Rationale for the Combination of Dendritic Cell-Based Vaccination Approaches With Chemotherapy Agents.

Owing to their central role in the initiation and regulation of antitumor immunity, dendritic cells (DCs) have been widely tested for use in cancer immunotherapy. Despite several encouraging clinical applications, existing DC-based immunotherapy efforts have yielded inconsistent results. Recent work has identified strategies that may allow for more potent DC-based vaccines, such as the combination with antitumor agents that have the potential to synergistically enhance DC functions. Selected cytotoxic agents may stimulate DCs either by directly promoting their maturation or through the induction of immunogenic tumor cell death. Moreover, they may support DC-induced adaptive immune responses by disrupting tumor-induced immunosuppressive mechanisms via selective depletion or inhibition of regulatory subsets, such as myeloid-derived suppressor cells and/or regulatory T cells (Tregs). Here, we summarize our current knowledge on the capacity of anticancer chemotherapeutics to modulate DC phenotype and functions and the results of ongoing clinical trials evaluating the use of DC-based immunotherapy in combination with chemotherapy in cancer patients.

[Vulvar squamous precancerous lesions History and current state of the topic]. / Dlazdicobunecné prekancerózy vulvy Historie a soucasný stav problematiky.

This review article discribes the genesis and development of vulvar squamous precancerous lesions terminology and discusses the consensus of the International Society for the Study of Vulvovaginal Disease, the American Society for Colposcopy and Cervical Pathology, College of American Pathologists and the World Health Organization on the current terminology. The article describes the different types of vulvar squamous precancerous lesions, according to their etiology, incidence and malignant potential.

[Ganglioneuroma, a rare cause of soft neck tissues tumor in adult age]. / Ganglioneurom, raritní prícina nádoru mekkých tkání krku v dospelosti.

We present the case of a 26-year-old female patient with coincidental ultrasound finding of a neck tumour located below the left thyroid lobe. The tumour slightly increased in size over a year. Fine needle aspiration indicated the neuroectodermal origin of the tumour and surgical removal was performed. Although the tumour mass was carefully and successfully removed, post-operational Horners syndrome appeared. The tumour tissue was diagnosed as ganglioneuroma by histopathology.

[Gynaecological precanceroses from the clinical perspective - today and tomorrow]. / Gynekologické prekancerózy z pohledu klinika dnes a zítra.

During the last twenty-five years an enormous shift in our knowledge of cancerogenesis in all gynaecological precancerous and cancerous diseases can be seen. Early diagnosis of these lesions of the lower genital tract (vulva, vagina and cervix) is enabled mainly due to easy access. The major role in the pathogenesis of most precancerous lesions can be accounted to high risk human papillomavirus. Recently, new information about HPV genotypisation of single precancerous lesions and single histological cancer types were revealed. Thus we can better estimate the effect of vaccines on different age groups of women in relation to different types of cancer. The development and introduction of prophylactic vaccines into clinical practice was one of the major improvements of current medicine. Precancerous and cancer lesions of endometrium make themselves known by early symptoms such as perimenopausal and postmenopausal bleeding. Optimal diagnostic and therapeutic procedures have to be based on close cooperation between the clinician and pathologist.

[Review of precancerous vulvar lesions]. / Prekancerózní léze vulvy.

Classification of squamous vulvar precancerous lesions is based on the concept of vulvar intraepithelial neoplasia (VIN) and incorporates a three grade evaluation of the intensity of dysplastic changes (VIN I, II and III). On the basis of histological features, VIN has been subdivided into the usual VIN (u-VIN) and differentiated VIN (d-VIN), which represent the two basic pathways of the pathogenesis of vulvar squamous cell carcinoma. Although u-VIN is etiologically associated with the human papillomavirus (HPV) infection and histologically corresponds to cervical intraepithelial neoplasia, d-VIN represents the HPV-negative sequence of vulvar carcinogenesis, which is linked to lichen sclerosus (LS) and lichen simplex chronicus (LSC). u-VIN preferentially occurs in relatively young women with a history of cervical, vaginal or vulvar premalignant lesions. On the other hand, d-VIN usually affects postmenopausal women without anamnestic data of other dysplastic lesions of the lower female genital tract. d-VIN is characterized by a higher tendency of stromal invasion than u-VIN and its malignant potential is analogous to carcinoma in situ (VIN III). The histological appearance of d-VIN is subtle with basal atypia and a well-preserved differentiation of the superficial parts of the squamous epithelium, therefore it is frequently misdiagnosed for u-VIN I, LS or LSC in vulvar biopsies. Primarily because of the low diagnostic reproducibility of the u-VIN I category and the doubts about its precancerous potential as well as due to the questionable differentiation between u-VIN II and III, a revised VIN classification was proposed in 2004. The grading of vulvar precancerous lesions was abandoned, the u-VIN I category was discontinued and u-VIN II and III were merged. In the revised terminology, the term u-VIN represents HPV-associated high grade precancerous vulvar lesions (formerly u-VIN II and III) and d-VIN encompasses HPV-negative high grade dysplasias.

Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency.

Cells with DNA repair defects have increased genomic instability and are more likely to acquire secondary mutations that bring about cellular transformation. We describe the frequency and spectrum of somatic mutations involving several tumor suppressor genes in the rectal carcinoma of a 13-year-old girl harboring biallelic, germline mutations in the DNA mismatch repair gene PMS2. Apart from microsatellite instability, the tumor DNA contained a number of C:G→T:A or G:C→A:T transitions in CpG dinucleotides, which often result through spontaneous deamination of cytosine or 5-methylcytosine. Four DNA glycosylases, UNG2, SMUG1, MBD4 and TDG, are involved in the repair of these deamination events. We identified a heterozygous missense mutation in TDG, which was associated with TDG protein loss in the tumor. The CpGs mutated in this patient's tumor are generally methylated in normal colonic mucosa. Thus, it is highly likely that loss of TDG contributed to the supermutator phenotype and that most of the point mutations were caused by deamination of 5-methylcytosine to thymine, which remained uncorrected owing to the TDG deficiency. This case provides the first in vivo evidence of the key role of TDG in protecting the human genome against the deleterious effects of 5-methylcytosine deamination.

[Incidence and prognostic significance of mesorectal extranodal tumor deposits in patients with rectal carcinoma following neoadjuvant therapy]. / Výskyt a prognostický význam extranodálních nádorových depozit v mezorektu u pacientus karcinomem rekta po neoadjuvantní terapii.

BACKGROUND: Extranodal mesorectal deposits (ENDs) occur frequently in advanced rectal tumors. It is supposed they are related to a higher incidence of local recurrence and a poor prognosis. AIM: To discover both occurrence and impact of ENDs in patients with advanced rectal cancer after neoadjuvant therapy and surgery. PATIENTS, METHOD: 325 patients meeting following criteria were enrolled: rectal adenocarcinoma, neoadjuvant therapy, anterior or AP rectal resection, complete check up information. Both fresh and archive specimens were examined using standard histopathologic methods. RESULTS: ENDs were discovered in 45 from 325 cases. The occurrence of ENDs was significantly higher in increasing stage of tumor (p < 0.001) and in increasing tumor grade (p < 0.001). Positive correlation between number of involved lymph nodes and occurrence of ENDs (p = 0.005) was proved. The 5-year survival rates were border significantly decreased in patients with ENDs (p = 0.052). CONCLUSION: ENDs are the form of metastatic spreading of primary rectal cancer and have negative prognostic impact in 5 year survival and increase local recurrence of cancer.

Soluble form of carbonic anhydrase IX (CAIX) in transitional cell carcinoma of urinary tract.

We investigated the expression of cell-associated CAIX protein in histological sections of the transitional cell carcinoma (TCC) of the urinary tract and of the soluble form of CAIX (s-CAIX) shed by the tumor into the serum and urine of TCC patients. A total of 23 patients with histologically confirmed TCC or squamous cell carcinoma (SCC) were enrolled in the pilot study. Sixteen healthy individuals served as controls. Membrane-bound CAIX was present in the tumor cells near the endoluminal surface. Necrosis was observed in only 4 samples. Using Western blots, s-CAIX concentrated from urine was visualized as a double band at 50 and 54 kDa. In most cases, the presence of s-CAIX in the urine correlated with CAIX expression in the tumor. On the other hand, s-CAIX did not exceed the normal level in the serum of TCC patients. Urine from patients with TCC of the urinary bladder and renal pelvis contained s-CAIX, allowing the detection of tumors in approximately 70% of the patients. Moreover, two additional patients with suspected, but unconfirmed bladder tumor, with s-CAIX detected in urine, developed tumors identified as TCC within six months. We suggest that after a simple, rapid and sensitive test, monitoring s-CAIX levels in urine will be developed, it may be useful for early detection of relapse in patients following transurethral tumor resection.

High-dose density chemotherapy followed by simple trachelectomy: full-term pregnancy.

We report five patients with early-stage cervical cancer who do not fulfill criteria of fertility-sparing surgery (tumor more than 2 cm in the biggest diameter or infiltrating more than half of stroma). Five patients received three cycles of dose density neoadjuvant chemotherapy (NAC) at a 10-day interval: cisplatin plus ifosfamide in squamous cell cancer or plus doxorubicin in adenocarcinoma with good tolerance. After NAC, they underwent laparoscopic pelvic lymphadenectomy and vaginal simple trachelectomy. Two patients had no residual tumor, two had only microscopic residual disease, and one had macroscopic residual disease. Two women became pregnant 5 and 8 months after surgery, one delivered in term healthy baby and one is now in the second trimester of pregnancy without any complications. NAC followed by fertility-sparing surgery seems to be feasible treatment for women with tumor bigger than 2 cm or infiltrated more than half of the stroma.

[The clinical significance of sentinel lymph node micrometastases in breast cancer]. / Klinický význam mikrometastáz karcinomu prsu v sentinelové uzline.

OBJECTIVE: The advent of sentinel lymph node biopsy and improvements in histopathological and immunohistochemical analysis has increased the rate at which micrometastases are identified. However their significance has been the subject of much debate. Published studies have reported divergent results regarding the significance and implications of axillary lymph node micrometastases. Some studies demonstrate no associations, whilst others have found these to be indicators of poor prognosis, associated with non-SLN involvement, in addition to local and distant failure. The objective of our study was to evaluate the impact of sentinel lymph node micrometastatic cancer to prognosis of the disease. DESIGN: Retrospective study. SETTING: Departments of Gynecology and Obstetrics, Faculty Hospital, Prague. METHODS: From January 2000 to December 2006 in 87 cases with sentinel axillary node negative cancer we reexamined the axillary tissue blocks by serial sectioning, haematoxilin-eosin staining and immunohistochemistry. Additional 15 cases of micrometastatic sentinel node involvement detected by frozen section were included. The overall and disease free survivals of patients with sentinel negative status (N0-67 cases) and with sentinel node micrometastases (Nmic-35 cases) were evaluated. The median follow-up was 60 months (24-96 months). RESULTS: Micrometastases (Nmic) were found in 20 cases (23%). From the group of 67 nodes negative patients (N0) in 7 cases (10.5%) developed tumor recurrence and from the group of 35 Nmic in 5 cases developed five tumor recurrences (13.3%). In the group of N0 patients developed 2 regional recurrences and 3 patients died, but 2 patients died of other causes. In the group of Nmic developed one regional recurrence and 3 patients died of generalization of disease. CONCLUSION: Our study demonstrated that the presence of sentinel node micrometastases is associated with risk of development of distant metastases and generalization of the disease, but not with higher risk of regional recurrence.

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.

[Progression and regression low grade intraepitelial squamous lesions in context of positivity of high risk human papillomavirus]. / Progrese a regrese low grade intraepiteliálních skvamózních neoplazií v závislosti na prítomnosti HPV HR viru.

OBJECTIVE: Evaluation of regression and progression of histologically confirmed low grade squamous intraepithelial lesions (LG SIL) in women under the age of 35 in context of positivity of high risk human papillomavirus (HPV HR). Evaluation of sensitivity of PAP smear and HPV HR test in women with LG SIL. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, Charles University Prague, 2nd Medical Faculty, University Hospital Motol. PATIENTS AND METHODS: 166 women with SIL low or repeated ASC-US PAP smear were included to the study. 1 to 3 punch biopsy under the expert colposcopy and HPV HR test were performed in all women. Follow up were done every 6 month in all women with histologically confirmed LG SIL. RESULTS: LG SIL was detected in 120 women. Sensitivity of PAP smear was 72.3% and sensitivity of HPV HR test 60.2 % in women with LG SIL. 84 women (70 %) were HPV HR positive. Regression of LG SIL was detected in 20 (23 %) HPV HR positive women and in 18 (50%) HPV HR negative women. This difference is statistically significant (p = 0.0094). Progression of LG SIL was detected in 24 (29 %) HPV HR positive women and in 4 (11%) women HPV HR negative women. This difference is borderline statistically significant (p = 0.058). Progression of LG SIL to the carcinoma in situ or invasive cancer had not been detected during follow up period. CONCLUSION: PAP smear is a standard for LG SIL detection in women under the age of 35 and HPV HR test is not so important for LG SIL detection in this group of women. HPV HR test could be useful for prediction of the risk of progression, but positivity of HPV HR in LG SIL cannot indicate surgical treatment (conisation) in this cohort of women under the age of 35.

[Sentinel lymph nodes identification in vulvar cancer--methods and technique]. / Detekce sentinelových uzlin u karcinomu vulvy--metody a technika.

OBJECTIVE: To evaluate detection of sentinel lymph nodes (SLN) in squamous vulvar cancer with blue dye and 99mTc. The study describes technique of application, timing, management, detection rate (DR), specific side detection rate (SSDR) and false negative rate. DESIGN: Prospective clinical study. SETTING: Department of Obstetrics and Gynecology, Charles University Prague, 2nd Medical Faculty, Teaching Hospital Motol. PATIENTS AND METHODS: 46 women with squamous cell carcinoma tumors stage I or II, <4 cm with no clinical suspect lymph nodes were included. Blue dye alone was used in 16 women and the combination of 99mTc and blue dye was used in 30 women. Radiocoloid 99mTc was applied 3-5 hours and blue dye 3-5 minutes prior to ingvinal incision. RESULTS: We detected 88 SLN in 61 inguinal spaces. The detection rate in the blue dye group was 68.8 % (11 cases). One false negative SLN (6.3 %) appeared in this group. In blue dye+ 99mTc group detection rate was 100 % with no false negative SLN. CONCLUSION: Detection of SLN in squamous vulvar cancer with the combination of 99mTc and blue dye was statistically significantly more effective than using the blue dye alone.

[Fertility sparing surgery in early cervical cancer today and tomorrow]. / Fertilitu zachovávající operace u casného stadia karcinomu delozního hrdla dnes a zítra.

OBJECTIVE: Describtion and evaluation of proposed protocol for conservative, fertility sparing surgeries in the treatment of early stages of cervical cancer and its comparison to most frequently used protocols regarding its reproductive and oncological outcomes. DESIGN: Prospective clinical study. SETTING: Department of Obstetrics and Gynecology, Charles University Prague, 2nd Medical Faculty, University Hospital Motol. PATIENTS AND METHODS: 24 patients that fitted into the inclusion criteria were recruited in the study (6 in stage T1A2 and 18 T1B1). Inclusion criteria were: tumor less than 20 mm in largest diameter, less than 1/2 of the stromal invasion, SCC serum levels within normal range, signed informed consent. Minimum follow up was 24 months. Described therapeutic protocol, evaluation of oncological and reproductive outcomes and comparison with different fertility sparing regimens were performed. RESULTS: In four cases (16.7%) peroperative histopatghological evaluation (frozen section: FS) detected metastatic involvement of lymphatic nodes. In one case (4.1%) following 14 months since initial surgery, reccurent disease in uterine isthmus was detected. The patient underwent chmotherapy and she is 36 months in complete remission. In the series of 15 women planning pregnancy 11 subjects become pregnant so far. Eight deliveries occurred (one in 24th week of gestation--650g, one in 34w--2240g, one in 36w--2700g and five between 37-39w). Only one newborn was delivered in the cathegory of extreme prematurity. CONCLUSION: Sentinel node detection involving peroperative histopathological evaluation followed by subsequent serial processing and together with 2-step therapeutic management increases efectivity of fertility sparing surgeries. Less radical surgery on uterine cervix: reconisaton (in stage IA2) or simple trachelectomy (in early stage T1B1) with negative finding after laparoscopic lymph node dissection has comparative results with radical trachelectomy and abdominal radical trachelectomy. Pregnancy rates and pregnancy outcomes particularly regarding in term delivery is the best after treatment of early stages of cervical cancer using proposed protocol, while very promising results are published in studies with radical vaginal trachelectomy as well. Results published for the patients treated with abdominal radical trachelectomy are unsatisfactory.