Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients.

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.

The identification of patients at high risk for recurrent disease after treatment for early-stage cervical cancer.

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).

Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers.

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.

Arterio-arterial anastomoses do not prevent the development of twin anemia-polycythemia sequence.

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.