[Assisted Reproduction and Preimplantation Genetic Diagnosis in Patients Susceptible to Breast Cancer]. / Asistovaná reprodukce a preimplantacní genetická diagnostika u pacientek ohrozených karcinomem prsu.

BACKGROUND: Assisted reproduction, as well as pregnancy itself, in patients with breast cancer or other hereditary type of cancer, is a widely discussed topic. In the past, patients treated for breast cancer were rarely involved in the discussion about reproductive possibilities or infertility treatment. However, current knowledge suggests, that breast cancer is neither a contraindication to pregnancy, nor to assisted reproduction techniques. On the contrary, assisted reproduction and preimplantation genetic diagnosis methods might prevent the transmission of genetic risks to the fetus. AIM: In this review we summarize data concerning pregnancy risks in patients with increased risk of breast cancer. In addition, we introduce current possibilities and approaches to fertility preservation prior to assisted reproduction treatment as well as novel methods improving the safety of fertility treatment. In the second part of this review, we focus on karyomapping--an advanced molecular genetic tool for elimination of germinal mutations in patients with predisposition to cancer. Moreover, the rapid development of preimplantation genetic diagnosis methods contributes to detection of both chromosomal aneuploidy and causal mutations in a relatively short time-span.

Different fusion configurations of evolutionarily conserved segments in karyotypes of Potamochoerus porcus and Phacochoerus africanus.

The karyotype of the red river hog Potamochoerus porcus (2n = 34) differs from that of the domestic pig by the presence of 2 fusion chromosomes homologous to pig chromosomes 13/16 and 15/17. Moreover, chromosomes corresponding to pig chromosomes 13/16 and 1 are both acrocentric. Hybridization with region-specific painting probes confirmed tandem fusion of pig chromosomes 13 and 16, and a pericentric inversion of the pig chromosome 1p equivalent in P. porcus. The chromosome complement of the wart hog Phacochoerus africanus (2n = 34) differs from the pig karyotype in 2 centric fusions, 13/16 and 15/17. Karyotypic relationships among different Suidae species are discussed in the article. Besides fusions 13/16 and 15/17, which are common to several suids, another fusion of pig chromosomes 14 and 18 is suggested to exist in the karyotype of Sus cebifrons.

Investigation of chromosome aneuploidies in early porcine embryos using comparative genomic hybridization.

Although numerical chromosome errors are known to be prevalent in early human embryos and are likely to be a considerable factor influencing the mortality of early embryos and implantation failure, in domestic animals data about the frequency and nature of errors is limited. The objectives of this study were to investigate the whole chromosome set of in vivo obtained early pig embryos, applying methods of whole genome amplification and comparative genomic hybridization (CGH) and to contribute to the comprehensive understanding of the topic. The embryos were collected from gilts 72 h after insemination. Further, they were lysed and underwent whole genome amplification by multiple displacement amplification. In a subsequent CGH, amplified DNA was compared to control DNA using different fluorescent labeling and hybridization to male pig mitoses. 11 (14.3%) of the 77 pig embryos examined were observed to be aneuploid. We found chromosome errors comprising loss/gain of one or a few chromosomes (10.4%) but also extensive chromosome imbalances (3.9%). Chromosomes 8, 11, 12, 13, 17, and X were most frequently involved in aneuploidies, when compared to chromosomes 2, 9, and 18, which were rarely involved in chromosome errors.

Nonseminomatous germ cell testicular tumors clinical stage I: differentiated therapeutic approach in comparison with therapeutic approach using surveillance strategy only.

Surveillance after orchiectomy alone becomes popular for the management of clinical stage I nonseminomatous germ cell testicular tumors (CS I NSGCTT). Effort to identify patients at high risk of relapse leads to searching for risk factors of CS I NSGCTT. The aim of the study was to analyse own long-term experiences with different therapeutic approaches in CS I NSGCTT patients according to risk factors of the disease progression and to correlate these results with the group of patients who were treated with surveillance strategy only. From 11/1984 to 12/1991 a total of 145 patients with CS I NSGCTT were treated with surveillance strategy only (group A) and were followed-up to 1/2007. Patients, who had the disease progression, were treated with systemic chemotherapy. The disease progression was experienced in 52 patients (35.9 %). The overall survival rate of the patients in this group was 130/145 (89.7 %). From 1/1992 to 1/2007 a total of 323 patients with CS I NSGCTT were stratified to different risk-adapted therapeutic approaches (groups B1-3) according to histopathologic findings of primary tumor removed by inguinal orchiectomy. 111 patients (group B1) with vascular invasion and majority of embryonal carcinoma component in the primary tumor were treated with adjuvant chemotherapy (2 cycles of BEP). Disease progression developed in two patients (1.9 %). Other patients live without evidence of disease (NED). None of them died. Among 11 patients (group B2) with vascular invasion and majority with teratomatous elements in the primary tumor underwent primary retroperitoneal lymph node dissection (RPLND), 9 were found to be pathological stage I. The disease progression was observed in two patients (18.2 %), they died 87-122 months following orchiectomy. Two patients (18.2 %) with pathological stage II received adjuvant chemotherapy. Other 7 patients live with NED following RPLND. 201 patients (group B3) without vascular invasion have been followed after orchiectomy alone. They were kept under close surveillance, consisting of regular follow-up with tumor markers, chest x-ray and CT of the retroperitoneum. The disease progression was observed in 39 patients (19.4 %), who were treated with BEP chemotherapy. Three of them (7.7 %) died after a mean follow-up of 32.7 months following orchiectomy. The overall survival rate of all patients in group B1-3 was 98.4 %. Introduction of different therapeutic approaches in CS I NSGCTT patients according to risk factors of the disease progression might reduce the overall relapse rate of these patients from 35.9 % (group A) to 19.4 % (group B3) (P< 0.001). Surveillance procedure is recommended only in patients without vascular invasion in the primary tumor.

Neo-adjuvant chemotherapy with delayed orchiectomy in patients with advanced germ cell testicular cancer.

A total of 13 patients with advanced germ cell testicular cancer underwent initial PVB chemotherapy without previous orchiectomy. Complete response (CR) of metastases was observed in 5 patients following chemotherapy alone. The residual mass persisted in 8 patients (in 5 of them in the retroperitoneum, in two patients in the lungs only and in one patient in both localizations). The residual masses were removed surgically. There were no viable malignant tumors in the removed tissue on histological examination. Delayed orchiectomy was performed simultaneously with surgical removal of the residual mass in the retroperitoneum or in the lungs in 8 patients, and in 5 patients as a separate procedure in complete responders following chemotherapy alone. Residual viable tumor in the testis was found in three patients, necrotic or fibrotic tissue in 5 patients, and mature teratoma in 5 patients. In patients with advanced germ cell testicular cancer preference must be given to early beginning of intensive chemotherapy without tissue diagnosis of primary tumor by orchiectomy. Benefit of this therapeutic approach is the timely management of acute abdominal and/or pulmonary symptoms of life-threatening distant metastases.

Bilateral germ cell tumors of the testis.

In a retrospective study of 530 patients with testicular germ cell tumors treated between 1977 and 1993, a group of 12 patients (2.26%) with bilateral testicular tumors was analyzed. While bilateral tumors were simultaneously present in two cases (both with different histologic types), consecutive development of a tumor in the contralateral testis was observed in 10 patients 5.25 years (range, 3-13.5 years) after orchiectomy for the first tumor. The authors highlight the variability of histologic types in both testes, the need for an individual therapeutic approach with a view to previous therapy for the first tumor, the need for hormonal replacement as well as the possibility of testicular prosthesis implantation following bilateral orchiectomy.

Systemic chemotherapy for muscle invasive bladder cancer.

A total of 60 patients with muscle invasive transitional cell carcinoma of the bladder were entered into the nonrandomized study. The 1st group consisted of 30 patients treated by M-VAC neo-adjuvant chemotherapy followed by radical cystectomy when a residual tumor had been detected by biopsy made after the treatment. The overall clinical response was 70%. Fifteen (50%) out of 30 patients achieved clinical complete response (cCR). Objective pathologic response was attained in 6 (66.7%) of 9 evaluable patients who underwent radical cystectomy, pathologic complete response (pCR) was observed in two (22.2%) patients. Ten (33.3%) patients are still alive at a median follow-up of 22+ months. There were three (10%) drug-related deaths. The 2nd group consisted of 30 patients treated by CMV (with carboplatin) neo-adjuvant chemotherapy followed by radical pathologic response was attained in 9 (47.4%) of 19 evaluable patients, with pCR in 6 (31.6%) patients. Twenty four (80%) patients are still alive at a median follow-up of 13+ months. There was one (3.3%) drug-related death. The authors recommend immediate radical cystectomy following neo-adjuvant chemotherapy in all patients if their total status it allows.

Chemotherapy of testicular cancer: 10-year experience.

A total of 250 patients with germ cell testicular tumors were treated by PVB chemotherapy between 1982 and 1992. Mean age of patients was 28.9 years (range 15-52). Thirty-four patients in clinical Stage II (11 patients IIA, 13 patients IIB, and 10 patients IIC) underwent primary retroperitoneal lymphadenectomy (RPL) with subsequent chemotherapy. They were followed-up for a mean of 106.3 months (range 85-125). CR was achieved in 30 patients (88.2%). Three patients relapsed. Twenty-seven patients (79.4%) are alive with no evidence of disease (NED) after a minimum of 5 years since the start of therapy. One hundred and twenty-two patients underwent primary chemotherapy for clinical Stages IM (15 patients), IIA (31 patients, IIB (48 patients) and IIC (28 patients) with RPL in cases with residual mass in the retroperitoneum. They were followed-up for a mean of 47.7 months (range 6-122). CR was achieved in 115 patients (92.7%) (75 of them received chemotherapy alone, 40 patients achieved CR following combined cytostatic-surgical treatment). Eleven patients relapsed. One hundred and nine patients (89.3%) are alive with NED. Ninety-four patients in Stages III and IV (8 patients III, 86 patients IV) underwent primary chemotherapy with additional surgical removal of residual metastases. They were followed-up for a mean of 50.5 months (range 6-125). CR was achieved in 65 patients (69.1%) (32 of them received chemotherapy alone, 33 patients achieved CR following combined cytostatic-surgical treatment). Eleven patients relapsed. Fifty-seven patients (60.6%) are alive NED. There were 11 patients with advanced germ cell testicular cancer (Stages IIC and IV) who underwent initial PVB chemotherapy without previous orchiectomy. Delayed orchiectomy was done simultaneously with surgical removal of residual mass in the retroperitoneum or in the lungs or at completion of chemotherapy alone. The toxicity of chemotherapy was moderate. There were drug-related deaths in ten patients (4%).

Management of germ cell testicular cancer with pulmonary metastases.

Twenty eight patients with germ cell testicular cancer pulmonary metastases received primary chemotherapy including bleomycin, etoposide, and cisplatin (BEP). Complete response was achieved in 21 (75%) patients, in 11 of them CR was achieved following chemotherapy alone. Postchemotherapy surgery of residual mass was performed in 12 (42.9%) patients with normalized serum tumor markers. Retroperitoneal lymph node dissection was performed in one patient, pulmonary surgery in four, and both postchemotherapy treatments in 7 patients. Overall cure rate was 89.3%, 26 (92.9%) patients are still alive at a mean follow-up of 19.7+ months (range, 3-34+ months) after the treatment start. Two (7.1%) patients died: one of them due to disease progression during chemotherapy, and the second one due to postoperative complication (acute respiratory failure). Relapse of disease was observed in one patient 21 months following CR achievement, and sequential chemotherapy was introduced. Authors recommend surgical remove of all radiologically detected residual deposits, because the available imaging methods are not adequate for determining the histologic composition of residual mass, which is decisive for further therapy and has prognostic value.

In vitro antiproliferative effect of interferon alpha in solid tumors: a potential predictive test.

An in vitro test for the antiproliferative effect of human leukocyte interferon (IFN-alpha) was performed in primary cultures of tumor cells obtained from 32 patients with either malignant melanoma (13), renal carcinoma (4) or bladder carcinoma (15). Our results demonstrated activity of IFN in all three groups of solid tumors. However, appreciable differences in sensitivity to antiproliferative effect of IFN between individual tumors of the same type were found. The potential of this antiproliferative test for prediction of treatment response in IFN-therapy is discussed.

Orchiectomy alone for clinical stage I nonseminomatous germ cell tumors of the testis (NSGCTT): a minimum follow-up period of 5 years.

AIMS AND BACKGROUND: Surveillance after orchiectomy alone has gained great popularity in the management of stage I NSGCTT. Preliminary results were enthusiastic, but critical voices have been raised against general use of this option as routine management. In an effort to identify patients at high risk of relapse, there has been a search for adverse prognostic factors of stage I nonseminomatous germ cell testicular tumors (NSGCTT). The aim of the study was to identify those patients in whom a surveillance policy is less likely to be successful. METHODS: Eighty patients with stage I NSGCTT were followed for at least 5 years. They were assigned to their respective clinical stage on the basis of physical examination, chest X-ray, CT of the retroperitoneum and post-orchiectomy tumor markers. The criteria for inclusion in clinical stage I were normal results of these examinations. The policy of surveillance consisted of regular follow-up with tumor markers, chest X-ray and CT of the retroperitoneum. Patients who relapsed were treated with cisplatin-containing chemotherapy. In all patients, diagnostic delay, pre-orchiectomy tumor markers, T staging category, size, histopathology and vascular invasion in the primary tumor, and semen analysis were recorded. RESULTS: Follow-up revealed that 51 of the 80 patients (63.7%) were free of disease 61-110 months (mean, 83.1) after orchiectomy. Relapse was detected in 29 patients (36.3%) 3-58 months (mean, 13) after orchiectomy. The overall survival rate was 95%. The main risk factors of relapse were: vascular invasion, a major embryonal carcinoma and a minor teratoma component in the primary tumor, and low sperm count before orchiectomy. CONCLUSIONS: The authors recommend the following risk-adapted treatment procedures: retroperitoneal lymph node dissection in patients with vascular invasion and a major teratoma component, adjuvant chemotherapy in patients with vascular invasion and a major embryonal carcinoma component, and surveillance policy in patients without vascular invasion.

Extragonadal germ cell tumours.

In a retrospective study of patients treated for germ cell tumours, the authors found seven patients with primary extragonadal tumours in the retroperitoneum. These tumours are, in terms of histology, identical with germ cell tumours of the testis. The disease manifests itself by pain in the kidney region, palpable abdominal mass, weight loss, fever, and gynaecomasty. The diagnosis was confirmed histologically by examining tissue specimens obtained by probatory laparotomy and from the supraclavicular lymph nodes. The choice of therapy and prognosis of disease depend on the histological evidence. Orchiectomy is unnecessary provided both testes are clinically unaltered.

Hydrostatic pressure technique and intravesical instillation of formalin: new methods for the control of severe bleeding from the bladder.

Intractable haemorrhages of the bladder in consequence of wide-spread tumours or of haemorrhagic cystitis secondary to radiation therapy involve serious therapeutic problems. Failure of the conventional therapy to bring the haemorrhage under control imposes more active measures so as to avert the danger of exsanguination. The condition of the patients is, however, generally incompatible with major surgery. In this situation the authors resorted to the hydrostatic pressure technique and to intravesical instillations of formalin. Their observations with these procedures are reported.

The value of scrotal ultrasound in patients with suspected testicular tumour.

A prospective study was designed to assess the value of scrotal ultrasound in the diagnosis of testicular neoplasm. Comparison of findings yielded by ultrasound with those made on surgical exploration of the scrotal contents in 56 patients showed a sensitivity of 94.6%, specificity of 57.9% and an overall accuracy of ultrasound of 82.1%. While capable of distinguishing intra- from extratesticular structure, scrotal ultrasound is not specific enough to differentiate a tumour from benign diseases involving testicular parenchyma. Still, it may add new information to the clinical examination of the scrotum, and reduce the number of probatory surgical procedures in patients with the finding of an intrascrotal mass. This paper describes the ultrasound pictures of a normal testis, testicular tumours and extratesticular disease that are most often considered in the differential diagnosis of testicular tumours.

The incidence of carcinoma in situ in postpubertal undescended testis.

In a retrospective study of 32 adult males undergoing "preventive" orchiectomy for unilateral undescended testis the average age of the patients at the time of orchiectomy was 28.3 years (range 16-63). Macroscopically, all the testes were atrophic and there was no evidence of tumour. In all surgically removed testes histological examination showed atrophied germinative epithelium and absence of spermatogenesis. In one patient, aged 16, an obvious carcinoma in situ was identified. In another 3 patients, aged 18, 19 and 29, atypical germ cells were found. Unilateral undescended testis in postpubertal patients should be treated by orchiectomy instead of orchiopexy.

Chronic ischaemia of the ileal neobladder: clinical manifestations and management.

Recently, bladder replacement with intestinal reservoir is becoming more common as urinary diversion in a selected group of patients after radical cystectomy. Complications occurred in two patients, 2 and 7 months, respectively, after successful radical cystoprostatectomy and reconstruction of the ileal neobladder, due to chronic ischaemic changes of the latter. Their clinical manifestations and management are discussed. Some of the possible potential mechanisms responsible for ischaemic changes of the reservoir are reviewed.

Bilateral testicular germ-cell tumors--a single centre long-term experience.

OBJECTIVES: The incidence of bilateral testicular tumors (BTT) had increased over the preceding decade. The aim of the present study is to analyse a group of patients with BTT and to high-light the need for long-term follow-up of patients treated in a single centre. MATERIAL AND METHODS: 27 (2.8%) out of 960 patients with germ-cell testicular tumors (GCTT), treated between 4/1977 and 8/2001, developed bilateral disease. All of them underwent radical orchiectomy (in one patient was done delayed orchiectomy after primary chemotherapy due to advanced disease). Additional treatment was planned according to the histologic type and clinical stage of the disease, and previous treatment as well. The survival data were reviewed. RESULTS: 24 out of 27 patients (88.9%) developed the 2nd tumor metachronously (median interval 66 months, range, 4-197 months) and three (11.1%) had synchronous BTT. Only 7 patients (25.9%) had identical histological types on both sides (6 of them with pure seminomas, one with embryonal carcinoma). Two of three synchronously developed BTT had different histologic types on both sides. GCTT of one histologic type were observed in respect of the first tumor: 11 seminomas, three embryonal carcinomas, in respect of the 2nd tumor: 10 seminomas, three embryonal carcinomas, in respect of the 2nd tumor: 10 seminomas, three embryonal carcinomas and one mature teratoma. GCTT of more than one histologic type were observed in respect of the first and the 2nd tumors: 6 mixed GCTT with seminoma component and 7 without seminoma component. Majority of BTT was presented in clinical stage I (in respect of the first tumor in 70.4%, in respect of the 2nd tumor in 62.9%). The median duration of the follow-up after the diagnosis of the first GCTT was 149 months (range, 13-288 months) and after the diagnosis of the contralateral GCTT was 68 months (range, 1-167 months). Twenty-five patients (92.6%) were alive with NED at their last follow-up visit. Two patients died by mean of 22.5 months (range, 21-24 months) after the 2nd orchiectomy. CONCLUSIONS: All patients with unilateral GCTT have an increased risk of developing a contralateral testicular tumor, even decades after diagnosis. Management should be individualised for each patient.

Primary chemotherapy in the management of low stage (IIA and IIB) non-seminomatous germ cell testicular tumours.

In a prospective study a total of 65 patients in clinical stages IIA and IIB nonseminomatous testicular tumours were treated by primary chemotherapy followed by retroperitoneal lymphadenectomy in cases with residual disease. The patients were given a combination of cisplatin, vinblastine and bleomycin, or also etoposide. Sixty-two patients (95.4%) achieved complete response: 39 (60%) by chemotherapy alone and 23 (35.4%) following surgical removal of residual disease. Three patients died; there were two drug-related deaths during PVB chemotherapy, one patient had progression of disease following chemotherapy and died as a result of disease dissemination. Three patients relapsed from complete response following chemotherapy, two of them died within 19 and 29 months after the onset of therapy. The third patient received second-line chemotherapy and gained complete response again. Of the 65 patients, 60 (92.3%) survive with no evidence of disease. The follow-up period ranged from 6 to 79 months (mean 39.4 months, median 39 months).

Advantages of converting incontinent to continent urinary diversion.

A modified Mainz pouch with catheterizable stoma was constructed in six patients who had originally undergone incontinent urinary diversion by ureteroileostomy 7 to 22 years previously for bladder exstrophy or neurogenic bladder with total urinary incontinence. The surgical technique differed from the standard as follows: after stomal excision, the preexisting ileal loop was detubularized and combined with additional ileal and colonic segments for pouch construction. In patients in whom the original ureteroileal anastomoses were patent and the contrast medium refluxed freely to the upper urinary tract during loopography, the ureters were not reimplanted but kept intact. In all patients the ileal valve was connected as stroma to the umbilicus. In addition, two patients underwent construction of a standard Mainz pouch. One had had primary ureterosigmoidostomy and the other one ureterostomies, 10 and 3 months previously, respectively. The urodynamic characteristics of the reservoir were normal in all. In six ureteropelvic units dilation improved significantly and in two patients the bilateral loop-ureter reflux diminished. Long-term follow-up (up to 45 months) showed no further impairment of the kidneys.

Delayed orchiectomy after chemotherapy in patients with advanced testicular cancer.

INTRODUCTION: The therapeutic procedures in the management of testicular cancer are determined by histological findings in the removed testis and by the extent of the disease at the time of diagnosis. However, all advanced tumors could be treated by primary chemotherapy regardless of the histological findings. The current imaging techniques (ultrasound of the testis, abdominal and chest CT examination) and laboratory tests (determination of serum tumor markers AFP and hCG) provide sufficient evidence for the presence of cancer. When the diagnosis of advanced tumor is evident, it is possible to start the treatment without orchiectomy. The aim of this study was to evaluate the advantages of neo-adjuvant chemotherapy with delayed orchiectomy in the management of advanced testicular cancer. MATERIAL AND METHODS: A total of 36 patients with advanced germ cell testicular cancer underwent primary PVB or BEP chemotherapy without previous orchiectomy. Mean age of patients was 32 years. Detailed medical, surgical and urological examination showed pulmonary metastases and/or extensive abdominal tumorous masses imitating acute abdominal crisis and impaired drainage of the kidney due to ureteral obstruction. Searching for the origin, testicular tumor was detected. Eleven patients had a bulky disease in the retroperitoneum (Stage IIC), two had enlarged retroperitoneal lymph nodes (Stage IIB), two had enlarged mediastinal lymph nodes (Stage III) and other 16 patients had also pulmonary metastases, and 5 pts had pulmonary metastases only. The patients were treated with cisplatin-containing combination chemotherapy. Following completion of chemotherapy, orchiectomy was performed alone or simultaneously with retroperitoneal lymph node dissection (RPLND) and/or lung metastasectomy in cases with persistent residual mass. Following orchiectomy the patients were regularly checked and in cases with viable malignant tumor found in the testis sequential chemotherapy was administered. Similarly when the relapse of the disease was detected, the patients were treated with sequential chemotherapy. RESULTS: Complete disappearance of metastases was observed in 12 patients following chemotherapy alone. The residual mass persisted in 24 patients (in 22 out of them in the retroperitoneum and in two patients also in the lungs) and was removed surgically. The viable tumor in the removed tissue was found in one patient. Delayed orchiectomy was performed simultaneously with surgical removal of residual mass in the retroperitoneum in 24 patients and as a separate procedure in 12 patients who have been considered to be complete responders following chemotherapy alone. Residual viable tumor in testicular specimen was found in three patients, necrotic or fibrotic tissue in 18, and mature teratoma in 15 patients. Overall survival of the patients was 26/36 (72.7%) at mean of 56.9 months (range 7-145 months, median 50 months) since the start of the treatment. CONCLUSIONS: In patients with advanced germ cell testicular cancer preference must be given to the early beginning of intensive chemotherapy without the need of tissue diagnosis of primary tumor that should be obtained by orchiectomy. Benefit of this therapeutic approach is the timely management of acute abdominal and/or pulmonary symptoms of life-threatening distant metastases.