Lukas Rob

Fertility-sparing surgery in patients with cervical cancer

There are several types of fertility saving procedures that can be done in patients with cervical cancer, which differ in terms of surgical approach and extent of paracervical resection. This review assesses oncological and pregnancy results after different procedures. The oncological results of vaginal radical trachelectomies (VRT) and abdominal radical trachelectomies (ART) are similar for tumours less than 2 cm in size, and are now considered safe surgical procedures. Oncological outcomes of VRT and ART in tumours larger than 2 cm are also identical, but the results cannot be considered satisfactory. Preliminary findings of less radical procedures (ie, deep cone and simple trachelectomy) in patients with tumours less than 2 cm, and negative sentinel and other pelvic lymph nodes, are comparable with the results of VRT and ART. Downstaging tumours larger than 2 cm by neoadjuvant chemotherapy is still an experimental procedure and will need multicentre cooperation to verify its oncological safety. Pregnancy results vary statistically with the different methods.

Human Tumor Cells Killed by Anthracyclines Induce a Tumor-Specific Immune Response

Immunogenic cell death is characterized by the early surface exposure of chaperones including calreticulin and HSPs, which affect dendritic cell (DC) maturation and the uptake and presentation of tumor antigens. It has also been shown that it is characterized by the late release of high mobility group box 1 (HMGB1), which acts through Toll-like receptor 4 (TLR4) and augments the presentation of antigens from dying tumor cells to DCs. Most of the data on immunogenic tumor cell death were obtained using mouse models. In this study, we investigated the capacity of clinically used chemotherapeutics to induce immunogenic cell death in human tumor cell lines and primary tumor cells. We found that only anthracyclines induced a rapid translocation of calreticulin, HSP70, and HSP90 to the cell surface and the release of HMGB1 12 hours after the treatment. The interaction of immature DCs with immunogenic tumor cells led to an increased tumor cell uptake and induces moderate phenotypic maturation of DCs. Killed tumor cell-loaded DCs efficiently stimulated tumor-specific IFN-γ-producing T cells. DCs pulsed with killed immunogenic tumor cells also induced significantly lower numbers of regulatory T cells than those pulsed with nonimmunogenic tumor cells. These data indicate that human prostate cancer, ovarian cancer, and acute lymphoblastic leukemia cells share the key features of immunogenic cell death with mice tumor cells. These data also identify anthracyclines as anticancer drugs capable of inducing immunogenic cell death in sensitive human tumor cells.

A less radical treatment option to the fertility-sparing radical trachelectomy in patients with stage I cervical cancer ☆

The purpose of the two pilot studies was to determine the feasibility and safety of using less-radical fertility-preserving surgery: laparoscopic lymphadenectomy with sentinel lymph node identification (SLNI) followed by a large cone or simple trachelectomy (LAP-I protocol) and the LAP-III protocol, which includes neoadjuvant chemotherapy (NAC). LAP-I: Forty women underwent laparoscopic SLNI, frozen-section analysis, and a complete pelvic lymphadenectomy as the first step of treatment. Seven days after final histopathological processing of dissected nodes, a large cone or simple vaginal trachelectomy was performed in patients with negative nodes. Nine women had a tumor larger than 20 mm, prompting the administration of three cycles of NAC before surgery. LAP-I: Six frozen sections were positive (15%). In these cases, a type III Wertheim was immediately performed. There were no false-negative SLNs. There was one central recurrence, but after chemoradiation therapy, there was no evidence of the disease 62 months post-treatment. Twenty-four of 32 women whose reproductive ability had been maintained tried to conceive. Of these 24 women, 17 became pregnant (71% pregnancy rate). Eleven mothers gave birth to 12 children (1 at 24 weeks, 1 at 34 weeks, 1 at 36 weeks, and 9 between 37 and 39 weeks). LAP-III: Nine patients were included. In 7 of these 9 women, reproductive ability was maintained, with 3 women becoming pregnant (1 full term and 2 ongoing). SLNI improves safety in fertility-sparing surgery. Large cone or simple trachelectomy combined with laparoscopic pelvic lymphadenectomy can be a feasible method that yields a high, successful pregnancy rate. NAC followed by fertility-sparing surgery is an experimental alternative treatment for larger tumors.

Less radical fertility-sparing surgery than radical trachelectomy in early cervical cancer.

The purpose of this pilot study was to determine feasibility and safety of a novel and less radical fertility-preserving surgery; laparoscopic lymphadenectomy with sentinel lymph node identification (SLNI) followed by large cone or simple trachelectomy. Obstetrical and oncologic outcomes were evaluated. Twenty-six patients (6-IA2, 20-IB1) selected on basis of favorable cervical tumor characteristics and the desire to maintain fertility underwent laparoscopic SLNI, frozen section (FS), and a complete pelvic lymphadenectomy as first step of treatment. All of nodes were submitted for microscopic evaluation (sentinel nodes for ultramicrostaging). After a 7-day interval, large cone or simple vaginal trachelectomy was performed in patients with negative nodes. The average of sentinel nodes per side was 1.50 and the average of total nodes was 28.0. Four FS were positive (15.4%). In these cases, Wertheim radical hysterectomy type III was immediately performed. We had no false-negative SLN neither on FS nor on final pathology assessment. Median follow-up was 49 months (18–84). One central recurrence (isthmic part of uterus) was observed 14 months after surgery. This patient was treated with radical chemoradiotherapy, and there was no evidence of the disease 36 months after treatment. Fifteen women planned pregnancy, 11 women became pregnant (15 pregnancies), and 7 women delivered eight children (one in 24 weeks, one in 34 weeks, one in 36 weeks, and five between 37 and 39 weeks). We conclude that lymphatic mapping and SLNI improves safety in this fertility sparing surgery. Large cone or simple trachelectomy combined with laparoscopic pelvic lymphadenectomy can be a feasible method with a high successful pregnancy rate

Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy.

BACKGROUND Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).

Less radical surgery than radical hysterectomy in early stage cervical cancer: a pilot study.

OBJECTIVE The purpose of this pilot study was to evaluate the feasibility and safety of a less radical surgery; laparoscopic lymphadenectomy followed by a simple vaginal hysterectomy in sentinel lymph node (SLN) negative early cervical cancer patients. Treatment-associated morbidity and oncological outcome were evaluated. PATIENTS AND METHODS From December 2000 to September 2007, 60 patients (50 squamous and 10 adenocarcinoma patients) in stages 3-IA1, 11-IA2 and 46-IB1 with median age of 44.6 years (range 33-64 years) were enrolled. Patients were selected based on favorable cervical tumors (IA1 with lymph-vascular space invasion [LVSI], IA2 and IB1 with tumor size less than 20 mm and less than half of stromal invasion). All patients underwent laparoscopic SLN identification using frozen section (FS). Negative SLN patients underwent complete pelvic laparoscopic lymphadenectomy and vaginal hysterectomy. FS positive patients underwent radical hysterectomy with low paraaortic lymphadenectomy. RESULTS The average number of sentinel nodes per side was 1.4 with detection rate per side of 95%. The average number of removed nodes was 23.2. Five patients (8.3%) were SLN positive. There were two false negative FS results (both were micrometastases in SLN). Median follow-up was 47 months (range 12-92). There were no recurrences in 55 SLN negative patients and in 5 SLN positive patients. CONCLUSION Lymphatic mapping and SLN identification improved safety in less radical surgery in early stage cervical cancer. This preliminary study showed that it is both feasible and safe to reduce the radicality of parametrial resection for small tumor volume in SLN negative patients. Results also indicated that treatment-associated morbidity is low.

Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study

Objective. To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. Design. A preclinical and a clinical case–control trial. Setting. Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. Population. Pregnant and nonpregnant women and baboons receiving chemotherapy. Methods. Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard‐dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. Main outcome measures. Area under the curve (AUC), maximal plasma concentration, terminal elimination half‐life, clearance and distribution volume of each drug in pregnant and nonpregnant state. Results. Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. Conclusions. Although numbers were too small for statistical significance, pregnancy‐associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long‐term follow‐up of women treated with chemotherapy during pregnancy is underscored.

A prospective study of sentinel lymph node status and parametrial involvement in patients with small tumour volume cervical cancer

OBJECTIVE The purpose of prospective study is to determine incidence and distribution of pelvic lymph node (LN) involvement, sentinel lymph node (SLN) involvement and pathologic parametrial involvement (PI) in stage Ia2 and small Ib1 cervical cancer. PI is defined as positive parametrial LN or discontinuous malignant cells in parametrium. METHODS After radical abdominal hysterectomy, 158 women patients were stratified into two groups based on tumour size: In Group 1 (91 women) tumours were less than 20 mm and less than half of stromal invasion. In Group 2 (67 women) tumours were between 20 and 30 mm and infiltration was not more than 2/3 of cervical stroma. RESULTS In Group 1 positive SLN was detected in 11(12.1%) patients; of these, 3 (27.3%) had positive PI. In 80 women with negative SLN PI was not detected. In Group 2 positive SLN was detected in 14 (20.9%) patients: PI was found in four (28.6%) of these 14 patients. No PI was detected in 53 women with negative SLN. CONCLUSION No PI was observed in early cervical cancer if SLNs were negative. However, we found PI in 28.0% of women with positive SLN. Statistical analysis revealed that the results were highly significant. Based on our results, radical removal of parametrium in SLN negative patients is questionable.

High hydrostatic pressure induces immunogenic cell death in human tumor cells

Recent studies have identified molecular events characteristic of immunogenic cell death (ICD), including surface exposure of calreticulin (CRT), the heat shock proteins HSP70 and HSP90, the release of high‐mobility group box protein 1 (HMGB1) and the release of ATP from dying cells. We investigated the potential of high hydrostatic pressure (HHP) to induce ICD in human tumor cells. HHP induced the rapid expression of HSP70, HSP90 and CRT on the cell surface. HHP also induced the release of HMGB1 and ATP. The interaction of dendritic cells (DCs) with HHP‐treated tumor cells led to a more rapid rate of DC phagocytosis, upregulation of CD83, CD86 and HLA‐DR and the release of interleukin IL‐6, IL‐12p70 and TNF‐α. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor‐specific T cells. DCs pulsed with HHP‐treated tumor cells also induced the lowest number of regulatory T cells. In addition, we found that the key features of the endoplasmic reticulum stress‐mediated apoptotic pathway, such as reactive oxygen species production, phosphorylation of the translation initiation factor eIF2α and activation of caspase‐8, were activated by HHP treatment. Therefore, HHP acts as a reliable and potent inducer of ICD in human tumor cells.

Presentation, Management and Outcome of 32 Patients with Pregnancy‐Associated Breast Cancer: A Matched Controlled Study

Abstract:  Pregnancy‐associated breast cancer (PABC) is a rare and challenging problem. We sought to describe epidemiology, management and outcome of women in whom breast cancer was diagnosed during pregnancy or within one year after delivery. Thirty‐two women with PABC were referred to two European Union oncology centers between 1995 and 2007, 16 during pregnancy and 16 within 1 year after delivery. Data concerning diagnosis, management, delivery and fetal and maternal outcome were recorded. A group of 32 patients (matched controls) presenting with nonpregnancy‐associated breast cancer (non‐PABC) was matched for age at diagnosis, tumor size and stage to each PABC patient. Differences in outcome between the PABC and non‐PABC groups were then assessed. Histological features were similar in both groups, except that estrogen receptor‐negative tumors were more common in the PABC group. Three patients received chemotherapy and two others underwent surgery during pregnancy, with no excess toxicity or severe maternal/fetal adverse effects. All children in the PABC group were healthy, except for one exposed to epirubicin in utero and born with rectal atresia. Overall survival was similar in PABC and non‐PABC patients (p = 0.449). The subgroup of patients with breast cancer diagnosed within one year after delivery showed a shorter time to relapse than controls or patients with gestational cancer (p = 0.0178). PABC is a special situation, necessitating individualized, multi‐disciplinary management. Prognosis is similar for women with nongestational cancer matched for age and stage though poorer outcome postpartum should be further investigated.