Treatment-related Morbidity Rates Research Articles

The Woven EndoBridge for intracranial aneurysms: Radiological outcomes and factors influencing occlusions at 6 and 24 months.

To identify factors influencing short- and mid-term radiological outcomes of intracranial aneurysms (IAs) treated with the Woven EndoBridge (WEB). A total of 112 patients were treated for IAs with the WEB in at our institution between 2013 and 2020. Patients with 6- and/or 24-months follow-up data were included in the study. Aneurysm occlusion was evaluated using the Raymond-Roy occlusion classification (RR). RR 1 and RR 2 were considered as adequate outcomes, while RR 3 inadequate. Data were available for 91 patients (56 females, 62%) at 6months and 62 of those patients (39 females, 58%) at 24 months. The adequate occlusion (RR 1/RR 2) rate was 89% (n = 81/91) at the 6-months follow-up and 91% (n = 56/62) at the 24-months follow-up. The treatment-related morbidity rate was 4% (n = 4/91), and mortality rate was 1% (n = 1/91). The predictor for inadequate occlusion at the 6-months follow-up was the lobular shape of an aneurysm (p = .01). The aneurysm's height (p = .02), maximal diameter (p = .001), width (p = .002), aspect ratio (p = .03), dome-to-neck ratio (p = .04), and lobular shape (p= .03) were predictive factors for inadequate occlusion at 24months. All the thrombosed aneurysms (n = 3) showed unfavorable radiological outcomes and required re-treatment within 24months. None of the patient-related factors were significant. The WEB provides favorable occlusion rates and low complications for both ruptured and unruptured wide-necked IAs. Unfavorable radiological outcomes after WEB treatment may be related to aneurysm morphology and size.

Non-Infectious Morbidity during Pediatric Acute Myeloid Leukemia Chemotherapy in the Netherlands: A 15-Year Overview

IntroductionTogether with considerable improvement in diagnostics and supportive care measures, treatment intensification has contributed to the improvement of pediatric acute myeloid leukemia (AML) survival outcomes. However, treatment-related toxicity is a consequence of intensified chemotherapy regimens, which has profound implications for both morbidity and mortality. Despite the known devastating impact of all types of toxicity on quality of life (QoL), studies presenting the different forms of non-infectious toxicity prevalent during the most recent Dutch pediatric AML protocols are lacking given that only prior protocols have been evaluated in this manner as of yet. Furthermore, the literature on non-infectious toxicity incidence in pediatric AML patients is relatively scarce. Therefore, the objectives of this study were to: 1) evaluate the cumulative incidence (C.I.) of severe, but non-lethal, non-infectious toxicity during AML treatment according to the last three consecutive protocols of the Dutch Childhood Oncology Group (DCOG), and 2) compare treatment-related toxicity frequencies between protocols.MethodsA retrospective chart review was performed on 245 Dutch patients diagnosed with de novo AML (acute promyelocytic leukemia, myeloid leukemia of Down Syndrome, and secondary AML were excluded) and treated according to ANLL-97/AML-12 (1998-2005) n=118, AML-15 (2005-2010) n=60, or DB-AML-01 (2010-2013) n=67. Table 1 details protocol specifics, including drug dosages per course. Grade 3-4 toxicities, including hematological toxicity, cardiotoxicity, respiratory toxicity, mucositis, typhlitis, nephrotoxicity, hepatotoxicity, neurotoxicity, pain, allergic anaphylactic reaction, and elevation of alanineaminotransferase or bilirubin were defined according to Common Terminology Criteria for Adverse Event version 4.0, excluding infectious toxicity. Grade 5 toxicity (treatment-related mortality) was beyond the scope of this study. Intensive care unit (ICU) admission data was additionally assessed. Toxicity C.I.s were determined via competing events analyses. Relapse and death were considered competing events. Patients were censored at time of stem cell transplantation. Per-protocol comparisons were conducted via Chi-square test, due to lack of sufficient power required to calculate C.I.s.ResultsMedian age at diagnosis was 6.0 years [interquartile range (IQR) 1.0-12.0], 58% were male. Mucositis was the most frequent form of non-hematological toxicity with a C.I. of 86.1% (standard error (S.E.) 3.5%), followed by hepatotoxicity (C.I. 27.4%, S.E. 2.9%), and respiratory toxicity (C.I. 24.6%, S.E. 3.0%) (Table 2). Eighty-three patients (C.I. 33.9%, S.E. 3.0%) were admitted to the ICU at least once, for a median of 6.0 days [IQR 2.0-15.0] (Table 2).Relatively more blood transfusions (both erythrocyte and thrombocyte) were administered to patients treated according to AML-15 (98.3%) and DB-AML-01 (97.0%) compared to AML-12 (86.4%) (p=0.01 and p=0.02, respectively). Relatively more patients suffered from severe mucositis during DB-AML-01 compared to AML-12 (43.4% vs. 25.4%, p=0.01). More patients treated according to AML-15 had bilirubin levels >3x upper limit of normal (ULN) compared to those treated according to AML-12 (13.3% vs. 3.4%, p=0.01). There were no differences in non-infectious toxicity frequency between AML-15 and DB-AML-01. Other forms of toxicity did not differ significantly between protocols. The percentage of patients admitted to the ICU at least once during treatment was 33.9% in AML-12, 26.7% in AML-15, and 40.3% in DB-AML-01.ConclusionsThe high incidence of severe short- and long-term toxicities during pediatric AML therapy poses substantial challenges for patients, families, and care providers. Mucositis was the most common form of non-hematological, non-infectious toxicity in the whole cohort and across all Dutch protocols. Toxicities were more prevalent during the more recent protocols (AML-15 and DB-AML-01) compared to AML-12. Therefore, our findings are important in that they substantiate the need to optimize pediatric AML care in a manner which decreases treatment-related toxicity and QoL impairment. High treatment-related morbidity rates stress the urge to improve supportive care and develop less toxic treatment, while maintaining efficacy. [Display omitted] DisclosuresZwaan: Sanofi: Consultancy.

Re-irradiation for recurrent and second primary cancers of the head and neck

PurposeTo evaluate a single-institutional experience with the use of re-irradiation for recurrent and new primary cancers of the head and neck. MethodsThe medical charts of 80 consecutive patients who underwent re-irradiation for local-regionally recurrent or second primary head and neck cancer between November 1998 and December 2015 were analyzed. Multivariate analysis was performed using Cox proportional hazard and logistic regression to determine predictors of clinical outcomes. ResultsSeventy-six of the 80 patients were evaluable. The median age was 57.5 (range 26.6–84.9); Intensity-modulated radiotherapy (IMRT) was used in 71 (93.4%) patients with a median dose of 60Gy. Thirty-one patients (40.8%) underwent salvage surgery before re-irradiation and 47 (61.8%) received concurrent systemic therapy. The median time interval between radiation courses was 25.3months (range 2–322months). The 2-year estimates of overall survival, progression free survival, locoregional control, and distant control were 51.0%, 31.3%, 36.8% and 68.3%, respectively. Patients who underwent salvage surgery prior to re-irradiation had significantly improved locoregional control, progression free survival, and overall survival (p<0.05, for all). On multivariate analysis, gross tumor volume (GTV) at re-irradiation and interval between radiation courses were associated with improved overall survival. Severe (grade⩾3) late complications were observed in 25 patients (32.8%). ConclusionsRe-irradiation for recurrent or second primary head and neck cancer is feasible and effective in select patients with head and neck cancer. The high observed rate of treatment-related morbidity highlights the continue challenges that accompany this approach.

Morphology Parameters for Mirror Posterior Communicating Artery Aneurysm Rupture Risk Assessment.

Recent studies have shown that posterior communicating artery (PComA) aneurysms are more likely to rupture. However, surgical intervention for PComA aneurysms may be associated with increased treatment-related morbidity rate. Therefore, it is meaningful to investigate the factors related to PComA aneurysm rupture. The purpose of this study was to identify morphological parameters that significantly correlate with PComA aneurysm rupture. We divided 14 pairs of mirror posterior communicating artery aneurysms (PComA-MANs) into ruptured and unruptured groups. Computed tomography angiography (CTA) imaging was evaluated with three-dimensional (3D) Slicer to generate models of the aneurysms and surrounding vasculature. Nine morphological parameters [size, height, width, neck width, aspect ratio (AR), bottleneck factor (BNF), height/width ratio (H/W), size ratio (SR), and bleb formation] were examined in the two groups for significance with respect to rupture. By contrast, statistically significant differences were found in ruptured and unruptured group for size, AR, BNF, SR, and bleb formation (P < 0.05). Parameters that had no significant differences between the two groups were height (P = 0.103), width (P = 0.078), neck width (P = 0.808), and H/W (P = 0.417). We conclude that MANs may be a useful model for the morphological analysis of intracranial aneurysm rupture. Larger size, higher AR, BNF, SR, and bleb formation may be related to rupture of PComA aneurysms. Larger sample studies minimizing the interference from patient-related factors and aneurysm type were expected for acquiring more accurate assessment of the relationship between these parameters and PComA aneurysm rupture.

Clinical Outcomes of Transoral Robotic Surgery for Head and Neck Tumors

In order to reduce treatment-related morbidity rates and increase patients' quality of life, robot-assisted surgery using the da Vinci surgical system (Intuitive Surgical Inc, Sunnyvale, California) has been studied actively in the field of head and neck surgery. This study analyzes our experiences therewith in order to evaluate the feasibility and efficacy of robot-assisted surgery via a transoral approach in the head and neck area. Between April 2008 and December 2011, 141 patients were treated with robot-assisted surgery via a transoral approach. Robot-assisted surgeries were successfully completed via a transoral approach in all patients. The mean robotic operative time was 69.3 minutes, and the mean time for setup of the robotic system was 10.4 minutes. The average blood loss during the operation was 29.6 mL (range, 0 to 300 mL). Patients who underwent robot-assisted surgery were satisfied with their cosmetic results and treatment outcomes. Robot-assisted surgery via a transoral approach was confirmed to be feasible and efficient in the field of head and neck surgery. Further research is needed to investigate the long-term functional and oncological results of robot-assisted surgery.

Organ-sparing Intensity-modulated Radiotherapy for Anal Cancer using the ACTII Schedule: A Comparison of Conventional and Intensity-modulated Radiotherapy Plans

AimsConventional external beam radiotherapy for anal cancer is associated with a high rate of treatment-related morbidity. The purpose of this retrospective study was to compare the dosimetric advantages of three intensity-modulated radiotherapy (IMRT) plans with the conventional plan with regards to organs at risk avoidance delivering the ACTII schedule of 50.4 Gy in 1.8 Gy/fraction: 17 fractions for phase 1 and 11 fractions for phase 2. Materials and methodsTen anal cancer patients (T1-3 N0-3) treated with the conventional plan using four fields and conformal boost were identified. The phase 1 planning target volume (PTV) included tumour, anal canal and inguinal, peri-rectal and internal/external iliac nodes. Phase 2 included identifiable disease only. Three step-and-shoot IMRT plans were generated: IMRT1: phase 1 inverse-planned IMRT with two- to four-field conformal phase 2; IMRT2: both phase 1 and phase 2 inverse-planned IMRT; IMRT3: phase 1 IMRT and phase 2 forward-planned IMRT. All IMRT plans were then compared against the conventional plan on PTV coverage, small bowel, genitalia, femoral heads, bladder and healthy tissue dose volume information. ResultsWhile achieving similar PTV coverage compared with the conventional plan, significant dose reductions were observed for IMRT plans in external genitalia, small bowel and healthy tissue. Reductions were also observed in the femoral heads and bladder. ConclusionsIMRT significantly reduces the dose to organs at risk while maintaining excellent PTV coverage in anal cancer radiotherapy.

Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer

BackgroundTo analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT)±chemotherapy (ChT). MethodsTreatment schedule was EBRT with 45–50.4Gy±concomitant cisplatin chemotherapy plus 4×7Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75Gy for rectum and sigmoid and 90Gy for bladder.Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. FindingsOne hundred and fifty-six consecutive patients (median age 58years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients.Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93±13Gy, D2cc 86±17Gy for bladder, 65±9Gy for rectum and 64±9Gy for sigmoid.Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2–5cm, and 92% for tumours >5cm (p=0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2–5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2–5cm, 65% for tumours >5cm, 74% for IB, 78% for IIB, 45% for IIIB.In regard to late morbidity in total 188 grade 1+2 and 11 grade 3+4 late events were observed in 143 patients. G1+2/G3+4 events for bladder were n=32/3, for rectum n=14/5, for bowel (including sigmoid) n=3/0, for vagina n=128/2, respectively. Interpretation3D conformal radiotherapy±chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings.

Long- term outcome of paediatric patients with ANCA vasculitis

BackgroundPrimary systemic vasculitis presenting in childhood is an uncommon but serious condition. As these patients transfer to adult clinics for continuing care, defining long term outcomes with emphasis on disease and treatment- related morbidity and mortality is important. The aim of this study is to describe the long- term clinical course of paediatric patients with ANCA vasculitis.MethodsThe adult patients in our vasculitis clinics who had presented in childhood, with a follow up time of greater than 10 years were included. We also reviewed the literature for articles describing the clinical outcome of paediatric patients with ANCA vasculitis.ResultsWe describe the clinical course of 8 adults who presented in childhood with ANCA vasculitis. 7 patients had Wegener's granulomatosis and 1 had microscopic polyangiitis. The median age at presentation was 11.5 years, and follow up time ranged form 11 to 30 years. Induction therapy for all patients was steroids and/or cyclophosphamide. Maintenance therapy was with azathioprine or mycophenolate mofetil. Biological agents were used in 3 patients for relapsed disease in adulthood only.Seven patients achieved complete remission. All patients experienced disease relapse, with a median of 4 episodes. Kidney function was generally well preserved, with median eGFR 76 ml/min. Only one patient developed end-stage renal failure and one patient died after 25 years of disease. Treatment-related morbidity rates were high; 7 suffered from infections, 4 were infertile, 2 had skeletal complications, and 1 developed malignancy.ConclusionClose long- term follow up of paediatric patients with ANCA vasculitis is imperative, as this patient cohort is likely to live long enough to develop significant treatment and disease- related morbidities. Prospective cohort studies with novel therapies including paediatric patients are crucial to help us determine the best approach to managing this complex group of patients. In addition, although not yet observed in our series, late cardiovascular morbidity remains a major longer-term potential concern for adult survivors of paediatric vasculitis.

MULTIMODALITY TREATMENT OF GIANT INTRACRANIAL ARTERIOVENOUS MALFORMATIONS

Giant arteriovenous malformations (AVMs) (i.e., those greater than 6 cm at maximum diameter) are difficult to treat and often carry higher treatment morbidity and mortality rates than do smaller AVMs. In this study, we reviewed the treatment, angiographic results, and clinical outcomes in 53 patients with giant AVMs who were treated at Stanford between 1987 and 2001. The patients selected included 20 males (38%) and 33 females (62%). Their presenting symptoms were hemorrhage (n = 20; 38%), seizures (n = 18; 34%), headaches (n = 8; 15%), and progressive neurological deficits (n = 7; 13%). One patient was in Spetzler-Martin Grade III, 9 were in Spetzler-Martin Grade IV, and 43 were in Spetzler-Martin Grade V. The mean AVM size was 6.8 cm (range, 6-15 cm). AVM venous drainage was superficial (n = 7), deep (n = 20), or both (n = 26). At presentation, 31 patients (58%) were graded in excellent neurological condition, 17 were graded good (32%), and 5 were graded poor (9%). The patients were treated with surgery (n = 27; 51%), embolization (n = 52; 98%), and/or radiosurgery (n = 47; 89%). Most patients received multimodality treatment with embolization followed by surgery (n = 5), embolization followed by radiosurgery (n = 23), or embolization, radiosurgery, and surgery (n = 23). Nineteen patients (36%) were completely cured of their giant AVMs, 90% obliteration was achieved in 4 patients (8%), less than 90% obliteration was achieved in 29 patients (55%) who had residual AVMs even after multimodality therapy, and 1 patient was lost to follow-up. Of the 33 patients who either completed treatment or were alive more than 3 years after undergoing their most recent radiosurgery, 19 patients (58%) were cured of their AVMs. The long-term treatment-related morbidity rate was 15%. The clinical results after mean follow-up of 37 months were 27 excellent (51%), 15 good (28%), 3 poor (6%), and 8 dead (15%). The results in this series of patients with giant AVMs, which represents the largest series reported to date, suggest that selected symptomatic patients with giant AVMs can be treated successfully with good outcomes and acceptable risk. Multimodality treatment is usually necessary to achieve AVM obliteration.

Multimodality Treatment of Giant Intracranial Arteriovenous Malformations

Giant arteriovenous malformations (AVMs) (i.e., those greater than 6 cm at maximum diameter) are difficult to treat and often carry higher treatment morbidity and mortality rates than do smaller AVMs. In this study, we reviewed the treatment, angiographic results, and clinical outcomes in 53 patients with giant AVMs who were treated at Stanford between 1987 and 2001. The patients selected included 20 males (38%) and 33 females (62%). Their presenting symptoms were hemorrhage (n = 20; 38%), seizures (n = 18; 34%), headaches (n = 8; 15%), and progressive neurological deficits (n = 7; 13%). One patient was in Spetzler-Martin Grade III, 9 were in Spetzler-Martin Grade IV, and 43 were in Spetzler-Martin Grade V. The mean AVM size was 6.8 cm (range, 6-15 cm). AVM venous drainage was superficial (n = 7), deep (n = 20), or both (n = 26). At presentation, 31 patients (58%) were graded in excellent neurological condition, 17 were graded good (32%), and 5 were graded poor (9%). The patients were treated with surgery (n = 27; 51%), embolization (n = 52; 98%), and/or radiosurgery (n = 47; 89%). Most patients received multimodality treatment with embolization followed by surgery (n = 5), embolization followed by radiosurgery (n = 23), or embolization, radiosurgery, and surgery (n = 23). Nineteen patients (36%) were completely cured of their giant AVMs, 90% obliteration was achieved in 4 patients (8%), less than 90% obliteration was achieved in 29 patients (55%) who had residual AVMs even after multimodality therapy, and 1 patient was lost to follow-up. Of the 33 patients who either completed treatment or were alive more than 3 years after undergoing their most recent radiosurgery, 19 patients (58%) were cured of their AVMs. The long-term treatment-related morbidity rate was 15%. The clinical results after mean follow-up of 37 months were 27 excellent (51%), 15 good (28%), 3 poor (6%), and 8 dead (15%). The results in this series of patients with giant AVMs, which represents the largest series reported to date, suggest that selected symptomatic patients with giant AVMs can be treated successfully with good outcomes and acceptable risk. Multimodality treatment is usually necessary to achieve AVM obliteration.

Dissecting aneurysms of the vertebral artery: a management strategy.

The authors present a retrospective analysis of their experience in the treatment of vertebral artery (VA) dissecting aneurysms and propose a management strategy for such aneurysms, with special emphasis on the most formidable VA dissecting aneurysms, which involve the origin of the posterior inferior cerebellar artery (PICA). Since 1998, 18 patients with VA dissecting aneurysms, 11 of whom presented with subarachnoid hemorrhage (SAH), have been treated by endovascular surgery at the authors' institution. Obliteration of the entire segment of the dissected site with coils (internal trapping) was performed for aneurysms without involvement of the origin of the PICA (12 cases; among these the treatment-related morbidity rate was 16.7%). The treatment strategy applied to PICA-involved VA dissecting aneurysms presenting with SAH (three cases) included proximal occlusion of the parent artery followed by internal trapping of the aneurysm (one case), proximal occlusion of the parent artery followed by occipital artery (OA)-PICA bypass (one case), and two-staged internal trapping of the aneurysm involving double PICAs (one case). For PICA-involved VA dissecting aneurysms that were not associated with SAH at presentation (three cases), OA-PICA bypass was performed and followed by internal trapping of the aneurysm (two cases). In the remaining case in which a fetal-type posterior communicating artery was present, internal trapping was performed following successful balloon test occlusion (BTO). Overall, there was no sign of infarction in the PICA territory, despite complete occlusion of aneurysms involving the PICA. There was no recurrent bleeding or ischemic symptoms during the follow-up periods. The overall treatment-related morbidity rate for the VA dissecting aneurysms involving the PICA was 16.7%. Dissecting VA aneurysms that do not involve the PICA can be safely treated by internal trapping. For those lesions that do involve the PICA, a decision-making algorithm is advocated to maximize the efficacy of the treatment as well as to minimize the risks of treatment-related morbidity based on BTO.

Long‐term results of 60 patients with pathologic stage I &amp; IIA Hodgkin's disease treated with exclusive mantle radiation therapy

Between January 1972 and December 1982 60 patients with pathological stage IA and IIA Hodgkin's disease (HD) were submitted to Mantle irradiation only. Twenty-five were in stage I (32.1%) and 35 in stage II (67.9%). All patients were submitted to staging laparotomy. Cases with large mediastinal mass were excluded from this series. Delivered doses were 44 Gy in involved areas, 40 Gy on the mediastinum and 36 Gy on uninvolved sites. Twenty-four patients in stage I (96%) and 33 in stage II (94.2%) obtained complete remission. Actuarial 10- and 20-yr overall (OS) rates were 86% and 79.1%, respectively. Event-free (EFS) and relapse-free (RFS) survival rates at 10 and 20 yr were 67.5% and 62.1%, respectively. The occurrence of disease relapse resulted in the only statistical significant prognostic factor for OS in both univariate and multivariate analysis. Distant and extranodal recurrences were significantly (P<0.01) related to a reduced OS. On multivariate analysis stage was the only determinant factor for increased RFS. Extended field RT proved to be an effective curative modality for stage I HD patients, whereas 15 out of 33 patients in stage II relapsed requiring salvage therapy. Long-term analysis of survival and treatment-related morbidity rates will improve our knowledge and assist the physicians to choose the therapeutic option to offer to HD patients.

Fast Neutron Radiotherapy for the Treatment of Carcinoma of the Urinary Bladder

The major clinical investigation employing fast neutrons in the treatment of invasive bladder cancer are reviewed. Although data suggest that preoperative radiation schedules employing neutrons may result in a greater degree of pathologic downstaging than conventional precystectomy photon regimens, this has not led to an improved survival rate for neutron-treated patients over photon-treated patients. Randomized clinical trials comparing primary neutron irradiation and primary photon irradiation do not disclose an advantage for neutrons over photons as measured by survival rate or freedom from local tumor recurrence. The late complications in normal pelvic tissues following neutron irradiation with low-energy beams exceed those experienced after photon irradiation and have led to an unexpectedly high rate of treatment-related morbidity and mortality. A partial explanation for the toxicity may be attributed to the use of neutron beams with poor depth dose characteristics for the treatment of what is a deep-seated malignancy. An additional explanation is the documented lack of a differential in radioresponsiveness to neutrons between the bladder primary tumor and adjacent normal pelvic tissues.