Adjacent Normal Structures Research Articles

Optimized radiotherapy in a locally advanced oropharyngeal carcinoma: Comparison of IMRT and proton beam

Curative treatment of oropharyngeal carcinoma with conventional radiation is limited by the tolerance of adjacent normal structures and the severity of acute reactions. Our aim was to compare the isodose distribution and dose volume histograms of two state of the art radiotherapy modalities, IMRT and proton beam radiation therapy in a patient with an advanced oropharyngeal carcinoma. Treatment plans were independently generated for a patient with T4N2c SCC of the right tongue base. Following standard head immobilization, 2.5 mm axial images were obtained with contrast enhancement using a GE CT-simulator. An MRI was also obtained before treatment planning. The contrast-enhanced tumor, entire base of tongue, and involved lymph nodes were contoured as GTV. The rest of the lymphatic system including supraclavicular lymph nodes contoured as CTV. The CTV also included a 1 cm margin around the GTV in the oropharynx. Spinal cord, brain stem, mandible, right and left parotids were delineated as Organs At Risk (OAR). The GTV and CTV were prescribed to 70.2 and 59.4 Gy respectively at 1.8 Gy per fraction, with 5 mm margins. Normal tissue constraints were 44, 54, and 60 Gy for spinal cord, brainstem and mandible respectively. Parotid doses were kept as low as possible. The same volumes, target doses and dose constraints were used for both treatment plans. The most significant finding was the uniformity of dose within the two target volumes and in normal tissues proximal to the CTV. The dose encompassing the GTV and CTV was much more homogeneous and conformal in the proton beam plan. The proton DVH for the GTV was steeper than that of IMRT and resulted in almost all of GTV uniformly receiving the prescribed dose of 70.2 Gy. In the IMRT plan, most of the GTV received a dose in excess of what was prescribed, 50 % of the GTV received a dose of >75 Gy and 25 % >78 Gy. The CTV coverage with protons was also better than with IMRT. Protons had more sparing of non-target tissues. Doses in the IMRT plan were spread out beyond the target volumes producing unwanted radiation at the non-target tissues such as the anterior oral cavity. The DVH for OAR, mandible and spinal cord also demonstrated a better distribution with protons. The median dose to the mandible was less than 10 Gy with protons while 47 Gy with IMRT. Fifty percent of the spinal cord volume received less than 30 Gy with protons, in contrast, 90% received >30 Gy with IMRT (see Figure). Because of the proximity of lymphatic CTV to both parotid glands, there was little difference in parotid doses between IMRT and protons. Protons produced superior dose distributions to the GTV and CTV with less dose to OAR and non-target tissues than IMRT in an advanced oropharyngeal cancer. The inhomogeneity of dose and the location of hot spots within the oropharynx with IMRT is problematic. This can cause an excessive mucositis and compromise the delivery of concurrent chemo radiotherapy and possibly lead to late morbidity. Even though the IMRT plan provided acceptable OAR doses, there is less organ dose with protons and potential risk of late injury.

42 oral Dose escalation and toxicity limitation in prostate cancer therapy: conforming external beam treatment to dose delivered to prostate and critical adjacent normal structures by I-125 permanent implants

42 oral Dose escalation and toxicity limitation in prostate cancer therapy: conforming external beam treatment to dose delivered to prostate and critical adjacent normal structures by I-125 permanent implants

Dermatofibrosarcoma protuberans: a report on 29 patients treated by Mohs micrographic surgery with long-term follow-up and review of the literature.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon tumor of the skin. Clinically, it often masquerades as a benign, indolent tumor on the trunk and extremities. Microscopically, it extends far beyond assessed clinical margins, spreading locally in the dermis, subcutaneous tissue, and muscle. The local recurrence rate in patients with DFSP who undergo wide local excision ranges from 0% to 21%. Recent preliminary reports indicate more consistently favorable cure rates with Mohs micrographic surgery (MMS). However, to date only a few scattered reports have documented long-term 5-year follow-up. The authors present data on 29 patients with DFSP who underwent MMS. In addition, they reviewed the medical literature to summarize the accumulated experience of MMS treatment in the management of DFSP. The authors conducted a retrospective review of a series of 40 consecutive patients with DFSP who underwent MMS over the last 20 years. Of these, there were 29 patients with > 5 years of follow-up who formed the basis of the current review. The literature also was searched for patients with DFSP who underwent MMS with > 5 years of follow-up At the University of Wisconsin Mohs Surgery Clinic, 29 patients with > 5 years of follow-up were treated. There were 16 women and 13 men. Eight patients developed recurrent disease after previous non-Mohs treatment. Site distribution was 45% head and neck and 55% trunk and extremities. In the current series, there were no local recurrences, with a local 5-year cure rate of 100%. In the literature review, which included the current series, there were 136 patients with DFSP who underwent Mohs surgery with > 5 years of follow-up. Nine patients in the current series developed local recurrences, including five patients who underwent a second Mohs procedure. The local cure rates after the first and second Mohs surgeries were 93.4% and 98.5%, respectively. The rate (percent) and time to local recurrence was 50% at 3 years and 75% at 5 years. However, 25% of local recurrences appeared late, after the usual 5-year recommendation. In a series of 29 patients with of DFSP and in an accompanying update of the medical literature, 136 patients with DFSP underwent MMS with > 5 years of follow-up. There were no regional and/or distant metastases. However, late recurrences beyond the usual recommended 5-year follow-up may occur. Therefore, all patients with DFSP, especially those with recurrent tumors, should be followed for an extended period. The accumulated data continue to confirm that, when DFSP is discovered early and is accessible readily to excision by MMS, a favorable outcome can be expected with minimal trauma or sacrifice of adjacent normal structures and with a low recurrence rate.

Computed tomography perfusion of squamous cell carcinoma of the upper aerodigestive tract. Initial results.

To define the computed tomography (CT) perfusion characteristics of head and neck squamous cell carcinoma. Fourteen consecutive patients with untreated squamous cell cancers of head and neck underwent CT of the head and neck along with CT perfusion imaging through the primary site. For the perfusion studies, CT density changes in blood and tissues were kinetically analyzed using the commercially available CT Perfusion 2 software (General Electric Medical Systems. Milwaukee, WI) on a GE Advantage Windows workstation. This yielded parameter maps of fractional tissue blood volume (mL/100 g), blood flow (mL x 100 g(-1) x min(-1)), mean transit time (s), and microvascular permeability surface area product (mL x 100 g(-1) x min(-1)). One head and neck radiologist analyzed perfusion data. Regions of interest (ROI) were placed over the primary tumor site, tongue base, and adjacent muscle groups. The average values of tissue blood volume (BV), blood flow (BF), mean transit time (MTT), and capillary permeability surface area product (CP) were then calculated for the tumor and compared with the average values for the tongue base and adjacent musculature. To determine a statistically significant difference between the tumor and muscle parameters, the Wilcoxon sign test, a nonparametric test for paired data, was employed. The average values of CP, BF, and BV were higher in primary tumor (41.9, 132.9, 6.2, respectively) than in tongue base or adjacent muscular structures. The MTT was reduced in primary tumors (4.0) compared with adjacent normal structures. The above differences were statistically significant (P<0.05). We obtained baseline perfusion data for head and neck squamous cell cancers and compared it with adjacent normal structures. Our initial results suggest that CT perfusion parameters (CP, BF, BV, and MTT) can be used to help differentiate head and neck squamous cell carcinoma (SCCA) from adjacent normal tissue.

Nomograms Inserted into NCCN Prostate Cancer Guidelines

Nomograms Inserted into NCCN Prostate Cancer Guidelines

Structural and radiometric asymmetry in brain images

This paper presents a general framework for analyzing structural and radiometric asymmetry in brain images. In a healthy brain, the left and right hemispheres are largely symmetric across the mid-sagittal plane. Brain tumors may belong to one or both of the following categories: mass-effect, in which the diseased tissue displaces healthy tissue; and infiltrating, in which healthy tissue has become diseased. Mass-effect brain tumors cause structural asymmetry by displacing healthy tissue, and may cause radiometric asymmetry in adjacent normal structures due to edema. Infiltrating tumors have a different radiometric response from healthy tissue. Thus, structural and radiometric asymmetries across the mid-sagittal plane in brain images provide important cues that tumors may be present. We have developed a framework that registers images with their reflections across the mid-sagittal plane. The registration process accounts for tissue displacement through large deformation image warping. Radiometric differences are taken into account through an additive intensity field. We present an efficient multi-scale algorithm for the joint estimation of structural and radiometric asymmetry. Results for nine MR images of patients with tumors and four normal control subjects are presented.

Extended field-of-view sonography: advantages in abdominal applications.

To show the advantages of extended field-of-view sonography in abdominal applications. Thirty-one cases were prospectively analyzed in our study. Extended field-of-view images were obtained when the radiologist decided that they would offer potential advantages for the examination. When extended field-of-view scanning was used, the radiologist determined prospectively whether it was useful according to several categories. Images were obtained with a 2- to 5-MHz curved array transducer or 4- to 9- and 5- to 12-MHz linear array transducers. Extended field-of-view sonography provided several potential benefits over conventional sonography in the abdominal area. The advantages of extended field-of-view sonography were better demonstration of the spatial relationship between lesions and adjacent normal structures in 18 cases (58%), accurate quantification of sizes or volumes of large organs or lesions in 16 (52%), better display of the extended and tubular structures in 6 (19%), usefulness for clinical consultations in 7 (23%), and documentation comparable with that of computed tomography or magnetic resonance imaging in 10 (32%). Extended field-of-view sonography provided the anatomic context of the lesion in its surroundings and allowed precise measurement and tracing of the extended and tubular structures. The method has notable advantages and clinical applications.

Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently described in situ hybridization technique in archival samples (Meeker AK, Gage WR, Hicks JL, Simon I, Coffman JR, Platz EA, March GE, De Marzo AM: Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. American Journal of Pathology 2002, 160:1259-1268) for assessment of telomere length in tissue microarrays containing a variety of noninvasive pancreatic ductal lesions. These included 82 PanIN lesions of all histological grades (24 PanIN-1A, 23 PanIN-1B, 24 PanIN-2, and 11 PanIN-3) that were selected from pancreatectomy specimens for either adenocarcinoma or chronic pancreatitis. Telomere fluorescence intensities in PanIN lesions were compared with adjacent normal pancreatic ductal epithelium and acini (62 of 82 lesions, 76%), or with stromal fibroblasts and islets of Langerhans (20 of 82 lesions, 24%). Telomere signals were strikingly reduced in 79 (96%) of 82 PanINs compared to adjacent normal structures. Notably, even PanIN-1A, the earliest putative precursor lesion, demonstrated a dramatic reduction of telomere fluorescence intensity in 21 (91%) of 23 foci examined. In chronic pancreatitis, reduction of telomere signal was observed in all PanIN lesions, whereas atrophic and inflammatory ductal lesions retained normal telomere length. Telomere fluorescence intensity in PanIN lesions did not correlate with proliferation measured by quantitative Ki-67-labeling index or topoisomerase IIalpha expression. Thus, telomere shortening is by far the most common early genetic abnormality recognized to date in the progression model of pancreatic adenocarcinomas. Telomeres may be an essential gatekeeper for maintaining chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal epithelium. A critical shortening of telomere length in PanINs may predispose these noninvasive ductal lesions to accumulate progressive chromosomal abnormalities and to develop toward the stage of invasive carcinoma.

Intensity Modulated Radiotherapy (IMRT) Decreases Treatment-Related Morbidity and Potentially Enhances Tumor Control

Intensity modulated radiation therapy (IMRT), a new form of three-dimensional conformal radiation therapy (3DCRT), optimizes the concept of computer-controlled radiation deposition in tumor (target) while sparing adjacent normal structures. A retrospective review was done on the initial 185 patients with tumors in different sites including prostate cancer, head and neck cancer, pediatric tumors, adult brain tumors, and previously irradiated recurrent tumors treated with IMRT.Preliminary findings indicate that IMRT is a new clinically feasible tool in radiation oncology. Treatment-related morbidity profile was favorable. Tumor response, local control, and the ability to palliate previously irradiated patients are encouraging. Intensity modulated radiation therapy will allow dose escalation, leading to better tumor control.

Image-guided radiosurgery in the treatment of spinal metastases

The authors describe a new method for treating metastatic spinal tumors in which noninvasive, image-guided, frameless stereotactic radiosurgery is performed. Stereotactic radiosurgery delivers a high dose of radiation in a single or limited number of fractions to a lesion while maintaining delivery of a low dose to adjacent normal structures. Image-guided radiosurgery was developed by coupling an orthogonal pair of real-time x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the radiation beam to treatment sites associated with radiographic landmarks. This procedure can be conducted in an outpatient setting without the use of framebased skeletal fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Four patients with spinal metastases underwent radiosurgery with total prescription doses of 1000 to 1600 cGy in one or two fractions. Alignment of the treatment dose with the target volume was accurate to within 1.5 mm. During the course of each treatment fraction, patient movement was less than 0.5 mm on average. Dosimetry was highly conformal, with a demonstrated ability to deliver 1600 cGy to the perimeter of an irregular target volume while keeping exposure to the cord itself below 800 cGy. These experiences indicate that frameless radiosurgery is a viable therapeutic option for metastatic spine disease.

Incorporate organ motion into MLC leaf sequencing for intensity modulated radiation therapy

Purpose: Intensity modulated radiation therapy (IMRT) has been shown to provide highly conformal dose to the target while significantly sparing the normal tissues. IMRT plans have been routinely delivered via multileaf collimators (MLC) using either dynamic or step-and-shoot mode. The effect of organ motion is usually considered by applying a 1-2 cm margin around the target. The actually delivered target dose distribution is different from the ideal dose distribution and the normal tissues in the margin area receive much higher doses, which may yield higher complications later on. The purpose of this work is to incorporate organ motion into MLC leaf sequencing for IMRT treatments. Our objective is to study the feasibility of this approach and the clinical advantages in terms of dose coverage and normal tissue sparing. Materials and Methods: An MLC leaf sequencer which compensates for organ motion has been created. In this feasibility study, the breast motion was mimicked by a typical breathing pattern of breast cancer patients obtained by measurement using external and internal markers. The leaf sequencer would read in the breathing pattern as a function of leaf pair locations as if the breathing pattern were fed into the MLC controller. The MLC leaf trajectories were adjusted based on breathing motion and Monte Carlo dose calculations were performed using MCDOSE on patient CT phantoms at different phases of the breathing cycle. An in-house program was used to interpolate the intermediate CT slices between the two extreme CT slices of breathing motion: inspiration and expiration. Accurate correlation between the voxels at any point of the breathing cycle was established so that the doses could be accumulated accurately. The calculation results of motion adaptive IMRT plan were compared with those of ideal plan and actually delivered plan without organ motion correction. The effect of time delay of leaf movement was also studied on the IMRT doses for the cases of 0.1, 0.2 and 0.5 second delay. Results: In all the cases studied, target dose conformity and uniformity were improved for the motion adaptive IMRT plan, and the doses to the critical structures, especially those surrounding the target, were greatly reduced. A motion adaptive IMRT plan was superior to a plan without organ motion correction, and it could fully recover the ideal IMRT plan assuming a perfect tracking of MLC leaf movement on breast motion. Our current optical/radiographical tracking system can provide real time organ motion measurement and correction with a time delay of about 1 second. The discrepancy caused by a 0.1 second delay was only 2% in the target coverage, which was considered clinically acceptable. The dose differences caused by the 0.2 and 0.5 second delays were found to be 4% and 10%, respectively. Conclusion: This feasibility study has shown that ignorance of the organ motion in the breast cancer treatments will result in lower dose to the target than prescribed and 50% higher dose to the surrounding normal tissues than allowed. By including organ motion into the MLC leaf sequencing, the target dose uniformity and conformity can be significantly improved and the dose to the adjacent normal tissues and critical structures can be greatly reduced by applying smaller treatment margins. In addition, the leaf motion delay was found to be insignificant in the treatment delivery. It is shown that this new approach can be introduced to the clinical routine to improve the current IMRT technique.

Image-guided hypo-fractionated stereotactic radiosurgery to spinal lesions.

This article demonstrates the technical feasibility of noninvasive treatment of unresectable spinal vascular malformations and primary and metastatic spinal tumors by use of image-guided frameless stereotactic radiosurgery. Stereotactic radiosurgery delivers a high dose of radiation to a tumor volume or vascular malformation in a limited number of fractions and minimizes the dose to adjacent normal structures. Frameless image-guided radiosurgery was developed by coupling an orthogonal pair of x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the therapy beam to treatment sites within the spine or spinal cord, in an outpatient setting, and without the use of frame-based fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Sixteen patients with spinal lesions (hemangioblastomas, vascular malformations, metastatic carcinomas, schwannomas, a meningioma, and a chordoma) were treated with total treatment doses of 1100 to 2500 cGy in one to five fractions by use of image-guided frameless radiosurgery with the CyberKnife system (Accuray, Inc., Sunnyvale, CA). Thirteen radiosurgery plans were analyzed for compliance with conventional radiation therapy. Tests demonstrated alignment of the treatment dose with the target volume within +/-1 mm by use of spine fiducials and the CyberKnife treatment planning system. Tumor patients with at least 6 months of follow-up have demonstrated no progression of disease. Radiographic follow-up is pending for the remaining patients. To date, no patients have experienced complications as a result of the procedure. This experience demonstrates the feasibility of image-guided robotic radiosurgery for previously untreatable spinal lesions.

Image-guided Hypo-fractionated Stereotactic Radiosurgery to Spinal Lesions

OBJECTIVE This article demonstrates the technical feasibility of noninvasive treatment of unresectable spinal vascular malformations and primary and metastatic spinal tumors by use of image-guided frameless stereotactic radiosurgery. METHODS Stereotactic radiosurgery delivers a high dose of radiation to a tumor volume or vascular malformation in a limited number of fractions and minimizes the dose to adjacent normal structures. Frameless image-guided radiosurgery was developed by coupling an orthogonal pair of x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the therapy beam to treatment sites within the spine or spinal cord, in an outpatient setting, and without the use of frame-based fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Sixteen patients with spinal lesions (hemangioblastomas, vascular malformations, metastatic carcinomas, schwannomas, a meningioma, and a chordoma) were treated with total treatment doses of 1100 to 2500 cGy in one to five fractions by use of image-guided frameless radiosurgery with the CyberKnife system (Accuray, Inc., Sunnyvale, CA). Thirteen radiosurgery plans were analyzed for compliance with conventional radiation therapy. RESULTS Tests demonstrated alignment of the treatment dose with the target volume within ± 1 mm by use of spine fiducials and the CyberKnife treatment planning system. Tumor patients with at least 6 months of follow-up have demonstrated no progression of disease. Radiographic follow-up is pending for the remaining patients. To date, no patients have experienced complications as a result of the procedure. CONCLUSION This experience demonstrates the feasibility of image-guided robotic radiosurgery for previously untreatable spinal lesions.

A theoretical investigation into the role of tumour radiosensitivity, clonogen repopulation, tumour shrinkage and radionuclide RBE in permanent brachytherapy implants of 125I and 103Pd

There is growing clinical interest in the use of 125I (half-life 59.4 days) and 103Pd (half-life 16.97 days) for permanent brachytherapy implants. These radionuclides pose interesting radiobiological challenges because, even with slowly growing tumours, significant tumour cell repopulation may occur during the long period taken to deliver the full radiation dose. This results in a considerable amount of the prescribed dose being wasted. There may also be changes in the tumour volume during treatment (due to oedema and/or shrinkage), thus altering the relative geometry of the implanted seeds and causing additional dose rate variations. This assessment examines the interaction between the above effects and additionally includes allowance for the influence of the relative biological effectiveness (RBE) of the radiations emitted by the two radionuclides. The results are presented in terms of the biologically effective doses (BEDs) and likely tumour control probabilities (TCPs) associated with the various parameter combinations. The overall BED enhancement due to the RBE effect is shown always to be greater than the RBE itself and is greatest in tumours which are radio-resistive and/or fast growing. The biological dose uncertainties are found to be less with 103Pd and the TCPs associated with this radionuclide are expected to be significantly higher in the treatment of some ‘difficult’ tumours. Using typically prescribed doses 125I appears to be better for treating radiosensitive tumours with long doubling times and which shrink fairly rapidly. However, unless 125I doses are reduced, this advantage may well be offset by the greatly enhanced biological doses delivered to adjacent normal structures.

Intratumoral Adenovirus-Mediated Suicide Gene Transfer for Hepatic Metastases from Colorectal Adenocarcinoma: Results of a Phase I Clinical Trial

Animal studies have shown that direct injection of an adenoviral vector (Adv.RSV-tk) expressing the herpes thymidine kinase gene into established tumors in the liver, followed by systemic ganciclovir administration, was effective in inducing tumor necrosis. Toxicities were minimal at therapeutically effective vector doses, although severe hepatic necroinflammation was seen at much higher supratherapeutic doses. We conducted a clinical phase I trial in patients with metastatic colorectal adenocarcinoma in the liver to assess the safety of intratumoral Adv.RSV-tk injection (escalating doses) followed by intravenous ganciclovir (fixed dose). The vector was injected into a metastatic tumor in the liver under local anesthesia by percutaneous needle placement with concurrent ultrasonographic monitoring to prevent injection or leakage into adjacent normal liver structures. We treated 16 patients in five dose level cohorts of Adv.RSV-tk, from 1.0x10(10) to 1.0x10(13) virus particles per patient. Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. Other toxicities were also transient: grade 2-3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 of 16 patients. These results indicate that Adv.RSV-tk can be safely administered by percutaneous intratumoral injection in patients with hepatic metastases at doses up to 1.0x10(13) virus particles per patient, and can provide the basis for future clinical trials involving intratumoral adenoviral vector injection.

Analysis of tissue chimerism in nude mouse brain and abdominal xenograft models of human glioblastoma multiforme: what does it tell us about the models and about glioblastoma biology and therapy?

In situ hybridization coupled to immunohistochemistry for antigens of interest allows unequivocal identification of tumor cells from reactive stroma cells and normal adjacent structures in human glioblastoma multiforme grafts transplanted into nude mice. With this methodology, we have explored the development of glioblastoma multiforme solid grafts transplanted into nude mouse brains or flanks. The brain transplants closely resembled the human situation, particularly in relation to differentiation and growth patterns. The morphological features of peritumoral reactive gliosis were similar to those observed in humans. A mouse glial stroma within the main tumor masses was also demonstrated. Kinetic studies showed that the compartment of isolated tumor cells that infiltrated host brains and the reactive gliosis constituted two cycling cell populations. Despite VEGF protein expression by tumor cells and some reactive astrocytes, the abnormally permeable microvascular beds were not hyperplastic. The observation of a non-infiltrative pattern of growth when grafts were established in host flanks demonstrated that the organ-specific environment plays a determining role in the growth and invasive properties of glioblastoma. The phylogenetic distance between man and mouse and the recipient immunoincompetence should not impose serious limitations on the use of this model for studying malignant glioma biology and therapy in vivo.

Sex hormone-induced mammary carcinogenesis in the female Noble rats: Expression of Bcl-2 and Bax in hormonal mammary carcinogenesis

We have established a Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis, in which the role of androgen in promoting mammary carcinogenesis was highlighted. We have also established that stromal-epithelial interactions may be responsible for the promotional effects of testosterone in mammary carcinogenesis. Based on these understandings, in the present study we examined the expression of Bcl-2 and Bax in pre-malignant mammary glands from rats treated with different protocols of sex hormones for 7 weeks as well as sex hormone induced mammary tumours. We observed that Bcl-2 was strongly expressed in most of mammary tumour cells, whereas weak or negative in adjacent normal or hyperplastic ductal structures. On the contrary, Bax immunoreactivity was weak in mammary tumour cells while strongly expressed in adjacent normal or hyperplastic ductal structures. More importantly, the results from comparative study of 'pre-malignant' glands further showed that when animals were treated with 17beta-oestradiol, the mammary epithelial cells expressed high levels of Bcl-2. The results from rats treated with testosterone, either alone or in combination with oestrogen, give rise to high levels of Bax expression in 'pre-malignant' mammary glands. These observations indicate that in 'pre-malignant' mammary glands, treatment with testosterone, either alone or in combination with 17beta-oestradiol, may induce high apoptotic activities. However, in fully developed mammary tumours, the apoptotic activities apparently decrease in tumour cells. TUNEL assay provides further data to support this conclusion. Our study, thus, suggests that androgens may play a promoting role in mammary carcinogenesis by upregulation of Bax expression and induction of high apoptotic activities in 'pre-malignant' stage, which would provide a selective pressure favouring the expansion of the initiated cells.

Intrapartum fetal heart rate variability and subsequent neonatal cerebral edema

Objective: To determine whether fetal heart rate variability (FHRV) in the neurologically impaired neonate is associated with cerebral edema.Study design: Through retrospective chart review, singleton term infants with neonatal encephalopathy and permanent neurologic impairment were identified in a national registry of brain-injured infants. Cerebral edema was defined as follows: (1) ultrasound-generalized increases in echodensity throughout the brain with loss of normal landmarks or slitlike ventricles, (2) computed tomography scan-low attenuation throughout the brain, or mass effect as evidenced by sulcal effacement, displacement of the midline structures, ventricular distortion, or compression of subarachnoid spaces, and (3) low magnetic resonance imaging signal on T1-weighted images and high signal on T2-weighted images or morphologic change on T1-weighted image detected by gross enlargement of structures or by distortion of normal adjacent structures. Cases with a Hon intrapartum fetal heart rate (FHR) pattern (reactive pattern on admission followed by tachycardia and repetitive FHR decelerations) were selected. These cases were then categorized according to the FHR variability at the end of the monitor strip as follows: average ≥6 bpm or diminished (D) <6 bpm. Exclusion criteria were as follows: (1) nonqualifying FHR pattern—183; (2) no neuroimaging studies within 7 days of birth—48; (3) insufficient data—19; and (4) other—7.Results: Of 300 singleton term brain-injured neonates, 43 (14%) neonates met entry criteria. Prior to birth, the FHRV average was 10 (23%) or diminished (33 [77%]). Of these infants, cerebral edema was found in 18 (42%) patients. But, average FHRV was associated with significantly less cerebral edema (average 1/10 [10%] versus diminished 17/33 [52%] [P = 0.02]).Conclusions: In brain-injured neonates, cerebral edema appears to be associated with the Hon FHR pattern. Cerebral edema also appears to be associated with diminished FHRV. These findings suggest that the presence of average FHRV in the fetus with the Hon FHR pattern is associated with fetal brain injury, but not necessarily neonatal cerebral edema.

3-DIMENSIONAL VOLUME RENDERED COMPUTERIZED TOMOGRAPHY FOR PREOPERATIVE EVALUATION AND INTRAOPERATIVE TREATMENT OF PATIENTS UNDERGOING NEPHRON SPARING SURGERY

Purpose Computerized tomography (CT) is the diagnostic and staging modality of choice for renal neoplasms. Existing imaging modalities are limited by a 2-dimensional (D) format. Recent advances in computer technology now allow the production of high quality 3-D images from helical CT. Nephron sparing surgery requires a detailed understanding of renal anatomy. Preoperative evaluation must delineate the relationship of the tumor to adjacent normal structures and demonstrate the vascular supply to the tumor for the surgeon to conserve as much normal parenchyma as possible. We propose that helical CT combined with 3-D volume rendering provides all of the information required for preoperative evaluation and intraoperative management of nephron sparing surgery cases. We prospectively evaluated the role of 3-D volume rendering CT in 60 patients undergoing nephron sparing surgery for renal cell carcinoma at the Cleveland Clinic Foundation. Materials and Methods Triphasic spiral CT was performed preoperatively in 60 consecutive patients undergoing nephron sparing surgery for renal neoplasms. A 3 to 5-minute videotape was prepared using volume rendering software which demonstrated the position of the kidney, location and depth of extension of the tumor(s), renal artery(ies) and vein(s), and relationship of the tumor to the collecting system. These videotapes were viewed by a radiologist and urologist in the operating room at surgery, and immediately correlated with surgical findings. Corresponding renal arteriograms of 19 patients were retrospectively compared to 3-D volume rendering CT and operative findings. Results A total of 97 renal masses were identified in 60 cases evaluated with 3-D volume rendering CT before nephron sparing surgery. There were no complications related to the 3-D protocol and 3-D rendering was successful in all patients. The number and location of lesions identified by 3-D volume rendering CT were accurate in all cases, while enhancement and diagnostic characteristics were consistent with pathological findings in 95 of 97 tumors (98%). Of 77 renal arteries identified at surgery 74 were detected by 3-D volume rendering CT (96%). Helical CT missed 3 small accessory arteries, including 1 in a cross fused ectopic kidney. All major venous branches and anomalies were identified, including 3 circumaortic left renal veins. Of 69 renal veins identified at surgery 64 were detected by 3-D volume rendering CT (93%). All 5 renal veins missed by CT were small, short, duplicated right branches of the main renal vein. Renal fusion and malrotation anomalies were correctly identified in all 4 patients. Conclusions The 3-D volume rendering CT accurately depicts the renal parenchymal and vascular anatomy in a format familiar to most surgeons. The data integrate essential information from angiography, venography, excretory urography and conventional 2-D CT into a single imaging modality, and can obviate the need for more invasive imaging. Additionally, the use of videotape in an intraoperative setting provides concise, accurate and immediate 3-D information to the surgeon, and it has become the preferred means of data display for these procedures at our center.

Future directions in innovative minimally invasive surgery

Future directions in innovative minimally invasive surgery