Interstitial hypertension in head and neck tumors in patients: correlation with tumor size.

Elevated interstitial fluid pressure (IFP) is associated with poor blood supply and inadequate delivery of drugs to solid tumors. IFP was measured in squamous cell carcinomas of the head and neck region in humans using the wick-in-needle technique. In all lesions (n = 19), the IFP was elevated (4-33 mm Hg). Furthermore, the IFP increased with tumor size. The highest IFP was 33 mm Hg in a 24-ml tumor. In one tumor, the IFP was found to be negative (-2.6 mm Hg), which is comparable to that in human skin or subcutaneous tissue. The histopathology of this tumor was benign. If this pressure difference between malignant and benign lesions can be confirmed in a large number of tumors, then the IFP could be used to aid tumor detection during needle biopsy. The value of IFP as a predictor of response to radiotherapy, photodynamic therapy, hyperthermia, and chemotherapy should be assessed prospectively.

Effect of photodynamic treatment of human endothelial cells on cell volume and cell viability.

Photodynamic therapy (PDT) has yielded promising results in the treatment of malignant tumors. However, the mechanisms leading to tumor destruction during PDT are still not completely understood. In addition to effects on the microcirculation, damage to cellular structures has been observed following exposure of cells to PDT. A phenomenon preceding these events might possibly be cell swelling. We therefore studied the influence of treatment with Photofrin(R) (PF) and laser light on volume changes and cell viability of endothelial cells. Endothelial cells were obtained from human umbilical cord veins (HUVEC) by an adaption of the method of Maruyama. After subcultivation the cells were harvested and transferred as a cell suspension into a specially designed incubation chamber. Cells received either PF in concentrations of 1.5 or 3.0 mu g/ml and laser illumination 60 min post incubation (630 nm; 40 mW/cm(2), 4 Joule), PF alone, or laser treatment only. Following start of PF incubation and after phototreatment cell samples were taken for volume measurements using flow cytometry, and for studies of cellular morphology using scanning electron microscopy. Simultaneously, cell viability was monitored by the trypan blue exclusion test and the colorimetric MTT assay. Both control groups, HUVEC receiving PF or laser treatment alone, revealed constant cell volumes and cell viability during the entire course of the experiment. After PDT (60 min post-incubation) with 1.5 and 3.0 mu g PF/ml cell volume of HUVEC was increased at 15 min to 122%+/-6% and 140%+/-10% of baseline (100%), at 60 min to 152%+/-9% and 134%+/-18%, respectively (p<0.01). The number of viable cells was significantly reduced of samples treated with 1.5 and 3.0 mu g PF/ml at 15 min after PDT to 81%+/-3% and 76%+/-10% of baseline (100%), at 60 min after PDT to 32%+/-14% and 20%+/-15%, respectively (p<0.01). Scanning electron microscopy of cells exposed to PDT following 60 min incubation with Photofrin (3.0 mu g/ml) revealed significant cell damage. At the highest PF concentration HUVEC showed loss of microvilli and formation of blebs on the cellular surface. Our study demonstrates that PDT induces a significant increase in endothelial cell volume and a loss of cell viability. We suggest that swelling and damage of endothelial cells following PDT is a primary event finally contributing to cessation of blood flow and subsequent necrosis of tumors.

Fluorescence imaging and spectroscopy of 5-aminolevulinic acid induced protoporphyrin IX for the detection of neoplastic lesions in the oral cavity.

BACKGROUND: Semiquantitative fluorescence measurements following topical application of 5-aminolevulinic acid (5-ALA) in 16 patients with neoplastic lesions of the oral cavity were performed. METHODS: Time course and type of porphyrin accumulation were analyzed in neoplastic and surrounding healthy tissue by measuring emission spectra of 5-ALA-induced protoporphyrin IX fluorescence. Fluorescence images in the red and green spectral range from the tumor tissue were recorded with a charge-coupled device camera. RESULTS: Protoporphyrin IX fluorescence was detected in the oral mucosa of all patients after local application of 5-ALA. Protoporphyrin IX in neoplastic tissue accumulated earlier in comparison with the surrounding normal tissue. The maximum fluorescence contrast of 10:1 between tumor and host tissue was generally seen 1-2 hours after application, allowing a demarcation of tumor tissue even with the naked eye. CONCLUSION: Labeling of mucosal lesions of the oral cavity with Protoporphyrin IX fluorescence induced by the local application of 5-ALA seems to be a promising diagnostic procedure for neoplastic lesions that are difficult to visualize under white light examination. It is the aim of further investigations to evaluate the relevance of this new diagnostic procedure as a noninvasive and sensitive method for patients with oral cancer.

Photodynamic treatment for cancers of the head and neck.

A clinical study using photodynamic therapy (PDT) for the treatment of head and neck cancer was conducted between 1988 and 1994. 83 patients with Tis-2 tumors of the face, oropharynx and larynx were included into the study protocol. The study was designed in accordance with the GCP-guidelines as a prospective controlled protocol. At 48 h after an intravenous injection of 2 mg kgbw-1 Photosan-3 the laser illumination (630 nm) of the tumor and tumor-surrounding tissue was performed at 100 mW cm-2 and 100 J cm-2. A control biopsy from the former tumor area was taken 2 months after PDT to evaluate the histological response of the treated tumors. 51 out of 57 patients with basal cell carcinoma, 6 out of 7 patients with squamaous cell carcinoma of the skin, 6 out of 7 patients with oropharynx carcinoma and 11 out of 12 patients with larynx carcinoma showed a complete histologically confirmed response to the tumor following a single course of PDT over a follow up time of 13-71 months.

Photodynamic therapy in head and neck surgery.

The results of a clinical study of photodynamic therapy (PDT) on early stage cancer in head and neck surgery are presented in this report. 30 patients with T1 malignancies of the face and oropharynx have been treated primarily with PDT. After the longest follow up of 14 months two patients revealed recurrence of the disease or residual tumor, two patients have been retreated because of residual dysplastic cells in the control biopsy, and all other patients stay histologically proven free of disease. Hence, PDT appears to be a promising cancer treatment for different histological tumors that penetrate the host tissue definitely less than a laser beam of 630 nm, which is the appropriate wavelength for PDT. Deeper-penetrating malignomas may be accessable for PDT using insertable filters when applying interstitial laser light.

Use of the Draw-A-Person with conduct-disordered children.

The Draw-A-Person test was administered to 40 conduct-disordered and 40 nonconduct-disordered children and adolescents. There were 20 boys and 20 girls, ages 10 to 16 years, in each group. Two independent judges rated the drawings for presence or absence of indicators of aggressiveness that should accompany a conduct disorder, but no significant differences were found between groups or sexes.

[Photodynamic therapy with derivatives from hemotoporphyrines for recurrent laryngeal papillomatosis of the children. Early results]. / Terapia fotodinámica con derivados hematoporfirínicos en la papilomatosis laringeal infantil recidivante. Primeros resultados.

The big problem, unsolved till now, of the juvenile laryngeal Papillomatosis, is the high rate of recurrences compelling the affected to periodical surgery in order to remove the papillomatous masses that obstruct the airway. In this paper the AA. report 3 cases with infantile laryngeal papillomatosis treated with photodynamic therapy employing haematoporphyrinic derivatives inside cylindrical applicators introduced in the larynx through direct laryngoscopy. One month after the radiation the papillomata were completely gone and the mucous membrane looked normal and without any scar. In none of the cases could be seen synechiae. Two years follow-up with one recurrence detected after 15 months of a laser sitting.

[Photodynamic therapy with hematoporphyrin derivatives in cervico-facial basaliomas and epidermoid carcinoma in stage I and II]. / Terapia fotodinámica con derivados hematoporfirínicos en los estadios I y II de basaliomas y carcinomas epidermoides de localización cervicofacial.

Cancer of the cervico-facial region often requires destructive procedures followed by complicated reconstructive surgical techniques. We have studied 77 patients with T1 and T2 head and neck cancers, who get photodynamic therapy using hematoporphyrin derivates. Biopsies taken two months after therapy revealed histologic complete responses in 95% of the cases. Additionally the cosmetic results of the photodynamic therapy were superior to conventional surgery.

[Treatment of laryngeal papillomatosis with photodynamic laser therapy]. / Die Behandlung der Larynxpapillomatose mit Hilfe der photodynamischen Lasertherapie.

Laryngeal papillomas represent a disease of the head and neck that can be treated only symptomatically by surgical means. Twelve Patients (six adults and six children) with recurrent laryngeal papillomas were admitted to a pilot study for photodynamic laser treatment (Fig. 2). Forty-eight hours after intravenous application of hematoporphyrin derivative, PDT was performed by means of a specially developed laser light applicator (Fig. 1) under general anaesthesia. The laser light was generated by an argon-pumped dye laser system operating at a wavelength of 630 nm. On endoscopic evaluation the papilloma showed a whitish livid colour 24 hours after PDT. During the following 3-5 days the papilloma tissue was sloughed and the true and false vocal cords were covered by fibrin. Some 3-4 weeks after PDT the endolaryngeal mucosa had reepithelized in all patients with no signs of residual disease (Fig. 3). Despite the initial multifocal nature of the papilloma, even beyond the anterior commissure, no synechia developed.

[Photodynamic laser therapy in the field of otorhinolaryngology]. / Die photodynamische Lasertherapie im Bereich der Hals-, Nasen-, Ohrenheilkunde.

A clinical study was conducted on the application of photodynamic therapy on tumours in the head and neck region to assess the value of this new modality for superficial cancer (Tis-T2). Patients with recurrent laryngeal papillomatosis were included in a photodynamic treatment pilot study. 2 mg/kg body weight of haematoporphyrin-derivative (Photosan-3) was administered 48 hours prior to laser irradiation intravenously. The patients rooms were advised to avoid daylight for two to three weeks. Tumours of the facial skin were irradiated homogeneously by means of an optical bench. Directly after laser application we observed an extensive extravasation of the tumour tissue, whereas the surrounding normal tissue showed mild erythema. A dry crust formed subsequently, which disappeared within two weeks associated with re-epithelisation. Mucous membrane tumours showed fibrin layers in the tumour area 24 hours after laser application with selective tumour necrosis. These lesions also epithelised completely within three weeks. Scarring never occurred. Laryngeal tumours as well as laryngeal papillomas were treated by a cylindrical light applicator system and the patients admitted to intensive care unit for 24 hours after laryngoscopy because of risk of laryngeal oedema. 94 patients with tumours of the head and neck with different histological origins were treated photodynamically, as well as 21 patients with laryngeal papillomatosis. Two months after photodynamic laser treatment, controlled biopsies of the former tumour area were performed. 5 patients had a relapse during a maximum follow-up of 4.5 years. This signified a histologically confirmed full response rate of 95%, accompanied by good plastic and functional results.(ABSTRACT TRUNCATED AT 250 WORDS)

Endoscopically-controlled electrohydraulic intracorporeal shock wave lithotripsy (EISL) of salivary stones.

Twenty-nine patients with salivary stones were treated with the endoscopically-controlled electrohydraulic shock wave lithotripsy (EISL). This new minimally invasive treatment of sialolithiasis is performed under local anesthesia on an outpatient basis with little inconvenience to the patient. For endoscopy, a flexible fibroscope with an additional probe to generate shock waves is placed into the submandibular duct and advanced until the stone is identified. For shock wave-induced stone disintegration, the probe electrode must be placed 1 mm in front of the concrement. The shock waves are generated by a sparkover at the tip of the probe. By means of the endoscopically-controlled shock wave lithotripsy it was possible to achieve complete stone fragmentation in 20 out of 29 patients without serious side effects. In three patients, only partial stone fragmentation could be achieved due to the stone quality. Endoscopically-controlled electrohydraulic intracorporeal shock wave lithotripsy represents a novel minimally invasive therapy for endoscopically accessible salivary gland stones. The advantage in comparison to the endoscopically-controlled laser lithotripsy will be discussed.

[Importance of increased interstitial fluid pressure in therapy of malignant tumors of the head-neck area]. / Die Bedeutung des erhöhten interstitiellen Flüssigkeitsdrucks bei der Therapie von Malignomen der Kopf-Hals-Region.

Animal experiments showed that elevated interstitial fluid pressure (IFP) is associated with poor blood supply and inadequate supply of drugs to solid tumours. IFP is approximately 0 mmHg in most normal tissues. Up to now there have been only few studies showing elevated interstitial pressure in human tumours in situ: Mammary carcinomas, cervical carcinomas and colorectal cancers have an elevated IFP. We measured IFP in squamous cell carcinomas of the head and neck region in humans using the "wick-in-needle" technique. In all lesions (n = 25), the IFP was elevated (4-39 mmHg). The IFP increased with tumour size. The highest IFP was 39 mmHg in a 26 ml tumour. These results show that squamous cell carcinomas of the head and neck region in humans have an elevated interstitial fluid pressure. The elevation of IFP associated with inadequate delivery of drugs to the interstitium of malign tumours may reduce the response to therapy.

[Clinical and electron microscopy study of sudden deafness treatment with the 10% HES 200/0.5 and pentoxifylline combination]. / Klinische und elektronenmikroskopische Untersuchung zur Hörsturztherapie mit der Kombination 10% HES 200/0.5 und Pentoxifyllin.

The incidence of sudden hearing loss has increased. The pathogenetic mechanisms are still unknown, but viral infections and vascular phenomena with acute impairment of microvascular perfusion are thought to play a major role. Infusion of hydroxyethyl starch (HES) is used as a regimen to treat sudden hearing loss. In our clinic, anaphylactic reactions due to HES have not been observed so far. However, the use of HES is still discussed controversially due to long-term storage of HES molecules in tissue and due to high incidence of long-lasting pruritus. In a retrospective analysis of 118 patients treated with HES for sudden hearing loss, we observed pruritus starting in 64% of patients one to three weeks after therapy. This symptom with a duration between two weeks and four months was refractory to medical interventions. During therapy with HES improvement of hearing was observed in 75% of patients, in 62% improvement of hearing persisted still at the end of the observation period (7 months post infusionem). Light and electron microscopic assessment of human skin biopsies of one patient after treatment with HES showed storage of HES especially within dermal macrophages. Pathogenetically a pathway independent of histamin seems responsible for the induction of pruritus. Accordingly, classic antihistaminic drugs had no therapeutic effect in our patients. Dextran is used as an alternative to hydroxyethyl starch. In contrast to HES, the often mentioned higher incidence of severe anaphylactic reactions due to dextran has dramatically decreased with hapten inhibition (after preinjection of monovalent haptendextran Promit).(ABSTRACT TRUNCATED AT 250 WORDS)

[Photodynamic diagnosis of neoplasms of the mouth cavity after local administration of 5-aminolevulinic acid]. / Photodynamische Diagnostik von Neoplasien der Mundhöhle nach lokaler Applikation von 5-Aminolävulinsäure.

BACKGROUND: The aim of photodynamic diagnosis (PDD) is the complete visualization of all neoplastic lesions in a tumorous organ after topical or systemic application of a tumor selective photosensitizer. In this investigation we performed semiquantitative fluorescence measurements following topical application of 5-aminolevulinic acid (5-ALA) in 11 patients with neoplastic lesions of the oral cavity. METHODS: Time course and type of porphyrin accumulation were analyzed in neoplastic and surrounding normal tissue by measuring emission spectra of 5-ALA-induced protoporphyrin IX (PpIX) fluorescence at regular intervals for up to three hours following 15 min continuous rinsing of a 0.4% 5-ALA solution. After excitation with violet light of a high pressure xenon arc lamp (375-440 nm), fluorescence images in the red spectral range from the tumor tissue and the corresponding macroscopic visible tumor were recorded with a CCD camera. A quantitative analysis of the fluorescence contrast in neoplastic and surrounding tissue was performed using an optical multichannel analyzer. RESULTS: PpIX fluorescence was detected in the oral mucosa of all patients after local application of 5-ALA. PpIX in neoplastic tissue accumulated earlier in comparison to the surrounding normal tissue. The fluorescence contrast between tumor and host tissue was 10:1 and the maximum fluorescence was measured 1-2 hours following 5-ALA application. CONCLUSION: Labeling of mucosal lesions of the oral cavity with PpIX fluorescence induced by the local application of 5-ALA seems to be a promising diagnostic procedure for neoplastic lesions. Further investigations are required to assess the value of this new diagnostic procedure as a non-invasive and sensitive method for patients with head and neck cancer not only in pre- and postoperative diagnostic studies but also for a fluorescence-guided resection of tumors.

[Initial results with MRI-controlled laser-induced interstitial thermotherapy of head and neck tumors]. / Erste Ergebnisse der MRT-gesteuerten laserinduzierten interstitiellen Thermotherapie von Kopf- und Halstumoren.

Laser-induced interstitial thermo-therapy (LITT) was introduced as a minimally invasive form of therapy for tumors in different anatomic regions. However, in the orofacial region, it has not been used so far for inoperable T4 carcinomas. Since vascular and neural structures are often close to the tumor or are even involved, online monitoring of LITT is necessary. The aim of our study was to establish a method of monitoring LITT with MRI (magnetic resonance imaging) in the orofacial region. Five patients with T4 carcinomas of the orofacial region underwent LITT under anesthesia. A 1.5 T whole-body imager with a circular polarized head coil was used. Before and after the intervention, the region of interest was studied using T1- and T2-weighted sequences in axial and coronal planes, with and without contrast enhancement (intravenous Gd-DTPA). Temperature distribution was monitored with a T1-weighted 2D-FLASH (fast low angle shot) sequence. The positioning of the optical fibers was monitored with MRI. Nd:YAG laser equipment was used for laser application. The necrosis was best seen on contrast-enhanced MRI. Immediately after LITT, the outcome could be determined by MRI. We proposed that MRI-guided LITT be used for neoplasms in the orofacial region at advanced stages.

[Endoscopic controlled laser lithotripsy in the treatment of sialolithiasis]. / Die endoskopisch kontrollierte Laserlithotripsie zur Behandlung der Sialolithiasis.

The article describes the first successful application of endoscopically controlled laserlithotripsy in the ENT field in a patient with recurrent purulent sialadenitis of the left submandibular gland due to sialolithiasis. By means of endoscopically controlled laserinduced lithotripsy of salivary gland stones, it was possible to achieve complete stone fragmentation without harming the glandular duct and the gland.

[Time resolved laser fluorescence microscopy of hematoporphyrin derivative in vivo]. / Zeitaufgelöste Laserfluoreszenzmikroskopie von Hämatoporphyrin-Derivat in vivo.

Laser-assisted fluorescence microscopy proved a powerful method for quantitative in vivo measurement of HpD fluorescence. Therefore the aim of the present work was to study the distribution of HpD in tumor vs. adjacent tumor-free tissue of 10 animals over a period of 8 days. We measured additionally the differences in HpD uptake in different tumor subcompartments. In tumor tissue HpD fluorescence showed maximum values 5-9 hours after i.v. application of the drug. The relation tumor-free tissue at that time was about 3-8. The third day of examination showed nearly identical values for both tissues. Between day 5 and day 8 we found an increase of HpD contents in tumor vs. normal tissue in 50% of the examined animals. Comparative measurements in the tumor centre and the tumor edge showed a preferential uptake of HpD in the tumor edge area. Probably the higher retention of HpD in this area is due to the oedema zone surrounding the tumor and to extravasation of HpD.

[Microcirculatory effects of photodynamic therapy with hematoporphyrin derivative]. / Mikrozirkulatorische Effekte der photodynamischen Therapie mit Hämatoporphyrin-Derivat.

Hematoporphyrin derivative photosensitizes selectively malignant tumors following intravenous administration and shows typical fluorescence patterns in the range between 630 nm and 690 nm. Irradiation with laser light (630 nm) causes selective tumor necrosis due to a phototoxic effect. The site of action of this "photodynamic treatment (PDT)" remains obscure. In this study it could be demonstrated that directly after PDT a selective haemorrhage and thrombosis of blood vessels occurs in the tumor tissue. Furthermore, the arterioles of the surrounding normal tissue constrict completely. Venules of normal tissue showed slow thrombosis. Basically, the result of photodynamic treatment was a complete breakdown of tumor tissue microcirculation accompanied by partial damage to the surrounding normal tissue perfusion. This evaluation of the impact of PDT on tumor microcirculation led to the conclusion that a primary site of action of photodynamic therapy may contribute to the selective destruction of tumor microcirculation.

[Damage to tumor cells by photodynamic therapy]. / Die Schädigung von Tumorzellen durch die photodynamische Therapie.

Photodynamic therapy (PDT) is a new, promising method in the treatment of cancer. To gain insights into PDT-mediated tumour destruction we studied the influence of treatment with Photofrin and laser light on changes in cell volume and cell viability. A-Mel-3 tumour cells were subjected to Photofrin or illumination with laser light, or a combination of both (PDT). Cell volume was measured by flow cytometry and cell viability by the trypan blue exclusion test for up to 60 min after PDT and the respective controls. In addition, scanning and transmission electron microscopy were performed. Tumour cells incubated in concentrations of 0.75, 1.5 and 3.0 micrograms Photofrin/ml revealed a rapid increase in cell volume to 117%, 207% and 235% 30 min after PDT and to 147%, 210% and 199% 60 min after PDT. Cell viability with 1.5 and 3.0 micrograms Photofrin/ml and laser light was reduced to 83% and 44% at 30 min after PDT and to 38% and 17% 60 min after PDT. At Photofrin concentrations of 1.5 micrograms/ml and exposure to laser light scanning electron microscopy revealed extreme loss of microvilli and formation of blebs on the cellular surface. Transmission electron microscopy showed swollen mitochondria and ruptures of the cell membrane. This study demonstrates that PDT induces a significant time-dependent and dose-related increase in tumour cell volume. We suggest that the PDT-induced swelling of tumour cells contributes to the increase of interstitial fluid pressure and to impairment of microvascular perfusion of tumours.