24-hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24-hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24-hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes.

The prognosis of patients with metastatic cervical cancer is poor with a median survival of 8-13 months. Despite the potency of chemotherapeutic drugs, this treatment is rarely curative and should be considered palliative only. The last decades, targeted therapies such as immunotherapy have emerged as an attractive option for the treatment of these patients. Immunotherapy can consist of different modalities such as monoclonal antibodies, adoptive lymphocyte transfer and vaccines, which all are intended to augment the antitumor immune responses in cancer patients. The available evidence indicates that both active and adoptive immunotherapeutical strategies are quite effective against small tumor burdens, but are usually insufficient to eradicate the disease in patients with advanced stages of different kinds of cancer, despite strong induction of tumor-specific immune responses. Although chemotherapy and immunotherapy have not shown to be curative as single modalities, accumulating evidence suggests that combinations of these treatments hold potential for improved clinical outcomes in advanced stages of cancer. Therefore, the combination of chemotherapy and immunotherapy is no longer considered incompatible, because of the emerging insight that certain chemotherapy-based cancer treatments may activate the immune system against the tumor through several molecular and cellular mechanisms. Chemotherapeutic agents and immunotherapy may thus be synergistic and enhance the clinical response. In this review, we show the rationale for combined chemo-immunotherapeutic strategies, and summarize recent data from clinical trials performed in patients with different types of cancer. Challenges such as the selection of the optimal dose and treatment schedule, will be discussed as well as the identification of immune-specific biomarkers. Furthermore, we evaluated the long-term clinical outcomes of patients with advanced cervical cancer treated with HPV16 E6/E7 SLP vaccination with or without chemotherapy. Finally, the future of vaccination therapy in combination with chemotherapy for the treatment of cervical cancer is discussed.

Monochorionic twin pregnancies are associated with increased perinatal morbidity and mortality. The vascular placental anastomoses in these pregnancies can cause severe complications. We describe a case of twin anemia-polycythemia sequence (TAPS) with an atypical placental angioarchitecture. During pregnancy serial ultrasound examinations of both twins revealed no amniotic fluid discordance and no abnormal Doppler ultrasound measurements (umbilical cord pulsatility index and middle cerebral artery peak systolic velocity). The twins, born at 33 + 3 weeks gestation after spontaneous onset of labour, were found to be anemic and polycythemic, respectively. Placental examination with colored dye injection showed, apart from small ateriovenous anastomoses, an arterio-arterial anastomosis. As arterio-arterial anastomoses have not been described in cases with spontaneous TAPS to date, it was postulated that such anastomoses carried a protective effect against the development of this complication., (2009 Elsevier Ltd. All rights reserved.)

Background: We analyzed the results in two centers of using bovine jugular vein graft for right ventricular outflow tract reconstruction., Methods: From April 1999 to July 2005, 133 children with a median age of 30.9 months (range, 4 days to 19 years) underwent graft implantation. Echocardiography was performed during follow-up and retrospectively reviewed., Results: Nongraft-related early mortality occurred in 8 patients. Late mortality occurred in 11 patients, 2 late deaths were graft related (endocarditis). Median follow-up was 31.6 months (range, 1 to 73). Twelve patients received a new graft, because of endocarditis (3), distal pulmonary artery branch stenosis (4), graft obstruction caused by fibrosis (4), or thrombosis (1). Echocardiography Doppler studies showed good conduit function, with 92% of the patients having absent, trivial, or only mild valve regurgitation at last follow-up. A moderate degree of conduit stenosis due to external compression was observed in 2 patients. Twenty-five patients with otherwise intact conduits had hemodynamically significant distal stenosis. In most cases, the pulmonary branch stenosis was related to preoperative small pulmonary arteries and young age at operation. At 31.6 months, significant graft dilatation was observed in 4 grafts and was related to pulmonary artery branch obstruction or pulmonary hypertension. Calcification did not occur in 5 years time. Survival was 85.7%, freedom from conduit explantation was 91%, and freedom from intervention for pulmonary artery branch stenosis was 80% after 5 years., Conclusions: The bovine jugular vein graft is a valuable right ventricular outflow tract conduit, but younger age and small pulmonary arteries increase the risk of distal conduit stenosis.