Zeljko Kastelan

Varicella Zoster Infection in Renal Transplant Recipients: Prevalence, Complications and Outcome

Varicella zoster virus (VZV) is an important pathogen after renal transplantation. In the present study, we examined the prevalence, clinical presentation and outcome of VZV infections in renal transplant recipients. Charts and medical records of adult renal allotransplant recipients were investigated to find patients with VZV infection. From December 1972 until July 2010, 1,139 patients received kidney allograft at our institution. VZV infection was diagnosed in 40 patients (3.51%). 28 patients (70%) had intensified immunosuppression prior to VZV infection occurrence. Median time of onset was 2.13 years after transplantation (range 9 days to 19.2 years). 35 patients developed VZV during the first post-transplant year (median 0.61 years). Four patients developed VZV infection more than 12 years after transplantation. 33 patients (82.5%) had dermatomal distribution, 5 (12.5%) disseminated herpes zoster (HZ), and 2 patients (5%) who were VZV IgG-negative before transplantation, developed chickenpox. Immunosuppression was reduced and patients received acyclovir. Cutaneous scarring was recorded in 7 cases (17.5%). Two patients developed post-herpetic neuralgia, which was accompanied by scarring and skin depigmentation in 1 of them. Five patients (12.5%) experienced relapse of HZ. Timely initiation of therapy may prevent development of complications and the visceral form of disease. Based on our experience with development of chickenpox, we suggest active immunization for all seronegative patients before organ transplantation.

The clinical course of patients with adrenal incidentaloma: is it time to reconsider the current recommendations?

OBJECTIVE The current guidelines for the management of adrenal incidentaloma advise hormonal and radiological follow-up of patients for 2-5 years after the initial diagnosis. However, the vast majority of adrenal incidentaloma are non-functional benign cortical adenomas that require no treatment, so the routine application of the current strategies often results in a number of unnecessary biochemical and radiological investigations. The aim of this study was to analyse the clinical course of patients with adrenal incidentaloma and to provide a critical review of the current management strategy of the disease. DESIGN AND METHODS This was a retrospective study performed in the Croatian Referral Center for adrenal gland disorders. The study included 319 consecutive patients with adrenal incidentaloma, 174 of which were followed for at least 24 months. RESULTS The vast majority of patients were diagnosed with benign adrenal masses, whereas in about 5% of them adrenal tumor corresponded to adrenal carcinoma or metastasis. Tumor density was found to be superior to tumor size in distinguishing benign adrenal masses from malignant tumors and pheochromocytomas. During the follow-up, no patient demonstrated a clinically significant increase in tumor size. In addition, no changes, either in metanephrines and normetanephrines or in the activity of renin-aldosterone axis, were observed during the follow-up. Six patients developed subclinical Cushings syndrome (SCS) whereas eight patients with SCS showed biochemical remission during follow-up. CONCLUSION The study suggests that the risk of an adrenal mass initially diagnosed as benign and non-functional becoming malignant or hormonally active is extremely low. Therefore, the clinical management of those patients should be tailored on an individual basis in order to avoid unnecessary procedures.

MAGE‐A10 cancer/testis antigen is highly expressed in high‐grade non‐muscle‐invasive bladder carcinomas

Bladder cancer is a common urinary malignancy and a prevalent cause of cancer‐related death. Current therapies of early stage non‐muscle‐invasive bladder cancer (NMIBC) are frequently associated with undesirable toxicities and recurrence. Active antigen‐specific immunotherapy may provide a valid therapeutic option for patients with NMIBC. Cancer‐testis antigens (CTA) expressed in various tumour types and in a limited range of healthy tissues may represent potential targets for specific immunotherapy. MAGE‐A10 is probably the most immunogenic antigen of the MAGE‐A family. We evaluated the expression of MAGE‐A10 in NMIBC. Seventy‐nine patients undergoing surgical treatment for NMIBC were enrolled in the study. MAGE‐A10 gene expression was assessed by quantitative real‐time polymerase chain reaction. Immunohistochemistry was performed on paraffin‐embedded sections. MAGE‐A10 gene was specifically expressed in one‐third of NMIBC (n = 24: 32.43%). Gene expression was correlated with high tumour grade. MAGE‐A10 protein was exclusively detectable in nuclei of tumour cells. More importantly, MAGE‐A10 protein was also more frequently detectable in high‐grade tumours (p = 0.0001) and in stage T1 tumours invading subepithelial tissue or lamina propria (p = 0.01). A strong correlation between MAGE‐A10 staining score and tumour grade and stage could accordingly be observed. These data indicate that MAGE‐A10 expression is a feature of aggressive NMIBC and might be used as a novel target for specific immunotherapy of these cancers.

Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population

Genome-wide association studies in patients with testicular germ-cell tumors (TGCT) from Great Britain and the United States have identified six susceptibility loci in or near biologically plausible candidate genes. However, these loci have not been replicated in an independent European sample. We performed a genetic replication study of previously identified TGCT susceptibility loci in a Croatian case-control sample and performed additional analyses as concerning histological subtypes or tumor staging. We analyzed six single-nucleotide polymorphisms [rs2900333 (ATF7IP), rs210138 (BAK1), rs755383 (DMRT1), rs995030 (KITLG), rs4624820 (SPRY4), and rs4635969 (TERT/CLPTM1L)], each representing one of the published susceptibility loci/genes. Five susceptibility loci were found to be also associated in the Croatian population with P-values between 2.1e-10 (rs995030; odds ratio [OR] 3.08) and 0.01739 (rs4635969; OR 1.37), which remained statistically significant after correction for multiple testing. Although rs2900333 near ATF7IP just showed borderline association with all-TGCT (OR 1.24, P = 0.062), it showed significant association with the more aggressive forms of the tumor (OR 1.51, P = 0.0067)-a clinically interesting finding, which however has to be replicated in an independent sample. Assessment of cumulative risks revealed that men with at least seven risk alleles have a more than 2.5-fold increased disease risk (OR = 2.73, 95% confidence interval = 1.98-3.79). In summary, we independently replicated the majority of TGCT susceptibility loci identified previously in a Croatian sample and suggested a possible role of genetic variation near ATF7IP in regulating disease progression.

Laparoscopic Adrenalectomy: Lessons Learned from 306 Cases

INTRODUCTION Laparoscopic adrenalectomy has become the standard of care for the surgical treatment of benign adrenal pathology. We present the following case series documenting our experience in refinement of this approach. PAIENTS AND METHODS Analysis of patient records identified those in whom laparoscopic adrenalectomy was performed from January 1997 through February 2010. Study variables included indications, operative time, blood loss, length of hospital stay, histopathological evaluation, and complications. RESULTS Laparoscopic adrenalectomy was performed in 306 patients using the transperitoneal lateral approach. No major operative complications were noted, and postoperative complications included a pulmonary embolism and 2 cases of pneumonia. Conversion to the open approach was necessitated in two cases. The median operative time was 95±29 minutes (range, 45-145 minutes). Estimated blood loss was 60 mL (range, 30-150 mL). The mean size of the removed gland was 5.9±1.6 cm (range, 3-13 cm). The mean size of the tumor was 5±2 cm (range, 0.5-12 cm). The median hospitalization was 4±3.7 days (range, 2-22 days). Adrenal pathology included adenoma (n=164), pheochromocytoma (n=79), hyperplasia (n=35), metastatic carcinoma (n=22), cyst (n=9), myelolipoma (n=9), hemangioma (n=3), ganglioneuroma (n=3), and melanoma (n=2). CONCLUSION Laparoscopic adrenalectomy is a safe and feasible approach to adrenal pathology, providing the patients with all the benefits of minimally invasive surgery.

Immunohistochemical analysis of the expression of MAGE-A and NY-ESO-1 cancer/testis antigens in diffuse large B-cell testicular lymphoma

BackgroundPrimary testicular lymphoma (PTL) is a rare and lethal disease. The most common histological subtype is diffuse large B-cell lymphoma (DLBCL). Standard treatments are frequently ineffective. Thus, the development of novel forms of therapy is urgently required. Specific immunotherapy generating immune responses directed against antigen predominantly expressed by cancer cells such as cancer-testis antigens (CTA) may provide a valid alternative treatment for patients bearing PTL, alone or in combination with current therapies.MethodsThree monoclonal antibodies (mAbs), 77B recognizing MAGE-A1, 57B recognizing an epitope shared by multiple MAGE-A CTA (multi-MAGE-A specific) and D8.38 recognizing NY-ESO-1/LAGE-1 were used for immunohistochemical staining of 27 PTL, including 24 DLBCL.ResultsExpression of MAGE-A1 was infrequently detectable in DLBCL specimens (12.50%), whereas multi-MAGE-A and NY-ESO-1/LAGE-1 specific reagents stained the cytoplasms of tumor cells in DLBCL specimens with higher frequencies (54.17% and 37.50%, respectively) with different expression levels.ConclusionsThese results suggest that MAGE-A and NY-ESO-1/LAGE-1, possibly in combination with other CTA, might be used as targets for specific immunotherapy in DLBCL.

Correlation between retroperitoneal lymph node size and presence of metastases in nonseminomatous germ cell tumors

Eighty-five patients had staging laparoscopic retroperitoneal lymph node dissection (L-RPLND) for nonseminomatous germ cell tumors at our institution. The largest lymph node size was measured and presence or absence of metastatic disease was determined. A total of 1139 lymph nodes have been removed and in 27 (31.8%) patients, metastases in one or more lymph nodes were detected. There were 338 (29.7%) hilar, 259 (22.7%) paraaortic, 221 (19.4%) interaortocaval, 171 (15%) paracaval, 133 (11.7%) preaortic and 17 (1.5%) precaval lymph nodes. The total number of lymph nodes with metastases was 74 (6.5%), and 1065 (93.5%) nodes did not have any metastases. The average size of a lymph node with metastases was 1.05 (0.3-3), and without metastases it was 0.55 (0.1-2.5) cm, (p<0.001). If we use > 1 cm size of a lymph node as a “cut-off” value for enlargement and presence of metastases, 60% of metastatic lymph nodes would be missed since they were all ≤ 1 cm. Our results have shown that decreasing size of lymph nodes which are considered positive from > 1 cm to 0.7 -0.8 cm can be recommended, with specificity and sensitivity equal 70%.

Laparoscopic partial nephrectomy with diode laser: a promising technique

OBJECTIVE The aim of this study was to evaluate application of diode laser in laparoscopic partial nephrectomy (LPN), and to question this technique in terms of ease of tumor excision and reduction of warm ischemia time (WIT). BACKGROUND DATA LPN is the standard operative method for small renal masses. The benefits of LPN are numerous, including preserving renal function and prolonging overall survival. However, reduction of WIT remains main challenge in this operation. In order to shorten WIT, many techniques have been developed, with variable results. PATIENTS AND METHODS We performed a prospective collection and analysis of health records for patients who were operated on between March 2011 and August 2012. Inclusion criteria were single tumor ≤ 4 cm, predominant exophytic growth and intraparenchymal depth ≤ 1.5 cm, with a minimum distance of 5 mm from the urinary collecting system. RESULTS We operated on 17 patients. Median operative time was 170 min. In all but two patients, we had to perform hilar clamping. Median duration of WIT was 16 min. Pathohistological evaluation revealed clear cell renal cancer and confirmed margins negative for tumor in all cases. Median size of the tumor was 3 cm. Median postoperative hospitalization was 5 days. Average follow up was 11.5 months. There were no intraoperative complications. One postoperative complication was noted: perirenal hematoma. CONCLUSIONS Laser LPN is feasible, and offers the benefit of shorter WIT, with effective tissue coagulation and hemostasis. With operative experience and technical advances, WIT will be reduced or even eliminated, and a solution to some technical difficulties, such as significant smoke production, will be found.

Immunolocalization and mRNA Expression of Bone Morphogenetic Protein-6 in Human Clear Cell Renal Carcinoma

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β superfamily of proteins. Dysregulation of BMP signaling has been suggested in the carcinogenesis of different organs. We determined BMP-6 mRNA and protein expression in localized human clear cell renal carcinoma (CCRC), obtained from 20 patients who underwent nephrectomy, by the real-time polymerase chain reaction and immunohistochemistry. 15/20 patients exhibited higher BMP-6 mRNA expression in malignant than in healthy renal tissue relative to the PBGD expression (p < 0.05). Immunostaining intensity for BMP-6 in healthy renal tissue ranged from 0 to 2 (average 0.9), as well as in renal clear cell carcinoma (average 1.1). Seven of 20 (35%) healthy tissue samples failed to stain with BMP-6 antibody, compared to 2/20 (10%) tumor samples (p < 0.05). BMP-6 immunostaining was positive in 18/20 CCRC samples. Staining was localized in the cytoplasm and/or membrane of malignant cells. Malignant tissue had significantly higher BMP-6 mRNA expression than healthy tissue. There was no significant correlation between BMP-6 mRNA and protein expression with disease presentation, disease progression and patients’ characteristics. Long-term follow-up of our patients is needed to determine the possible role of increased expression of BMP-6 in CCRC.

Lidocaine Suppository for Transrectal Ultrasound-Guided Biopsy of the Prostate: A Prospective, Double-Blind, Randomized Study

Aims: To investigate analgesia using lidocaine suppositories for prostate biopsy. Methods: From 2007 to 2009, 160 patients underwent transrectal ultrasound-guided prostate biopsy at the Department of Urology, KBC Zagreb. 80 patients received a 60-mg lidocaine suppository intrarectally at different time points from 15 to 120 min before biopsy and 80 patients received a glycerin suppository as placebo. The pain level was evaluated using a visual analogue scale (VAS). Results: There were no statistically significant differences between the groups, i.e. they were similar regarding patients’ age, prostate-specific antigen levels, prostate volume and the incidence of diagnosis of malignancy on biopsy. The mean pain score in the lidocaine group (3 ± 1) was significantly lower than the mean pain score in the glycerin group (4.1 ± 1.3) (p < 0.001). A noticeable trend towards lower pain scores in the lidocaine group was observed with more time elapsing from placing the suppository till the biopsy and the optimal time for performing biopsy starting approximately 1 h after placing the suppository. Conclusions: Lidocaine suppositories are an easy-to-use, self-applicable (by the patient) and cheap method of local analgesia, with acceptable results. Possible complications related to this procedure are insignificant.