Background
Metastatic germ cell tumors of the testis (GCTs) are risk‐stratified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification system. This risk ...classification is based on anatomical risk factors as well as tumor marker levels of AFP, HCG, and LDH assessed pre‐chemotherapy after orchiectomy treatment. An incorrect classification is possible when pre‐orchiectomy marker levels are used, possibly resulting in over‐ or undertreatment of patients. The aim was to investigate the potential frequency and clinical relevance of incorrect risk stratification using pre‐orchiectomy tumor marker levels.
Methods
A multicenter registry analysis, including patients with metastasized nonseminomatous GCT (NSGCT), was conducted by investigators of the German Testicular Cancer Study Group (GTCSG). Based on the marker levels at different timepoints, IGCCCG risk groups were calculated. The agreement was tested using Cohen's kappa.
Results
A total of 672 of 1910 (35%) patients were diagnosed with metastatic NSGCTs, and 523 (78%) had sufficient data for 224 follow‐up data points. By using pre‐orchiectomy tumor marker levels, 106 patients (20%) would have been incorrectly classified. Seventy‐two patients (14%) were classified into a higher risk category, and 34 patients (7%) were classified into a lower risk category. Cohen's kappa was 0.69 (p < 0.001), showing a strong agreement between the use of both marker timepoints. The treatment of misclassified patients would have resulted in an overtreatment of 72 patients or undertreatment of 34 patients.
Conclusions
The use of pre‐orchiectomy tumor marker levels may lead to an incorrect risk classification and might subsequently lead to under‐ or overtreatment of patients.
Retroperitoneal lymph node dissection (RPLND) and adjuvant chemotherapy are two adjuvant treatment options for patients with clinical stage I nonseminomatous germ cell tumors of the testis (NSGCT). ...Aim of this trial was to prove the advantage of one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy compared with RPLND in terms of recurrence.
Between 1996 and 2005, 382 patients were randomly assigned to receive either RPLND (n = 191) or one course of BEP (n = 191) after orchidectomy. The primary study end point was the rate of recurrence. The trial was powered to detect a 7% reduction (from 10% to 3%) of recurrence with chemotherapy compared with surgery.
After a median follow-up of 4.7 years, two and 15 recurrences were observed in the intention-to-treat population with chemotherapy and surgery, respectively (P = .0011). The difference in the 2-year recurrence-free survival rate between chemotherapy (99.46%; 95% CI, 96.20% to 99.92%) and surgery (91.87%; 95% CI, 86.87% to 95.02%) was 7.59% (95% CI, 3.13% to 12.05%). The hazard ratio to experience a tumor recurrence with surgery as opposed to chemotherapy was 7.937 (95% CI, 1.808 to 34.48).
To our knowledge, this is the largest randomized trial investigating adjuvant treatment strategies in clinical stage I NSGCT, which showed the superiority of one course BEP over RPLND performed according to community standards to prevent recurrence. Although not standard treatment, one course of BEP is active in an unselected group of patients with clinical stage I disease and merits further investigation.
Purpose
Uric acid (UA) calculi can be referred to chemolitholysis rather than invasive treatment. Dual-energy computed tomography (DECT) may be able to distinguish between UA and non-UA (NUA) ...calculi. The aim of this study was to evaluate the validity of third-generation DECT for the first time and to investigate whether combining DECT with clinical parameters can increase its predictive accuracy.
Materials and methods
All patients who presented to our emergency department between January 2015 and March 2017 with urinary stones were prospectively included in this observational study and underwent DECT with subsequent interventional stone removal. Stone composition was analyzed using infrared spectrometry as the gold standard. Predictive accuracy of DECT and clinical covariates was computed by assessing univariate and multivariate areas under the curve (AUCs).
Results
Of 84 patients with 144 urinary stones, 10 (11.9%) patients had UA stones according to infrared spectrometry, and the remaining stones were NUA or mixed stones. DECT had a positive predictive value of 100% and a negative predictive value of 98.5% for UA stones. The AUC for urine pH alone was 0.71 and 0.97 for DECT plus urine pH. No UA stones were found in patients with a urine pH above > 5.5. Mean DLP was 225.15 ± 128.60 mGy*cm and mean effective dose was 3.38 ± 1.93 mSv.
Conclusions
DECT is a safe method for assigning patients to oral chemolitholysis. Clinical preselection of patients based on urinary pH (< 6.0) leads to a more liable use of DECT. Third-generation DECT needs significant lower radiation doses compared to previous generations.
One cycle of adjuvant chemotherapy with bleomycin, etoposide and cisplatin (BEP) has shown superiority in recurrence-free survival over retroperitoneal lymph node dissection (RPLND) in patients with ...clinical stage (CS) I non-seminomatous germ cell tumours (NSGCTs) of the testis in the setting of a phase III trial. We report the recurrences and late toxicities of this study after 13 years of follow-up.
Questionnaires from 382 patients with CS I NSGCT treated with 1 cycle of adjuvant BEP (arm A) or RPLND + two cycles of adjuvant BEP in cases of pathological stage II disease (arm B) were evaluated regarding recurrences and late toxicity. Overall, information on recurrence status was available in 337 patients, and 170 questionnaires were evaluable for toxicity (arm A: 95; arm B: 75).
With a median follow-up of 13.8 years (0–22), 3 patients (1.6%) in arm A and 16 patients (8.4%) in arm B experienced recurrence. The 15-year PFS in arm A/B was 99% (CI 96–100%)/92% (CI 89–99%) (p = 0.0049). The 15-year OS in arm A/B was 93% (CI 87–97%)/93% (CI 86–97%) (p = 0.83). Eight patients (4.2%) in arm A and four patients (2.1%) in arm B showed metachronous secondary testicular cancer (p = 0.26). Five patients (2.6%) in arm A and four patients (2.1%) in arm B developed other malignancies. Toxicities were not significantly different apart from retrograde ejaculation, which occurred more frequently after RPLND (10% versus 24%, p = 0.01).
With long-term observation, one cycle of BEP remains superior to RPLND in preventing recurrence and was tolerated without any clinically relevant long-term toxicities.
•>13-year follow-up recurrences in CS I NSGCT more frequent with RPLND than after BEP x1.•No excess mortality due to secondary malignancies could be detected.•Late toxicities do not differ between 1 x BEP and RPLND.
Purpose
Due to the excellent cure rates for testicular cancer (TC), focus has shifted towards decreasing therapy-related morbidities. Thrombosis is a frequent complication of cisplatin chemotherapy. ...Furthermore, the optimal route of administration for chemotherapy is still under debate. The purpose of this study was to assess the patterns of care concerning dosing and duration of thromboprophylaxis currently utilized in TC patients in German-speaking countries as well as the route of chemotherapy administration.
Methods
A standardized questionnaire was sent to all members of the German TC Study Group (GTCSG) and to all the urological university hospitals in Germany. The questionnaire was also sent to the oncologic clinics at those universities where urologists do not administer chemotherapy.
Results
The response rate was 87% (55/63). Prophylactic anticoagulation with low-molecular-weight heparin (LMWH) was administered in 94% of the clinics. The dosing of LMWH was prophylactic (85%), high prophylactic (adjusted to bodyweight) (7%), or risk adapted (9%). After completion of chemotherapy, anticoagulation was continued in 15 clinics (33%) for 2 to 24 weeks, while the remainder stopped the LMWH upon cessation of chemotherapy. Chemotherapy was administered via central venous access in 59%, peripheral IV in 27%, or both in 14% of the clinics.
Conclusions
Most of the institutions performed some form of thromboprophylaxis, although the modes of application varied by institution type and amongst the urologists and oncologists. Prospective studies are needed to evaluate the incidence, date of occurrence, and risk factors of venous thrombosis during TC chemotherapy to provide a recommendation concerning prophylactic anticoagulation.
Because the efficacy of nonsurgical therapy of Peyronie’s disease is controversial, this review analyses the current status of conservative therapy of Peyronie’s disease.
A systematic survey on ...results of studies published as original papers in peer-reviewed journals is provided.
Oral drug therapies include potassium para-aminobenzoate (Potaba), vitamin E, colchicine, tamoxifen, propoleum, acetyl-l-carnitine, and propionyl-l-carnitine. Verapamil, interferon-α2a and interferon-α2b, collagenase, cortisone, hyaluronidase, and superoxide dismutase are considered intralesional therapies that have had various degrees of success. Other treatments include local gels, iontophoresis, extracorporeal shock wave therapy, and radiation.
This review analyses the current status of the conservative therapy of Peyronie’s disease, because the efficacy of the nonsurgical therapy is controversial.
The aim of the present study was to examine the biological differences between seminomas with occult and clinically apparent metastases at the time of diagnosis of the primary tumor to gain insight ...into the biology of these tumors and facilitate the identification of novel predictors of seminoma metastasis.
Total RNA including small RNAs was isolated from testicular tumors of patients with pure seminoma presenting with lymphogenic metastasis (n = 5, clinical stage IIb/c) and occult metastasis (n = 5, clinical stage I). The regulation of biological processes was examined (1) throughout the mRNA transcriptome (whole genome microarrays, 8×60 K Array, Agilent with 4 samples/group) and (2) the miRNA transcriptome employing small RNA next generation sequencing (SOLID, Life Technologies with 5 samples/group). Protein coding genes (mRNAs) and small RNAs showing a significant (≥2-fold) difference between the groups were identified. Finally (3), we examined 95 candidate miRNAs in 36 apparent metastasized and another 5 occult metastasized seminoma using logistic regression analysis.
Among 19,596 genes, on average 12,894 mRNAs appeared expressed (65.8%, SD+/-2.4; range, 62.0-69.3%) and 16.99×106/13.94×106 small RNA reads were identified for apparent/occult metastasized seminoma. These reads on average convert into 9,901/9,675 small RNAs including 422/404 mature microRNAs. None of these mRNAs/small RNAs met our selection criteria for candidate genes. From 95 candidate miRNAs 44 appeared expressed, with 3 of them showing weak but significant (p = 0.05) differences among both groups.
Occult and apparent metastasized seminomas are biologically almost indistinguishable and probably represent no separate tumor entities. These findings may simplify future research on seminoma metastasis.
We aimed to better discriminate metastasized (lymphogen/occult/both combined) from non-metastasized seminoma based on post-transcriptional changes examined in the peripheral blood.
Total RNAs ...including small RNAs were isolated from the peripheral blood of patients suffering from metastasized testicular tumours (lymphogen, n = 5, clinical stage IIb/c; occult, n = 5, clinical stage I) and non-metastasized patients (n = 5, clinical stage I). Small RNA next generation sequencing (SOLID, Life Technologies) was employed to examine post-transcriptional changes. We searched for small RNAs showing at least 50 reads and a significant ≥ 2-fold difference using peripheral blood small RNAs of non-metastasized tumours as the reference group. Candidate small RNAs were examined in univariate logistic regression analysis and combinations of two small RNAs were further examined using support vector machines.
On average 1.3 x 10(7), 1.2 x 10(7) and 1.2 x 10(7) small RNA reads were detectable in non-metastasized, lymphogen and occult metastasized seminoma, respectively of which 73-76% remained after trimming. From these between 80-82% represented annotated reads and 7.2-7.8% (1.6-1.7 x 10(4)) were annotated small RNA tags. Of them 137 small RNAs showed > 50 reads and a ≥ two-fold difference to the reference. In univariate analysis we detected 33-35 different small RNAs which significantly discriminated lymphogen/occult/combined metastasized from non-metastasized seminoma and among these different comparisons it were the same small RNAs in 44-79%. Many combinations of two of these small RNAs completely discriminated metastasized from non-metastasized seminoma irrespective of the metastasis subtype.
Metastasized (either lymphogen or occult) seminoma can be completely discriminated from non-metastasized seminoma with a combination of two small RNAs measured in the peripheral blood.
Predicting metastasized seminoma using gene expression Ruf, Christian G.; Linbecker, Michael; Port, Matthias ...
BJU international,
July 2012, 2012-Jul, 2012-07-00, 20120701, Letnik:
110, Številka:
2b
Journal Article
Recenzirano
Study Type – Prognosis (cohort)
Level of Evidence 2a
What's known on the subject? and What does the study add?
Treatment options for testis cancer depend on the histological subtype as well as on the ...clinical stage. An accurate staging is essential for correct treatment. The ‘golden standard’ for staging purposes is CT, but occult metastasis cannot be detected with this method. Currently, parameters such as primary tumour size, vessel invasion or invasion of the rete testis are used for predicting occult metastasis. Last year the association of these parameters with metastasis could not be validated in a new independent cohort. Gene expression analysis in testis cancer allowed discrimination between the different histological subtypes (seminoma and non‐seminoma) as well as testis cancer and normal testis tissue.
In a two‐stage study design we (i) screened the whole genome (using human whole genome microarrays) for candidate genes associated with the metastatic stage in seminoma and (ii) validated and quantified gene expression of our candidate genes (real‐time quantitative polymerase chain reaction) on another independent group. Gene expression measurements of two of our candidate genes (dopamine receptor D1 DRD1 and family with sequence similarity 71, member F2 FAM71F2) examined in primary testis cancers made it possible to discriminate the metastasis status in seminoma. The discriminative ability of the genes exceeded the predictive significance of currently used histological/pathological parameters. Based on gene expression analysis the present study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance.
OBJECTIVE
•
To evaluate the usefulness of gene expression profiling for predicting metastatic status in testicular seminoma at the time of first diagnosis compared with established clinical and pathological parameters.
PATIENTS AND METHODS
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Total RNA was isolated from testicular tumours of metastasized patients (12 patients, clinical stage IIa–III), non‐metastasized patients (40, clinical stage I) and adjacent ‘normal’ tissue (n= 36).
•
The RNA was then converted into cDNA and real‐time quantitative polymerase chain reaction was run on 94 candidate genes selected from previous work.
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Normalised gene expression of these genes and histological variables, e.g. tumour size and rete testis infiltration, were analysed using logistic regression analysis.
RESULTS
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Expression of two genes (dopamine receptor D1 DRD1 and family with sequence similarity 71, member F2 FAM71F2, P= 0.005 and 0.024 in separate analysis and P= 0.004 and 0.016 when combining both genes, respectively) made it possible to significantly discriminate the metastasis status. Concordance increased from 77.9% (DRD1) and 72.3% (FAM71F2) in separate analysis and up to 87.7% when combining both genes in one model.
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Only primary tumour size in separate analysis (continuous or categorical with tumour size >6 cm) was significantly associated with metastasis (P= 0.039/P= 0.02), but concordance was lower (61%).
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When we combined tumour size with our two genes in one model there was no further statistical improvement or increased concordance.
CONCLUSION
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Based on gene expression analysis our study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance.
Tumor cells shed exosomes, which are released to the blood. Detecting tumor-derived exosomes containing RNA in plasma (liquid biopsy) is currently being investigated for early identification of ...occult metastases or relapses. Isolation of exosomes is laborious, resulting in low RNA yields. As a more robust (but less sensitive) alternative, the authors examined whether whole blood can be used as well. Tumor samples from nonmetastasized seminoma (n = 5) and colon cancer patients (n = 6) were taken during surgery. Whole-blood samples were taken before and 5-7 d after surgery. A whole genome mRNA microarray screening was performed. Candidate genes were selected based on two criteria: (1) gene expression in the presurgical whole-blood sample/tumor biopsy; and (2) a two-fold decrease in the copy number of candidate genes was expected in the postsurgical whole-blood sample 5-7 d after intervention, relative to the presurgical blood sample. The rationale behind this is the loss of tumor material in the body and the decline in the release of tumor-derived RNA in exosomes. For both tumor entities and for each patient, several hundred candidate genes could be identified. In a group-wise comparison, 20 candidate genes could be identified in the seminoma and 32 in the colon cancer group. These findings indicate that whole blood might be suitable for a liquid biopsy. However, this study identified the short period after surgery (5-7 d) as a possible confounder. The authors plan to add an additional time point several weeks after the operation to discriminate tumor candidate genes from genes induced by the surgery.
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