Initial surveillance in men with marker negative clinical stage IIA non-seminomatous germ cell tumours.

OBJECTIVES: To assess whether extended surveillance with repeated computed tomography (CT) scans for patients with clinical stage IIA (CS IIA; <2 cm abdominal node involvement) and negative markers (Mk-) non-seminomatous germ cell tumours (NSGCTs) can identify those with true CS I. To assess the rate of benign lymph nodes, teratoma, and viable cancer in retroperitoneal lymph node dissection (RPLND) histopathology for patients with CS IIA Mk- NSGCT. PATIENTS AND METHODS: Observational prospective population-based study of patients diagnosed 2008-2019 with CS IIA Mk- NSGCT in the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) registry. Patients were managed with surveillance, with CT scans, and tumour markers every sixth week for a maximum of 18 weeks. Patients with radiological regression were treated as CS I, if progression with chemotherapy, and remaining CS IIA Mk- disease with RPLND. The end-point was the number and percentage of patients down-staged to CS I on surveillance and rate of RPLND histopathology presented as benign, teratoma, or viable cancer. RESULTS: Overall, 126 patients with CS IIA Mk- NSGCT were included but 41 received therapy upfront. After surveillance for a median (range) of 6 (6-18) weeks, 23/85 (27%) patients were in true CS I and four (5%) progressed. Of the remaining 58 patients with lasting CS IIA Mk- NSGCT, 16 received chemotherapy and 42 underwent RPLND. The RPLND histopathology revealed benign lymph nodes in 11 (26%), teratoma in two (6%), and viable cancer in 29 (70%) patients. CONCLUSIONS: Surveillance with repeated CT scans can identify patients in true CS I, thus avoiding overtreatment. The RPLND histopathology in patients with CS IIA Mk- NSGCT had a high rate of cancer and a low rate of teratoma.

Validation of a prediction model for post-chemotherapy fibrosis in nonseminoma patients.

OBJECTIVE: To validate Vergouwe's prediction model using the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) RETROP database and to define its clinical utility. MATERIALS AND METHODS: Vergouwe's prediction model for benign histopathology in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) uses the following variables: presence of teratoma in orchiectomy specimen; pre-chemotherapy level of alpha-fetoprotein; ß-Human chorionic gonadotropin and lactate dehydrogenase; and lymph node size pre- and post-chemotherapy. Our validation cohort consisted of patients included in RETROP, a prospective population-based database of patients in Sweden and Norway with metastatic nonseminoma, who underwent PC-RPLND in the period 2007-2014. Discrimination and calibration analyses were used to validate Vergouwe's prediction model results. Calibration plots were created and a Hosmer-Lemeshow test was calculated. Clinical utility, expressed as opt-out net benefit (NBopt-out ), was analysed using decision curve analysis. RESULTS: Overall, 284 patients were included in the analysis, of whom 130 (46%) had benign histology after PC-RPLND. Discrimination analysis showed good reproducibility, with an area under the receiver-operating characteristic curve (AUC) of 0.82 (95% confidence interval 0.77-0.87) compared to Vergouwe's prediction model (AUC between 0.77 and 0.84). Calibration was acceptable with no recalibration. Using a prediction threshold of 70% for benign histopathology, NBopt-out was 0.098. Using the model and this threshold, 61 patients would have been spared surgery. However, only 51 of 61 were correctly classified as benign. CONCLUSIONS: The model was externally validated with good reproducibility. In a clinical setting, the model may identify patients with a high chance of benign histopathology, thereby sparing patients of surgery. However, meticulous follow-up is required.

Continuing increased risk of second cancer in long-term testicular cancer survivors after treatment in the cisplatin era.

Using complete information on total treatment burden, this population-based study aimed to investigate second cancer (SC) risk in testicular cancer survivors (TCS) treated in the cisplatin era. The Cancer Registry of Norway identified 5,625 1-year TCS diagnosed 1980-2009. Standardized incidence ratios (SIRs) were calculated to evaluate the total and site-specific incidence of SC compared to the general population. Cox regression analyses evaluated the effect of treatment on the risk of SC. After a median observation time of 16.6 years, 572 TCS developed 651 nongerm cell SCs. The SC risk was increased after surgery only (SIR 1.28), with site-specific increased risks of thyroid cancer (SIR 4.95) and melanoma (SIR 1.94). After chemotherapy (CT), we observed 2.0- to 3.7-fold increased risks for cancers of the small intestine, bladder, kidney and lung. There was a 1.6- to 2.1-fold increased risk of SC after ≥2 cycles of cisplatin-based CT. Radiotherapy (RT) was associated with 1.5- to 4.4-fold increased risks for cancers of the stomach, small intestine, liver, pancreas, lung, kidney and bladder. After combined CT and RT, increased risks emerged for hematological malignancies (SIR 3.23). TCS treated in the cisplatin era have an increased risk of developing SC, in particular after treatment with cisplatin-based CT and/or RT.

Primary surgery results in no survival benefit compared to primary radiation for oropharyngeal cancer patients stratified by high-risk human papilloma virus status.

We changed the primary oropharynx squamous cell carcinoma (OPSCC) treatment recommendation from primary radiation therapy (RT) to tumor surgery and neck dissection, followed by RT around the year 2000 with apparently improved survival. However, high-risk human papilloma virus (hr-HPV)-16-caused OPSCCs have increased during this period. Furthermore, hr-HPV+ OPSCC carry a better prognosis than hr-HPV-negative patients. We have, therefore, evaluated the 5-year survival in the period from 1992 to 1999 versus 2000 to 2008 stratified by hr-HPV tumor infection status. Ninety-six OPSCC patients were treated from 1992 to 1999 compared with 136 patients from 2000 to 2008. The 5-year disease-specific survival (DDS) and overall survival (OS) were recorded, while the health-related quality of life (HRQoL) scores were obtained from some of the cured patients. Thirty-eight (40 %) in the first period and 86 OPSCCs (63 %) in the second period were hr-HPV+. In the first period, 16 versus 62 patients in the last period were treated by neck dissection, primary tumor surgery, and RT. DSS among all the hr-HPV-negative patients in the first period was 51 versus 55 % in the second period, and the corresponding OS was 33 versus 31 %, respectively. The DSS among all the hr-HPV+ patients was 78 % in the first period versus 77 % in the second period, while the OS was 71 versus 69 %, respectively. The HRQoL scores among successfully treated patients were worse following surgery, plus RT than RT only. The hr-HPV-adjusted 5-year survival in OPSCC patients was similar between the two time periods. A decreased HRQoL was associated with surgical therapy, which indicates that hr-HPV+ OPSCC patients may be treated by primary RT followed by major surgery only if RT treatment fails.

Basosquamous Basal Cell Carcinoma with Bone Marrow Metastasis.

Basal cell carcinoma (BCC) is the most common cancer in Caucasians. It is slow growing and rarely metastasizes. If left untreated over time, invasive growth can occur. We present a patient case with a primary BCC located in the right sub-mammary area, with extensive metastases to the skeleton and bone marrow. Histopathological examination of the tumour showed BCC with a diverse growth pattern. There were no signs of local metastases. Surgery was successfully performed. Three months post-surgery the patient developed normocytic anaemia and elevated inflammation markers. [18F]FDG PET/CT showed extensive FDG uptake in the entire skeleton and bone marrow. Biopsy confirmed the infiltration of BCC with similar histopathological features as the primary tumour. Prognosis of metastasized BCC is poor and, therefore, long-term follow-up of patients with risk factors is of importance.

Unilateral or Bilateral Retroperitoneal Lymph Node Dissection in Nonseminoma Patients with Postchemotherapy Residual Tumour? Results from RETROP, a Population-based Mapping Study by the Swedish Norwegian Testicular Cancer Group.

BACKGROUND: The distribution of retroperitoneal lymph node metastases for patients with nonseminoma and a residual tumour of 10-49 mm in a population-based setting is unknown. This information is needed to justify selection of patients for a unilateral template resection. OBJECTIVE: To describe the location of retroperitoneal metastases and recurrences in patients with nonseminoma germ cell tumour (NSGCT) with a residual tumour of 10-49 mm. DESIGN, SETTING, AND PARTICIPANTS: RETROP is a population-based prospective observational mapping study of 213 patients in Sweden and Norway with a retroperitoneal residual tumour of 10-49 mm who underwent postchemotherapy retroperitoneal lymph node dissection for metastatic NSGCT during 2007-2014 with median follow-up of 100 mo. Patients were classified according to the testis primary tumour and the distribution of unilateral or bilateral lymph node metastases (with reference to the aorta) present on pre- and/or postchemotherapy computed tomography (CT) scans. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The distribution and rate of teratoma or cancer in unilateral or bilateral retroperitoneal fields and the location and rate of retroperitoneal recurrence were measured. RESULTS AND LIMITATIONS: In total, 65% of the patients had unilateral retroperitoneal lymph node metastases (RLNMs) on CT scans. Patients with unilateral RLNMs had a low risk of contralateral teratoma or cancer (1.6% for right- and 2.6% for left-sided NSGCT) or retroperitoneal recurrence (0% for right- and 4% for left-sided NSGCT). A weakness of the study is that the pathology specimen could not be fully designated to one specific area for some of the patients. CONCLUSIONS: Men with postchemotherapy residual disease of 10-49 mm and unilateral metastases on pre- and postchemotherapy CT scans have a low risk of contralateral disease and should be considered for a unilateral template resection. PATIENT SUMMARY: The surgeon can use computed tomography (CT) scans in deciding on the extent of lymph node dissection in patients with testicular cancer.

Metachronous Contralateral Testicular Cancer in the Cisplatin Era: A Population-Based Cohort Study.

PURPOSE: It is hypothesized that cisplatin-based chemotherapy (CBCT) reduces the occurrence of metachronous contralateral (second) germ cell testicular cancer (TC). However, studies including treatment details are lacking. The aim of this study was to assess the second TC risk, emphasizing the impact of previous TC treatment. PATIENTS AND METHODS: Based on the Cancer Registry of Norway, 5,620 men were diagnosed with first TC between 1980 and 2009. Treatment data regarding TC were retrieved from medical records. Cumulative incidences of second TC were estimated, and standardized incidence ratios were calculated. The effect of treatment intensity was investigated using Cox proportional hazard regression. RESULTS: Median follow-up was 18.0 years, during which 218 men were diagnosed with a second TC after median 6.2 years. Overall, the 20-year crude cumulative incidence was 4.0% (95% CI, 3.5 to 4.6), with lower incidence after chemotherapy (CT) (3.2%; 95% CI, 2.5 to 4.0) than after surgery only (5.4%; 95% CI, 4.2 to 6.8). The second TC incidence was also lower for those age ≥ 30 years (2.8%; 95% CI, 2.3 to 3.4) at first TC diagnosis than those age < 30 years (6.0%; 95% CI, 5.0 to 7.1). Overall, the second TC risk was 13-fold higher compared with the risk of developing TC in the general male population (standardized incidence ratio, 13.1; 95% CI, 11.5 to 15.0). With surgery only as reference, treatment with CT significantly reduced the second TC risk (hazard ratio [HR], 0.55). For each additional CBCT cycle administered, the second TC risk decreased significantly after three, four, and more than four cycles (HRs, 0.53, 0.41, and 0.21, respectively). CONCLUSION: Age at first TC diagnosis and treatment intensity influenced the second TC risk, with significantly reduced risks after more than two CBCT cycles.

Testicular Cancer in the Cisplatin Era: Causes of Death and Mortality Rates in a Population-Based Cohort.

PURPOSE: Using complete information regarding testicular cancer (TC) treatment burden, this study aimed to investigate cause-specific non-TC mortality with impact on previous treatment with platinum-based chemotherapy (PBCT) or radiotherapy (RT). METHODS: Overall, 5,707 men identified by the Cancer Registry of Norway diagnosed with TC from 1980 to 2009 were included in this population-based cohort study. By linking data with the Norwegian Cause of Death Registry, standardized mortality ratios (SMRs), absolute excess risks (AERs; [(observed number of deaths - expected number of deaths)/person-years of observation] ×10,000), and adjusted hazard ratios (HRs) were calculated. RESULTS: Median follow-up was 18.7 years, during which non-TC death was registered for 665 (12%) men. Overall excess non-TC mortality was 23% (SMR, 1.23; 95% CI, 1.14 to 1.33; AER, 11.14) compared with the general population, with increased risks after PBCT (SMR, 1.23; 95% CI, 1.07 to 1.43; AER, 7.68) and RT (SMR, 1.28; 95% CI, 1.15 to 1.43; AER, 19.55). The highest non-TC mortality was observed in those < 20 years at TC diagnosis (SMR, 2.27; 95% CI, 1.32 to 3.90; AER, 14.42). The most important cause of death was non-TC second cancer with an overall SMR of 1.53 (95% CI, 1.35 to 1.73; AER, 7.94), with increased risks after PBCT and RT. Overall noncancer mortality was increased by 15% (SMR, 1.15; 95% CI, 1.04 to 1.27; AER, 4.71). Excess suicides appeared after PBCT (SMR, 1.65; 95% CI, 1.01 to 2.69; AER, 1.39). Compared with surgery, increased non-TC mortality appeared after 3 (HR, 1.47; 95% CI, 0.91 to 2.39), 4 (HR, 1.41; 95% CI, 1.01 to 1.99), and more than four (HR, 2.04; 95% CI, 1.25 to 3.35) cisplatin-based chemotherapy cycles after > 10 years of follow-up. CONCLUSION: TC treatment with PBCT or RT is associated with a significant excess risk of non-TC mortality, and increased risks emerged after more than two cisplatin-based chemotherapy cycles after > 10 years of follow-up.

Serum miR371 in testicular germ cell cancer before and after orchiectomy, assessed by digital-droplet PCR in a prospective study.

MicroRNA-371a-3p (miR371) has been suggested as a sensitive biomarker in testicular germ cell cancer (TGCC). We aimed to compare miR371 with the classical biomarkers α-fetoprotein (AFP) and ß-human chorionic gonadotropin (hCGß). Overall, 180 patients were prospectively enrolled in the study, with serum samples collected before and after orchiectomy. We compared the use of digital droplet PCR (RT-ddPCR) with the quantitative PCR used by others for detection of miR371. The novel RT-ddPCR protocol showed high performance in detection of miR371 in serum samples. In the study cohort, miR371 was measured using RT-ddPCR. MiR371 detected CS1 of the seminoma and the non-seminoma sub-types with a sensitivity of 87% and 89%, respectively. The total sensitivity was 89%. After orchiectomy, miR371 levels declined in 154 of 159 TGCC cases. The ratio of miR371 pre- and post-orchiectomy was 20.5 in CS1 compared to 6.5 in systemic disease. AFP and hCGß had sensitivities of 52% and 51% in the non-seminomas. MiR371 is a sensitive marker that performs better than the classical markers in all sub-types and clinical stages. Especially for the seminomas CS1, the high sensitivity of miR371 in detecting TGCC cells may have clinical implications.

Rectum motion and morbidity prediction: Improving correlation between late morbidity and DVH parameters through use of rectum planning organ at risk volumes.

BACKGROUND AND PURPOSE: The rectum is a major dose-limiting organ at risk (OR) in radiotherapy (RT) of prostate cancer. Methods to predict adverse effects in the rectum are therefore important but their precision often limited, not the least by the internal motion of this organ. In this study late rectal morbidity is investigated in relation to the internal motion of the rectum by applying the 'Planning organ at Risk Volume' (PRV) concept. MATERIALS AND METHODS: Late rectal morbidity was analysed in 242 prostate cancer patients treated to 70 Gy with conformal RT to either the prostate, the prostate and seminal vesicles or the whole pelvis (initial 50 Gy only). Late rectal morbidity was classified by the late gastro-intestinal (GI) RTOG toxicity scoring system. Cumulative dose-volume histograms (DVHs) were derived for the rectum OR and six rectum PRVs i.e. the OR expanded with six different margins (narrow/intermediate/wide in anterior direction or in both anterior and posterior direction). The difference in rectum dose-volume parameters between patients with Grade 0-1 vs. Grade 2 or higher morbidity was investigated by logistic regression and permutation tests. RESULTS: Late Grade 2 or higher morbidity was observed in 25 of 242 (10%) patients. The logistic regression analysis and the permutation tests reached significance (p ≤ 0.05) for only one dose level of the rectum OR (40 Gy). For the PRVs, several dose levels were found to be significant (p-value range: 0.01-0.046), most pronounced for the PRV with narrow margins of 6 mm anterior and 5 mm posterior with five intermediate (38-42 Gy) and ten high (62-71 Gy) dose levels. CONCLUSIONS: The statistical methods applied displayed consistently a small though significant difference in DVH parameters between patients with vs. without Grade 2 or higher late rectal morbidity for intermediate and high dose levels. The difference became most evident when using a PRV with narrow margins.

Characteristics and prognosis of primary treatment-naïve oral cavity squamous cell carcinoma in Norway, a descriptive retrospective study.

OBJECTIVES: Incidence of oral cavity squamous cell carcinomas is rising worldwide, and population characterization is important to follow for future trends. The aim of this retrospective study was to present a large cohort of primary oral cavity squamous cell carcinoma from all four health regions of Norway, with descriptive clinicopathological characteristics and five-year survival outcomes. MATERIALS AND METHODS: Patients diagnosed with primary treatment-naïve oral cavity squamous cell carcinomas at all four university hospitals in Norway between 2005-2009 were retrospectively included in this study. Clinicopathological data from the electronic health records were compared to survival data. RESULTS: A total of 535 patients with primary treatment-naïve oral cavity squamous cell carcinomas were identified. The median survival follow-up time was 48 months (range 0-125 months) after treatment. The median five-year overall survival was found to be 47%. Median five-year disease-specific survival was 52%, ranging from 80% for stage I to 33% for stage IV patients. For patients given treatment with curative intent, the overall survival was found to be 56% and disease-specific survival 62%. Median age at diagnosis was 67 years (range 24-101 years), 64 years for men and 72 years for women. The male: female ratio was 1.2. No gender difference was found in neither tumor status (p = 0.180) nor node status (p = 0.266), but both factors influenced significantly on survival (p<0.001 for both). CONCLUSIONS: We present a large cohort of primary treatment-naïve oral cavity squamous cell carcinomas in Norway. Five-year disease-specific survival was 52%, and patients eligible for curative treatment had a five-year disease-specific survival up to 62%.

Ten-Year Results From a Phase II Study on Image Guided, Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost in High-Risk Prostate Cancer.

PURPOSE: There is no consensus on how to treat high-risk prostate cancer, and long-term results from hypofractionated radiation therapy are lacking. We report 10-year results after image guided, intensity modulated radiation therapy with hypofractionated simultaneous integrated boost and elective pelvic field. METHODS AND MATERIALS: Between 2007 and 2009, 97 consecutive patients with high-risk prostate cancer were included, treated with 2.7 to 2.0 Gy × 25 Gy to the prostate, seminal vesicles, and elective pelvic field. Toxicity was scored according to Radiation Therapy Oncology Group criteria and biochemical disease-free survival (BFS) defined by the Phoenix definition. Patients were subsequently divided into 3 groups: high risk (HR; n = 32), very high risk (VHR; n = 50), and N+/s-prostate-specific antigen (PSA) ≥100 (n = 15). Differences in outcomes were examined using Kaplan-Meier analyses. RESULTS: BFS in the patients at HR and VHR was 64%, metastasis-free survival 80%, prostate cancer-specific survival 90%, and overall survival (OS) 72%. VHR versus HR subgroups demonstrated significantly different BFS, 54% versus 79% (P = .01). Metastasis-free survival and prostate cancer-specific survival in the VHR group versus HR group were 76% versus 87% (P = .108) and 74% versus 100% (P = .157). Patients reaching nadir PSA <0.1 (n = 80) had significantly better outcomes than the rest (n = 17), with BFS 70% versus 7% (P < .001). Acute grade 2 gastrointestinal tract (GI) and genitourinary tract (GU) toxicity occurred in 27% and 40%, grade 3 GI and GU toxicity in 1% and 3%. Late GI and GU grade 2 toxicity occurred in 1% and 8%. CONCLUSIONS: High-risk prostate cancer patients obtained favorable 10-year outcomes with low toxicity. There were significantly better results in the HR versus the VHR group, both better than the N+/PSA ≥100 group. A nadir PSA value < 0.1 predicted good prognosis.

Surgical Complications in Postchemotherapy Retroperitoneal Lymph Node Dissection for Nonseminoma Germ Cell Tumour: A Population-based Study from the Swedish Norwegian Testicular Cancer Group.

BACKGROUND: Reports on perioperative complications after postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for nonseminoma germ cell tumour (NSGCT) are from experienced single centres, with a lack of population-based studies. OBJECTIVE: To assess the complications of bilateral and unilateral PC-RPLND. DESIGN, SETTING, AND PARTICIPANTS: A prospective, population-based, observational multicentre study included all patients with NSGCT who underwent PC-RPLND in Norway and Sweden during 2007-2014. Of a total of 318 patients, 87 underwent bilateral PC-RPLND and 231 underwent unilateral PC-RPLND. The median follow-up was 6 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bilateral and unilateral PC-RPLND were compared for the outcomes of intra- and postoperative complications (graded by Clavien-Dindo) and retrograde ejaculation (with or without nerve-sparing surgery). Complications were reported as absolute counts and percentages. The χ2 test was used for comparisons. RESULTS AND LIMITATIONS: The incidence of intraoperative complications was higher for bilateral PC-RPLND than for unilateral PC-RPLND (14% vs 4.3%, p = 0.003), with ureteral injury as the most frequent reported complication (2% of the patients). Postoperative complications were more common after bilateral than after unilateral PC-RPLND (45% vs 25%, p = 0.001) with Clavien ≥3b reported in 8.3% and 2.2%, respectively (p = 0.009). Lymphatic leakage was the most common complication occurring in 11% of the patients. Retrograde ejaculation occurred more frequently after bilateral than after unilateral surgery (59% vs 32%, p < 0.001). Limitations of the study include reporting of retrograde ejaculation, which was based on a chart review. CONCLUSIONS: Intra- and postoperative complications including retrograde ejaculation are more frequent after bilateral PC-RPLND than after unilateral PC-RPLND. PATIENT SUMMARY: Lymph node dissection in patients with testicular cancer puts them at risk of complications. In this study, we present the complications after lymph node dissection.

Outcome in intermediate or high risk prostate cancer patients receiving radiation dose and hormone therapy.

BACKGROUND: To analyse the impact of radiation dose escalation and hormone treatment in prostate cancer patients according to risk groups. MATERIAL AND METHODS: Totally 494 prostate cancer patients received external beam radiation therapy, with or without androgen deprivation, between January 1990 and December 1999. The patients were divided into three risk groups, where the low risk group (stage T(1c), pretreatment prostate-specific antigen (PSA) level < or =10 ng/ml and WHO Grade 1) included 26 patients, the intermediate risk group (either stage T(2), PSA 10.1-20 ng/ml or WHO Grade 2) comprised 149 patients whereas the high-risk group (either stage T(3), PSA >20 ng/ml or WHO Grade 3) included 319 patients. RESULTS: In the intermediate risk group, the 5-years bNED rate was 92%, 69% and 61% after a radiation dose of 70 Gy, 66 Gy or 64 Gy, respectively (p < 0.001). In the high-risk group, the 5-year bNED rate was 79%, 69% and 34% for the same dose levels (p < 0.001). The 5-years CSS rates were not significantly different between the dose levels in the intermediate risk group while for the high-risk group it was 93%, 92% and 80% for the three dose levels (p < 0.001). Risk group and radiation doses were independent predictors of bNED, CSS and overall survival, for bNED also hormone treatment was independent predictors. CONCLUSION: Radiation dose is important for the outcome in intermediate and high risk prostate cancer patients. A dose of 70 Gy should be considered the minimal dose for these patients.

Quantitative PCR Measurement of miR-371a-3p and miR-372-p Is Influenced by Hemolysis.

Cell-free microRNAs have been reported as biomarkers for several diseases. For testicular germ cell tumors (GCT), circulating microRNAs 371a-3p and 372-3p in serum and plasma have been proposed as biomarkers for diagnostic and disease monitoring purposes. The most widely used method for quantification of specific microRNAs in serum and plasma is reverse transcriptase real-time quantitative PCR (RT-qPCR) by the comparative Ct-method. In this method one or several reference genes or reference microRNAs are needed in order to normalize and calculate the relative microRNA levels across samples. One of the pitfalls in analysis of microRNAs from serum and plasma is the release of microRNAs from blood cells during hemolysis. This is an important issue because varying degrees of hemolysis are not uncommon in routine blood sampling. Thus, hemolysis must be taken into consideration when working with circulating microRNAs from blood. miR-93-5p, miR-30b-5p, and miR-20a-5p have been reported as reference microRNA in analysis of the miR-371a-373 cluster. We here show how these three microRNAs are influenced by hemolysis. We also propose a new reference microRNA, miR-191-5p, which is relatively stable in serum samples with mild hemolysis. In addition, we show how hemolysis can have effect on the reported microRNA levels in patient samples when these reference microRNAs are used in samples with varying levels of hemolysis.

Late gastrointestinal morbidity after three-dimensional conformal radiation therapy for prostate cancer fades with time in contrast to genitourinary morbidity.

PURPOSE: To investigate the incidence, time course, and relation to irradiated volumes of late morbidity after three-dimensional conformal radiation therapy (RT) for prostate cancer. METHODS AND MATERIALS: From January 2000 to December 2001, a total of 247 patients with prostate cancer received a target dose of 70 Gy using conformal RT. Forty-eight patients (20%) received irradiation to the prostate only (Group P), 154 patients (62%) received irradiation to the prostate and seminal vesicles (Group PSV), and 45 patients (18%) received modified pelvic fields (Group MPF). Androgen deprivation was given to 86% of patients. Median follow-up was 62 months. Late gastrointestinal (GI) and genitourinary (GU) morbidity were recorded according to the Radiation Therapy Oncology Group scoring system. RESULTS: We observed 9%, 7%, and 25% Grade 2 or higher GI morbidity and 36%, 30%, and 21% Grade 2 or higher GU morbidity in Groups P, PSV, and MPF, respectively. In multivariate analyses, age and treatment group were independent predictors for the incidence of late Grade 2 or higher GI morbidity, whereas age and urinary symptoms before treatment were independent predictors for late Grade 2 or higher GU morbidity. Acute side effects predicted for late effects. The rectum dose-volume histogram parameters correlated with the incidence of late Grade 2 or higher GI morbidity, especially the fractional volume receiving more than 40-43 Gy. At 5 years of follow-up, the rate of Grade 2 late GI morbidity was only 1.4%, and Grade 2 or higher GU morbidity was 10.6%. CONCLUSIONS: The data presented here show that late GI morbidity after prostate RT is low and subsides with time.

Intensity-modulated radiotherapy of pelvic lymph nodes in locally advanced prostate cancer: planning procedures and early experiences.

PURPOSE: We present planning and early clinical outcomes of a study of intensity-modulated radiotherapy (IMRT) for locally advanced prostate cancer. METHODS AND MATERIALS: A total of 43 patients initially treated with an IMRT plan delivering 50 Gy to the prostate, seminal vesicles, and pelvic lymph nodes, followed by a conformal radiotherapy (CRT) plan delivering 20 Gy to the prostate and seminal vesicles, were studied. Dose-volume histogram (DVH) data for the added plans were compared with dose-volume histogram data for the sum of two CRT plans for 15 cases. Gastrointestinal (GI) and genitourinary (GU) toxicity, based on the Radiation Therapy Oncology Group scoring system, was recorded weekly throughout treatment as well as 3 to 18 months after treatment and are presented. RESULTS: Treatment with IMRT both reduced normal tissue doses and increased the minimum target doses. Intestine volumes receiving more than 40 and 50 Gy were significantly reduced (e.g., at 50 Gy, from 81 to 19 cm(3); p = 0.026), as were bladder volumes above 40, 50, and 60 Gy, rectum volumes above 30, 50, and 60 Gy, and hip joint muscle volumes above 20, 30, and 40 Gy. During treatment, Grade 2 GI toxicity was reported by 12 of 43 patients (28%), and Grade 2 to 4 GU toxicity was also observed among 12 patients (28%). With 6 to 18 months of follow-up, 2 patients (5%) experienced Grade 2 GI effects and 7 patients (16%) experienced Grade 2 GU effects. CONCLUSIONS: Use of IMRT for pelvic irradiation in prostate cancer reduces normal tissue doses, improves target coverage, and has a promising toxicity profile.

Inter-institutional analysis demonstrates the importance of lower than previously anticipated dose regions to prevent late rectal bleeding following prostate radiotherapy.

PURPOSE: To investigate whether inter-institutional cohort analysis uncovers more reliable dose-response relationships exemplified for late rectal bleeding (LRB) following prostate radiotherapy. MATERIAL AND METHODS: Data from five institutions were used. Rectal dose-volume histograms (DVHs) for 989 patients treated with 3DCRT or IMRT to 70-86.4 Gy@1.8-2.0 Gy/fraction were obtained, and corrected for fractionation effects (α/ß = 3 Gy). Cohorts with best-fit Lyman-Kutcher-Burman volume-effect parameter a were pooled after calibration adjustments of the available LRB definitions. In the pooled cohort, dose-response modeling (incorporating rectal dose and geometry, and patient characteristics) was conducted on a training cohort (70%) followed by final testing on the remaining 30%. Multivariate logistic regression was performed to build models with bootstrap stability. RESULTS: Two cohorts with low bleeding rates (2%) were judged to be inconsistent with the remaining data, and were excluded. In the remaining pooled cohorts (n = 690; LRB rate = 12%), an optimal model was generated for 3DCRT using the minimum rectal dose and the absolute rectal volume receiving less than 55 Gy (AUC = 0.67; p = 0.0002; Hosmer-Lemeshow p-value, pHL = 0.59). The model performed nearly as well in the hold-out testing data (AUC = 0.71; p < 0.0001; pHL = 0.63), indicating a logistically shaped dose-response. CONCLUSION: We have demonstrated the importance of integrating datasets from multiple institutions, thereby reducing the impact of intra-institutional dose-volume parameters explicitly correlated with prescription dose levels. This uncovered an unexpected emphasis on sparing of the low to intermediate rectal dose range in the etiology of late rectal bleeding following prostate radiotherapy.

Testing the new ICRU 62 'Planning Organ at Risk Volume' concept for the rectum.

BACKGROUND AND PURPOSE: To study the impact of the new ICRU 62 'Planning organ at Risk Volume' (PRV) concept on the relationship between rectum dose-volume histogram (DVH) data and toxicity. PATIENTS AND METHODS: The acute gastro-intestinal (GI) RTOG toxicity in 127 prostate cancer patients prescribed a total dose of 70 Gy with conformal irradiation to either the prostate, the prostate and seminal vesicles or the whole pelvis (initial 50 Gy only) were analysed. DVHs were derived for the rectum only and for rectum extended with six PRV margin sets (narrow/intermediate/wide; anterior/anterior and posterior). The data was analysed using permutation tests, logistic regression and effective uniform dose (EUD) calculations. RESULTS: Acute Grade 2 GI toxicity was seen in 22 of 127 cases (17%). Permutation tests showed that the difference between DVHs for patients with and without Grade 2 effects was significant, both for rectum only and rectum PRVs (P-value range: 0.02-0.04), with generally lower P-values for the PRVs. In the logistic regression, the fractional DVH variables (i.e. volumes) were significantly related to toxicity, with approximately 2-3 times as many significant dose levels for the PRVs as for rectum only. E.g. with wide anterior and posterior margins (16 and 11 mm, respectively) the relation was significant at 26 different dose levels (6-7, 13-14, 35-43, 60-71 and 73 Gy), compared to nine levels (38-40, 43-44 and 71-74 Gy) for rectum only. EUDs were significantly different for patients with and without Grade 2 effects both for rectum only and the PRVs (95% confidence interval for EUD increase with Grade 2 effects: 0.1-3.1 Gy). CONCLUSIONS: All statistical methods applied indicated a small, but definite difference in DVH parameters between patients with versus those without Grade 2 effects. The difference was most pronounced when margins of 16 mm anterior and 11 mm posterior were applied.