Malignant Small Tumor Research Articles

Minimally invasive localization of oncolytic herpes simplex viral therapy of metastatic pleural cancer

Herpes simplex virus-1 (HSV-1) oncolytic therapy and gene therapy are promising treatment modalities against cancer. NV1066, one such HSV-1 virus, carries a marker gene for enhanced green fluorescent protein (EGFP). The purpose of this study was to determine whether NV1066 is cytotoxic to lung cancer and whether EGFP is a detectable marker of viral infection in vitro and in vivo. We further investigated whether EGFP expression in infected cells can be used to localize the virus and to identify small metastatic tumor foci (<1 mm) in vivo by means of minimally invasive endoscopic systems equipped with fluorescent filters. In A549 human lung cancer cells, in vitro viral replication was determined by plaque assay, cell kill by LDH release assay, and EGFP expression by flow cytometry. In vivo, A549 cells were injected into the pleural cavity of athymic mice. Mice were treated with intrapleural injection of NV1066 or saline and examined for EGFP expression in tumor deposits using a stereomicroscope or a fluorescent thoracoscopic system. NV1066 replicated in, expressed EGFP in infected cells and killed tumor cells in vitro. In vivo, treatment with intrapleural NV1066 decreased pleural disease burden, as measured by chest wall nodule counts and organ weights. EGFP was easily visualized in tumor deposits, including microscopic foci, by fluorescent thoracoscopy. NV1066 has significant oncolytic activity against a human NSCLC cell line and is effective in limiting the progression of metastatic disease in an in vivo orthotopic model. By incorporating fluorescent filters into endoscopic systems, a minimally invasive means for diagnosing small metastatic pleural deposits and localization of viral therapy for thoracic malignancies may be developed using the EGFP marker gene inserted in oncolytic herpes simplex viruses.

Perforation Through Small Bowel Malignant Tumors

Data on 19 patients (6 women and 13 men) with malignancy perforation through small bowel tissue were retrospectively reviewed. The median patient age was 57 years (range, 41-81 years). The histopathology included lymphoma (seven patients), leiomyosarcoma (two patients), gastrointestinal stromal tumor (one patient), adenocarcinoma (one patient), metastatic carcinomas with unknown primary tumor (four patients), metastatic adenocarcinoma from the lung (one patient), and metastatic carcinomas from the hypopharynx (one patient), cervix (one patient), and lung (one patient). Resection of a segment of perforated bowel with primary anastomosis was performed in 16 patients, wedge resection of perforated lesion with plication in two patients, and loop ileostomy in one patient. Postoperative deaths occurred in 10 (52.6%) patients, owing to sepsis and organ functional failure. Seven patients died from the primary malignancy at a median follow-up of 6.5 months (range, 5 months to 1 year 9 months) after surgery. Moreover, two patients with small bowel lymphoma were alive with disease at 4 years 8 months and 7 years 1 month after surgery. In conclusion, perforation through small bowel malignant tumors had a high postoperative mortality rate. High index of suspicion of the disease with early surgical treatment may improve treatment outcomes.

An overview of ultra-wideband microwave imaging via space-time beamforming for early-stage breast-cancer detection

Ultra-wideband (UWB) microwave imaging has recently been proposed for detecting small malignant breast tumors. In this article, we review the current research status of this approach. First, we introduce the concept of microwave imaging via space-time (MIST) beamforming and related signal-processing algorithms. The objective of these signal-processing techniques is to form a spatial image of scattered microwave energy, and to identify the presence and location of malignant lesions from their scattering signatures. Next, we present numerical studies based on finite-difference time-domain simulations to demonstrate the efficacy of MIST beamforming for detecting small malignant breast lesions in both prone and supine configurations. Finally, the experimental feasibility of UWB microwave imaging is demonstrated using an initial imaging prototype and multilayered breast phantoms.

Desmoplastic small round cell tumor: a clinicopathologic study of 15 cases

To study the clinicopathologic features and immunophenotype of desmoplastic small round cell tumor (DSRCT), and to assess the feasibility of reverse transcriptase-polymerase chain reaction (RT-PCR) as a diagnostic adjunct for DSRCT in routine practice. The clinical (number = 15), cytologic (number = 1) and histopathologic (number = 14) features of 15 cases of DSRCT were investigated. The immunophenotype was studied by LSAB method using a panel of antibodies. RT-PCR was performed in one case using formalin-fixed, paraffin-embedded tissue for EWS-WT1 fusion gene mRNA. Among the 15 patients studied, 13 were males and 2 were females. Their age ranged from 12 to 38 years (mean age = 23.8 years). Most presented with vague abdominal discomfort, distension or pain, accompanied by nausea, constipation and weight loss. Physical examination showed a palpable abdominal mass with ill-defined borders and tenderness. Ultrasound and computerized tomographic examination revealed single or multiple nodular tumor mass(es) in the peritoneal cavity, measuring 3 cm to 25 cm in greatest diameter (mean tumor diameter = 8.6 cm). Cytologic examination in 1 case showed clusters of small round cells in a hemorrhagic background. The tumor nuclei were hyperchromatic and contained inconspicuous nucleoli. Mitotic figures were readily identified. The cytoplasm however was scant. Histologically, the tumor was composed of small, round, ovoid to spindled cells arranged in nests of various shapes and sizes, embedded in a desmoplastic and focally hyalinized stroma. Immuno- histochemically, all cases showed diffuse and strong staining for AE1/AE3, vimentin, desmin and neuron-specific enolase. Some of them also expressed CAM5.2, epithelial membrane antigen, CD57, chromogranin A, synaptophysin and WT1. They were all negative for myogenin, CK5/6, CD117, calretinin and CD99. RT-PCR successfully amplified the EWS-WT1 chimeric mRNA in 1 case using paraffin-embedded tissue. Subsequent DNA sequencing showed that the gene fusion involved exon 7 of EWS and exon 8 of WT1 genes. The fusion gene contained KTS sequence. DSRCT is a highly malignant small round cell tumor occurring predominantly in the abdominal or pelvic cavity of young to middle-aged males. It is characterized by multiphenotypic differentiation. The peculiar perinuclear dot-like staining pattern for vimentin and desmin is characteristic for DSRCT. EWS-WT1 fusion transcript can be detected in formalin-fixed, paraffin-embedded tissue by RT-PCR, which may thus serve as a useful diagnostic adjunct for DSRCT.

Microwave Imaging via Space–Time Beamforming: Experimental Investigation of Tumor Detection in Multilayer Breast Phantoms

Microwave imaging via space-time (MIST) beamforming has been proposed recently for detecting small malignant breast tumors. In this paper, we extend the previously presented two-dimensional space-time beamformer design to three-dimensional (3-D), and demonstrate its efficacy using experimental data obtained with a multilayer breast phantom. The breast phantom consists of a homogeneous normal breast tissue simulant covered by a thin layer of skin simulant. A small synthetic malignant tumor is embedded in the breast phantom. We have developed several tumor simulants that yield the range of dielectric contrasts between normal and malignant tissue that are expected in clinical scenarios. A microwave sensor comprised of a synthetic planar array of compact ultrawide-band (UWB) antennas is immersed in a coupling medium above the breast tissue phantom. At each position in the array, the antenna transmits a synthetically generated pulse (1-11 GHz) into the phantom. The received backscatter signals are processed by a data-adaptive algorithm that removes the artifact caused by antenna reverberation and backscatter from the skin-breast interface, followed by 3-D space-time beamforming to image backscattered energy as a function of location. Our investigation includes a numerical (finite difference time domain) and experimental study of the UWB antenna performance in the immersion medium, as well as a study of the influence of malignant-to-normal breast tissue dielectric contrast on dynamic range requirements and tumor detectability. This paper represents the first experimental demonstration of 3-D MIST beamforming in multilayer breast phantoms with malignant-to-normal dielectric contrasts down to 1.5 : 1 for a 4-mm synthetic tumor.

Still any role for transduodenal local excision in tumors of the papilla of Vater?

Tumors of the papilla and ampulla of Vater are rare neoplasms which are usually detected at an early stage due to their symptoms. The accurate preoperative histological diagnosis and staging of ampullary tumors is often difficult and inconclusive, leading to controversy over the adequate treatment of these lesions. Three procedures are currently being used to treat such tumors. Pancreatoduodenectomy (PD) is a procedure with low morbidity and mortality at experienced centers, and is considered the treatment of choice for invasive carcinoma and large benign ampullary lesions with suspicion of malignancy. Transduodenal local excision (TDE) of ampullary tumors is a relatively simple procedure with operative morbidity and mortality rates comparable to PD. TDE is challenged at endoscopic centers by endoscopic snare excision (ESE). Due to technical advances, the safety and outcomes of ESE for ampullary tumors have improved in recent years. ESE and TDE represent adequate methods for treatment of benign tumors and also for small malignant tumors detected at an early stage if the diagnosis and stage have been accurately established preoperatively. Due to the safety of PD and the technical advances of ESE, TDE is reserved for selected patients. Randomized controlled studies are needed to establish the correct indications for PD, TDE, and ESE.

Three-dimensional ultrasound in margin evaluation for breast tumor excision using Mammotome®

Sonographic evidence of tumor removal by Mammotome® excision does not confirm histological clearance. The operator finds it hard to determine if a malignant tumor has been fully removed, leaving a safe margin in the direction of each border; that is, the spatial orientation during tumor retrieval is not well-established by naked eye under sonographic guidance. We propose a computational imaging process to extract reasonable tumor contour in pre- and postoperative data sets for sonographic guidance so that Mammotome® excision can help the operator to evaluate the surgical outcome. There were five tumors in the study, including three benign and two malignant. The lesion of interest was delineated after 2-D examination was completed, then it was analyzed with 3-D breast ultrasound (US). To give a reference point for correlations between pre- and postoperative images, we used a marker tape pasted on the skin within the transducer scanning area and then the preoperative 3-D US images were obtained. Subsequently, 2-D breast US was applied during Mammotome® operation. After the Mammotome® procedures were finished, the postoperative 3-D US images were obtained; thus, we gained two different data sets of 3-D US images that were used for later analysis for evaluating the extension of postoperative margin status. From the results, the safe margin was not satisfactory in all directions, because the minimum differences measured by the proposed algorithm were not large enough in all five cases, and this was proved from two malignant mastectomy specimens. The experimental results representing this inadequate Mammotome® excision can be visualized through the computer aid. The comparison of tumor contour and excision margin may possibly be used for small malignant tumors in the future to improve the breast-conserving surgery. (E-mail: dlchen88@ms13.hinet.net)

Microwave imaging via space-time beamforming for early detection of breast cancer

A method of microwave imaging via space-time (MIST) beamforming is proposed for detecting early-stage breast cancer. An array of antennas is located near the surface of the breast and an ultrawideband (UWB) signal is transmitted sequentially from each antenna. The received backscattered signals are passed through a space-time beamformer that is designed to image backscattered signal energy as a function of location. The beamformer spatially focuses the backscattered signals to discriminate against clutter and noise while compensating for frequency-dependent propagation effects. As a consequence of the significant dielectric-properties contrast between normal and malignant tissue, localized regions of large backscatter energy levels in the image correspond to malignant tumors. A data-adaptive algorithm for removing artifacts in the received signals due to backscatter from the skin-breast interface is also presented. The effectiveness of these algorithms is demonstrated using a variety of numerical breast phantoms based on anatomically realistic MRI-derived FDTD models of the breast. Very small (2 mm) malignant tumors embedded within the complex fibroglandular structure of the breast are easily detected above the background clutter. The MIST approach is shown to offer significant improvement in performance over previous UWB microwave breast cancer detection techniques based on simpler focusing schemes.

MICROWAVE IMAGING VIA SPACE-TIME BEAMFORMING FOR EARLY DETECTION OF BREAST CANCER: BEAMFORMER DESIGN IN THE FREQUENCY DOMAIN

Microwave imaging via space-time beamforming has been proposed recently for early-stage breast cancer detection. In this paper we present an efficient frequency-domain approach to designing the beamformers. The low-power signal sequentially transmitted into the breast by each antenna in an array may be either an ultrawideband pulse or a sequence of sinusoidal signals with carrier frequencies corresponding to the discrete design frequencies. Backscattered waveforms collected at each transmitting antenna are processed in the frequency domain using beamformers designed to compensate for frequency-dependent propagation effects in normal breast tissue. Backscattered signal energy is computed and imaged as a function of location. We demonstrate the capability of this method to detect millimeter-sized tumors using representative backscattered waveforms computed from a two-dimensional anatomically realistic FDTD breast model. These simulation results show that localized regions of high energy levels in the images consistently correspond to small malignant tumors present in the breast.

Laparoscopic liver resection for malignant liver tumors: preliminary results of a multicenter European study.

To assess the feasibility, safety, and outcome of laparoscopic liver resection for malignant liver tumors. The precise role of laparoscopy in resection of liver malignancies (hepatocellular carcinoma [HCC] and liver metastases) remains controversial despite an increasing number of publications reporting laparoscopic resection of benign liver tumors. A retrospective study was performed in 11 surgical centers in Europe regarding their experience with laparoscopic resection of liver malignancies. Detailed questionnaires were sent to each surgeon focusing on patient characteristics, clinical data, type and characteristics of the tumor, technical details of the operation, and early and late clinical outcome. All patients had radiologic investigations at follow-up to exclude disease recurrence. From February 1994 to December 2000, 37 patients with malignant liver tumors were included in this study. Ten patients had HCC, including 9 with cirrhotic liver, and 27 patients had liver metastases. The mean tumor size was 3.3 cm, and 89% of the tumors were located in the left lobe or in the anterior segments of the right liver. Liver procedures included 12 wedge resections, 9 segmentectomies, 14 bisegmentectomies (including 13 left lateral segmentectomies), and 2 major hepatectomies. The transfusion rate, the use of pedicular clamping, the conversion rate (13.5% in the whole series), and the complication rate were significantly greater in patients with HCC. There were no deaths. Postoperative complications occurred in eight patients (22%). The surgical margin was less than 1 cm in 30% of the patients. During a mean follow-up of 14 months, the 2-year disease-free survival was 44% for patients with HCC and 53% for patients having hepatic metastases from colorectal cancer. No port-site metastases were observed during follow-up. In patients with small malignant tumors, located in the left lateral segments or in the anterior segments of the right liver, laparoscopic resection is feasible and safe. The complication rate is low, except in patients with HCC on cirrhotic liver. By using laparoscopic ultrasound, a 1-cm free surgical margin should be routinely obtained. The late outcome needs to be evaluated in expert centers.

Problems in the Local Hyperthermia of Inductively Heated Embolized Tissues

A mathematical model is suggested for the high-frequency heating of a live tissue containing a small malignant tumor. The tumor is preliminarily filled with a polymer to prevent heat extraction by flowing blood. The polymer must contain a dispersed ferromagnetic to ensure inductive heating. The unsteady-state temperature profiles obtained by numerically solving the biothermal equation are used to estimate the degree of thermal destruction of the tumor cells.

The Detectability of Hepatic Metastases in Candidates of Radiofrequency Ablation: Comparison for Helical CT Scanning and Late-Phase Pulse-Inversion Harmonic Imaging

Purpose: To compare dual-phase helical CT and pulse inversion harmonic US using microbubble contrast agents in the detection of hepatic metastases prior to radiofrequency (RF) ablation. Materials and Methods: Twenty-one patients in whom hepatic metastases from colorectal cancer had been diagnosed by dual-phase CT scanning and who were considered to be candidates for RF ablation underwent pulse-inversion barmonic US examination. Images were obtained 5 minutes after the bolus injection of microbubble contrast agent SH U 508 A (4.0 g, 300 mg/mL). The number of metastatic tumors revealed by CT and US was determined, and the findings were statistically analysed. The influence of the results of US examination on treatment planning was also evaluated. Results: In 21 patients, 48 metastatic lesions were detected by helical CT, and 56 lesions by US. These eight additional lesions revealed by US occurred in six patients (29%), and their diameter was 3-13 (mean, 7.2) mm. In three of these patients, RF ablation could not be performed, while in the other three, the additional lesions were ablated. Conclusion: Pulse-inversion harmonic US imaging using microbubble contrast agents may depict small hepatic metastatic tumors that were not apparent at CT. US-therefore appears to be useful in the planning of treatment prior to the RF ablation of hepatic metastases.

A beam-splitting device for use with fiber-coupled laser light sources for photodynamic therapy.

A device that divides light into eight, four or two beams of equivalent power with only minor total power loss was designed, built and tested. The apparatus accepts light from a 200 microm diameter, 0.16 numerical aperture, silica-silica multimode optical fiber connected to one of several laser light sources for photodynamic therapy (PDT) of cancer. The incorporation of a variable iris diaphragm into the optical couplers allows the power of the beams to be independently set. Each of the beams can be coupled to a 400 or 600 microm diameter optical fiber to deliver the therapeutic light to the patient. This device is used in our institute for PDT of patients with either numerous small malignant tumors or single tumors with large surface area.

First radiotherapy of human metastatic brain tumors delivered by a computerized tomography scanner (CTRx)

Purpose: This Phase I study was designed to evaluate the computed tomography (CT) scanner as a device for radiation therapy of human brain tumors (CTRx). This first use in humans of a modified CT for treatment was founded on extensive research experience with canine tumors. An additional objective was to increase the therapeutic radiation dose to tumors compared to normal tissue by concentration of infused contrast material in tumors, an effect available at diagnostic x-ray energies but not at megavoltage energies. Methods and Materials: A small metastatic brain tumor in each of eight patients received 3–5-weekly fractions of 5 Gy equivalent per fraction from a CT scanner modified to deliver radiation therapy. In each patient, one additional tumor, lying completely outside the volume treated by CTRx, served as a control. The tumor receiving CTRx was treated after infusion of iodinated x-ray contrast media (CM) for dose enhancement. Many of these patients also received conventional 40 Gy whole brain radiation, before, during, or after CTRx treatment. Results: None of the patients showed adverse reactions to the CM or necrosis of the normal brain from the CTRx boost radiation. Monte Carlo calculations of the radiation dose distributions in a model tumor showed that the CTRx irradiation of tumors carrying 10 mg or more of iodine per gram of tumor was as good or better than the dose distribution from conventional 10-MV X-rays. The treated tumor in two of the patients vanished after four treatments, whereas a control tumor in one patient remained constant and grew 4-fold in another patient. Conclusion: The CTRx concept effectively combines a modified CT scanner as a diagnostic device, as a simulator dedicated to radiotherapy, and as a treatment machine. Thus, CTRx could be very useful for radiation oncologists in controlling CM-enhanced and other small brain tumors.

PRIMARY SIGNET RING CELL ADENOCARCINOMA OF THE BLADDER WITH ELEVATED SERUM CARBOHYDRATE ANTIGENS 19-9 AND 50

An 85-year-old woman was admitted to the hospital with azotemia and bilateral hydronephrosis. Cystoscopy revealed a nonpapillary mass on the right wall of the bladder and a papillary tumor beside the left ureteral orifice. Histopathological analysis of a biopsy specimen revealed signet ring cell adenocarcinoma (see figure). Serum levels of carcinoembryonic antigen, and carbohydrate antigens 50 and 19-9 were 10.7 ng./ml. (normal less than 4.0), 223 units per ml. (normal less than 35) and 193.2 units per ml. (normal less than 37), respectively. The general poor health of the patient excluded all surgical treatment except nephrostomy. She died of cachexia 3 months after hospitalization. Autopsy revealed that signet ring cell adenocarcinoma had diffusely spread in the vesical mucosa and invaded the muscle layer. Although small metastatic tumors were seen in the left ureter, para-aortic lymph nodes and lung, no adenocarcinoma was observed in the digestive organs.

Experimental studies of stereotactic laser balloon hyperthermic treatment.

The hyperthermic treatment of small malignant brain tumors in basal ganglia and other eloquent cortical areas was investigated with a stereotactic Nd:YAG laser balloon unit. An Ultra Line fiber (Heraeus Laser Sonics, CA) was inserted into a 6 F silicone balloon catheter, which caused the laser beam to be directed 80 degrees laterally. The balloon was inflated with physiologic saline to make the tumor tissue surrounding the laser fiber hypoxic. The hypoxia enhances the thermal effect on the tumor. The laser power was set at 5 watts (W) and a computer, programmed with specific parameters using feedback control was used to maintain the tissue 10 mm distant from the laser fiber at a temperature of 45 degrees C. Forty five minutes of hyperthermic treatment was applied to an implanted subcutaneous glioma in a rat. The thermally induced damaged in the tumor appeared as a fan-shape lesion extending at a 100 degrees angle from the laser beam axis. The entire tumor could be treated by rotating the laser fiber in the balloon catheter.

Photodynamic therapy for villous adenomas of the colon and rectum.

Endoscopic thermal laser therapy of colorectal villous adenomas is associated with a high recurrence rate due to incomplete tumor ablation, as treatment over carries a risk of perforation. Photodynamic therapy has been shown to be a promising in the treatment of small malignant tumors, and may be useful for benign adenomas. Eight patients with nine colosigmoid villous adenomas measuring 1-5 cm in length were treated with photodynamic therapy using either haematoporphyrin derivative or Photofrin as photosensitizer and multiple (4-16) applications of interstitial photoirradiation with red light (630 nm, 100 mW x 500 s per application). All but one adenoma had previously been incompletely treated with Nd-YAG laser therapy. Some skin sensitivity to light was seen in one patient. Seven adenomas were eradicated (follow-up 9-56 months, median = 12) as judged by follow-up endoscopy and biopsy. No local complications were seen. Substantial necrosis was produced in the other two adenomas, but they were not completely destroyed, probably due to inadequate light. PDT holds promise in the non-surgical management of villous adenomas, particularly after initial tumour debulking with the Nd-YAG laser.

3DFT-FISP MRI with gadopentetate dimeglumine in differential diagnosis of small liver tumors.

We assessed the value of dynamic sequential three-dimensional Fourier transformation (3DFT) MRI in differentiating various types of small liver tumors. Forty-seven patients with 65 liver masses < 3 cm in size (42 hepatocellular carcinomas, 11 hemangiomas, 12 metastatic tumors) were studied by 3DFT fast imaging with steady-state precession (FISP) MRI [TR(ms)/TE(ms)/flip angle (degree): 20/8/30]. The slab thickness was 21-35 mm, and there were seven partitions. The 3DFT-FISP MR images were obtained immediately after 0.1 mmol/kg of gadopentetate dimeglumine was administered intravenously over 2-3 s (early phase), 60 s after (late phase I), and 120 s after (late phase II). Eighty-six percent of small hepatocellular carcinomas showed hyperintense enhancement relative to the surrounding liver parenchyma and iso- or hypointense enhancement with or without capsular enhancement in the late phase. Eighty-two percent of small hemangiomas showed peripheral globular enhancement in the early phase and total hyperintense or peripheral enhancement in the late phases. Ninety-two percent of the small metastatic liver tumors showed doughnut-like ring enhancement in the early phase. By dynamic 3DFT-FISP MRI, we were able to accurately evaluate the hemodynamics and morphological findings of each type of small liver tumor.

Primary Adenocarcinoma of the Jejunum in Pregnancy

A 29-year-old white woman at 32 weeks of gestation was diagnosed as having recurrent small bowel obstruction by an upper gastrointestinal radiographic series. At exploratory laparotomy a primary adenocarcinoma of the jejunum was resected. Primary small bowel malignant tumors are rare and generally occur late in life. These lesions are difficult to diagnose and commonly discovered only late in their clinical course. The possibility of such tumors should be considered in the differential diagnosis when recurrent abdominal pain accompanied by other signs and symptoms of small bowel obstruction is encountered during pregnancy.

Fractionated radiotherapy of small inoperable lesions of the brain using a non-invasive stereotactic frame

Arteriovenous malformations (AVMs) and benign or low grade, small malignant tumors can be treated by stereotactic radiotherapy in a single fraction. This report describes a technique for stereotactic treatment of small lesions using conventional, fractionated, photon beam irradiation. The Laitinen's stereoadapter, non-invasive head frame was used. This device was tested for accuracy by serial mountings and found to be accurate within 1 mm. The accuracy of the dose delivered was within 2%. Adaptation of this device to the linear accelerator required the design of secondary circular collimators which decreased the penumbra from 3–4 mm to 2–3 mm. The dose fall off outside the target volume is steep enough when using two non-coplanar arcs ( 90 to 10% within 1 cm). Thermoluminescent dosimetry (TLD) in a humanoid phantom showed good correlation with the calculated dose. This system permits delivery of fractionated radiation therapy to small volumes, easily and accurately, under stereotactic conditions.