Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma.

UNLABELLED: Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although IV rituximab mediates superior disease control of systemic non-Hodgkin lymphoma (NHL), it fails to completely eliminate the risk of meningeal recurrence, likely due to minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy, we conducted the first phase 1 study of intraventricular immunochemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg or 25 mg intraventricular rituximab twice weekly for 4 weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. More than 150 doses were administered without serious toxicity. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall complete response in CSF and/or brain parenchyma. Two patients achieved a first complete response of CNS NHL with intraventricular rituximab/MTX, including 1 with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab. We conclude that intraventricular rituximab in combination with MTX is feasible and highly active in the treatment of drug-resistant CNS NHL that is refractory or unresponsive to IV rituximab. KEY POINTS: Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.

Walter Eichler and his role in the development of electroneurography.

Walter Eichler (1904-1942) performed the first in situ nerve conduction studies in humans. Eichler's work has been largely overlooked and there have been no biographical accounts written of him. His 1937 paper, Über die Ableitung der Aktionspotentiale vom menschlichen Nerven in situ (On the recording of the action potentials from human nerves in situ) was translated and reviewed. Archival material was obtained on his career that was housed predominantly at the University of Freiburg im Breisgau. He had memberships in Nazi organizations but did not appear to be politically active. During his brief career, he constructed novel equipment and established seminal principles for performing nerve conductions on humans. The authors repeated his experiment in the ulnar nerve, which duplicated Eichler's findings. His recordings were quite remarkable given advances in technology. In summary, the Eichler paper is the first study in the development of in situ clinical electroneurography in humans. Many of his procedural observations are still fundamental in the current practice of electroneurography. As best can be determined, his study in humans did not appear ethically compromised. Although Eichler's personal background remains open to question, his paper is a seminal study in the history and development of clinical electroneurography.Abbreviations: AP: Action potential; C: Capacitor; CNP: Compound nerve potential; DC: Direct current; E1: Preferred term for active electrode; E2: Preferred term for reference electrode; NSDÄB: Nationalsozialistische Deutsche NSD-Ärtzebund (National Socialist German Doctors' League; NSDAP: Nationalsozialistische Deutsche Arbeiterpartei (National Socialist German Workers' Party/ Nazi Party); SS: Schutzstaffel (Protective Echelon or Squad of the Nazi party).

American influence on the origins of neurosurgery in the Netherlands.

Although the Netherlands played a major role in the revival of craniotomy in the late 19th century, modern neurosurgery made a late start there. Unlike the situation in other European countries, Dutch neurosurgery lacked a protagonist when, at the turn of the last century, craniotomy became less popular due to discouraging results. During two lecture tours in the US in the 1920s and 1930s, the influential Dutch neurologist Bernard Brouwer also visited the leading neurosurgical centers. He was deeply impressed by the high standards and results in the New World, and upon his return to Amsterdam, he decided to try to change the dismal state of Dutch neurosurgery. Funds were raised to send the general surgeon Ignaz Oljenick for training to Harvey Cushing, and close ties between Amsterdam and neuroscientists in the US remained. Several American neurosurgeons received part of their basic training in Amsterdam. A second Dutch surgeon, Ferdinand Verbeek, honed his neurosurgical skills under Dr. Walter Dandy. The strong American influence on the philosophy and everyday actions of Dutch neurosurgeons continues until this day.

Dexamethasone normalizes brain tumor hemodynamics as indicated by dynamic susceptibility contrast MRI perfusion parameters.

The purpose of this study is to demonstrate the utility of dynamic susceptibility contrast (DSC) MRI-derived perfusion parameters to characterize the hemodynamic effects of dexamethasone in a 9L gliosarcoma tumor model. Twenty-four rats underwent intracerebral inoculation with 9L tumor cells. Fifteen were treated with a total of 3mg/kg of dexamethasone on days 10-14 post-inoculation, while the remaining 9 rats served as controls. Fourteen days post-inoculation, MRI images, sensitive to total and micro-vascular cerebral blood flow (CBF), mean transit time (MTT), and intravoxel transit time distributions (TTD)s were obtained using a simultaneous gradient-echo(GE)/spin-echo(SE) DSC-MRI method. Dexamethasone-treated animals had a microvascular (SE) tumor CBF that was 45.9% higher (p = 0.0008) and a MTT that was 47.8% lower (p = 0.0005) than untreated animals. With treatment, there was a non-significant 91.3% increase in total (GE) vascular CBF (p = 0.35), and a significant decrease in MTT (49.1%, p = 0.02). The total vascular and microvascular TTDs from the treated tumors were similar to normal brain, unlike the TTDs in the untreated tumors. These findings demonstrate that DSC-MRI perfusion methods can be used to non-invasively detect the morphological and functional changes in tumor vasculature that occur in response to dexamethasone treatment.

FNAB cytology of extra-cranial metastasis of glioblastoma multiforme may resemble a lung primary: a diagnostic pitfall.

BACKGROUND: As extra-cranial metastasis of glioblastoma multiforme (GBM) is rare, it may create a diagnostic dilemma especially during interpretation of fine needle aspiration biopsy (FNAB) cytology. CASE PRESENTATION: We present transbronchial FNAB findings in a 62-year-old smoker with lung mass clinically suspicious for a lung primary. The smears of transbronchial FNAB showed groups of cells with ill-defined cell margins and cytological features overlapping with poorly differentiated non-small cell carcinoma. The tumor cells demonstrated lack of immunoreactivity for cytokeratin, thyroid transcription factor-1, and usual neuroendocrine markers, synaptophysin and chromogranin in formalin-fixed cellblock sections. However, they were immunoreactive for the other neuroendocrine immunomarker, CD56, suggesting neural nature of the cells. Further scrutiny of clinical details revealed a history of GBM, 13 months status-post surgical excision with radiation therapy and systemic chemotherapy. The tumor recurred 7 months earlier and was debulked surgically and with intra-cranial chemotherapy. Additional evaluation of tumor cells for glial fibrillary acidic protein (GFAP) immunoreactivity with clinical details resulted in final interpretation of metastatic GBM. CONCLUSION: Lack of clinical history and immunophenotyping may lead to a diagnostic pitfall with possible misinterpretation of metastatic GBM as poorly differentiated non-small cell carcinoma of lung in a smoker.

Antiangiogenic effects of dexamethasone in 9L gliosarcoma assessed by MRI cerebral blood volume maps.

Depending on dose, dexamethasone has been shown to inhibit or stimulate growth of rat 9L gliosarcoma and decrease the expression of vascular endothelial growth factor (VEGF), an important mediator of tumor-associated angiogenesis. We demonstrate, by constructing relative cerebral blood volume (rCBV) maps with MRI, that dexamethasone also decreases total blood volume while increasing microvascular blood volume in Fischer rats bearing intracranial 9L gliosarcoma. Animals were inoculated with 1 x 10(5) 9L gliosarcoma tumor cells. On days 10-14 after tumor cell inoculation, animals were intra-peritoneally injected with dexamethasone (3 mg/kg) over 5 days. MRI-derived gradient echo (GE) and spin-echo (SE) rCBV maps were created to demonstrate total vasculature (GE) and microvasculature (SE). After MRI studies were performed, the rat's vasculature was perfused with a latex compound. Total vessel volume and diameters were assessed by microscopy. Dexamethasone decreased the tumor-enhancing area of postcontrast T1-weighted images (P < 0.0001) and total tumor volume(P = 0.0085). In addition, there was a greater than 50% decrease in GE rCBV (total vasculature) (P = 0.007) as well as a significant decrease in total fractional blood volume, as validated by histology (P = 0.0007). Conversely, there was an increase in SE rCBV signal (microvasculature) in animals treated with dexamethasone (P = 0.05), which was consistent with microscopy (P < 0.0001). These data demonstrate that (1) dexamethasone selectively treats tumor vasculature, suggesting a vessel-size selective effect and (2) MRI-derived rCBV is a noninvasive technique that can be used to evaluate changes in blood volume and vascular morphology.

Post-radiation dedifferentiation of meningioma into osteosarcoma.

BACKGROUND: A number of osteoblastic meningiomas, primary osteosarcomas of the meninges, and post-radiation osteosarcomas of the head have been reported. However, postradiation dedifferentiation of meningioma into osteosarcoma has not been reported previously. CASE PRESENTATION: In 1987 a caucasian man, then 38 years old, presented with a pituitary macroadenoma. He underwent a subtotal resection of the tumor and did well until 1990 when a recurrent tumor was diagnosed. This was treated with subtotal resection of the tumor, followed by radiation therapy for six weeks to a total of 54 Gy. He was considered "disease-free" for nearly ten years. However, most recently in July 2000, he presented with a visual field deficit due to a second recurrence of his pituitary macroadenoma, now with suprasellar extension. At this time, as an incidental finding, a mass attached to the dura was noted in the left parietal hemisphere. This dura-based mass had grown rapidly by January 2001 and was excised. It showed histological, immunohistochemical, and electron microscopic features of malignant meningioma and osteosarcoma with a sharp demarcation between the two components. CONCLUSIONS: We report a rare case of a radiation induced dedifferentiation of meningioma into osteosarcoma, which has not been reported previously.

Pseudo-reorganization of language cortical function at fMR imaging: a consequence of tumor-induced neurovascular uncoupling.

A left-handed patient with a grade II left frontal lobe astrocytoma had spontaneous seizures causing speech arrest and uncontrolled right upper extremity movements. Word-generation functional MR (fMR) imaging showed activity nearly exclusively in the right inferior frontal gyrus. The clinical history of the speech arrest and the intraoperative mapping proved left-hemisphere language dominance. Tumor involvement of the left inferior frontal gyrus caused uncoupling of the blood oxygenation level-dependent (BOLD) and neuronal response, leading to the erroneous fMR imaging appearance of right-hemisphere language dominance. Discrepancies between BOLD and intraoperative mapping in areas near lesions illustrate the complementary nature of these techniques.

Characterization of a first-pass gradient-echo spin-echo method to predict brain tumor grade and angiogenesis.

BACKGROUND AND PURPOSE: No widespread clinical method provides specific information about the angiogenic characteristics of gliomas. We characterized blood volume and vascular morphologic parameters from combined gradient-echo (GE) and spin-echo (SE) MR imaging and assessed their relationship to tumor grade, a known correlate of glioma angiogenesis. METHODS: Simultaneous GE and SE echo-planar imaging was performed with bolus gadolinium administration (0.20-0.25 mmol/kg) in 73 patients with glioma. To diminish possible T1 changes due to contrast agent extravasation, a preload (0.05-0.10 mmol/kg) was administered before the study, and a postprocessing correction algorithm was applied. Image maps of total (GE) and microvascular (SE) relative cerebral blood volume (rCBV) and the mean vessel diameter (mVD) calculated from the ratio of GE and SE relaxation rate changes (DeltaR2*/DeltaR2) were compared with tumor grade. A nonparametric K nearest-neighbor decision rule was applied to determine if the combined data could be used to distinguish low-grade (I-II) from high-grade (III-IV) tumors on a per-patient basis. RESULTS: For whole tumors, significant correlations were found between GE rCBV and grade (P < .0001) and between mVD and grade (P = .0001) but not between SE rCBV and grade (P = .08). For areas of highest SE rCBV (microvascular hotspots), SE rCBV and tumor grade were significantly correlated (P = .0007). In terms of differentiation, 69% of low-grade tumors and 96% of high-grade tumors were correctly classified. CONCLUSION: Combined GE and SE MR imaging provides information consistent with neoplastic angiogenesis, demonstrating its potential to aid in optimizing treatments, categorizing lesions, and influencing patient care.

The role of diffusion tensor imaging in establishing the proximity of tumor borders to functional brain systems: implications for preoperative risk assessments and postoperative outcomes.

Diffusion Tensor Imaging (DTI) is a new MRI imaging technique sensitive to directional movements of water molecules, induced by tissue barriers. This provides a new form of contrast that allows the identification of functional white matter tracts within the brain, and has been proposed as a technique suitable for presurgical planning in brain tumor patients. Resection of primary brain tumors improves survival, functional performance, and the effectiveness of adjuvant therapies, provided that surgically-induced neurological deficits can be avoided. Diffusion Tensor Imaging (DTI) has the potential to establish spatial relationships between eloquent white matter and tumor borders, provide information essential to preoperative planning, and improve the accuracy of surgical risk assessments preoperatively. We present our experience in a series of 28 brain tumor patients where the integration of functional magnetic resonance imaging (fMRI) and DTI data was used to determine key anatomic spatial relationships preoperatively. Twice as many functional systems were localized to within 5 mm of tumor borders when DTI and fMRI were utilized for preoperative planning, compared to that afforded by fMRI alone. Our results show that the combined use of fMRI and DTI can provide a better estimation of the proximity of tumor borders to eloquent brain systems sub-serving language, speech, vision, motor and premotor functions. Additionally, a low regional complication rate (4%) observed in our series suggests that preoperative planning with these combined techniques may improve surgical outcomes compared to that previously reported in the literature. Larger studies specifically designed to establish the accuracy and predictive value of DTI in brain tumor patients are warranted to substantiate our preliminary observations.

Lesion-induced pseudo-dominance at functional magnetic resonance imaging: implications for preoperative assessments.

OBJECTIVE: To illustrate how lesion-induced neurovascular uncoupling at functional magnetic resonance imaging (fMRI) can mimic hemispheric dominance opposite the side of a lesion preoperatively. METHODS: We retrospectively reviewed preoperative fMRI mapping data from 50 patients with focal brain abnormalities to establish patterns of hemispheric dominance of language, speech, visual, or motor system functions. Abnormalities included gliomas (31 patients), arteriovenous malformations (AVMs) (11 patients), other congenital lesions (4 patients), encephalomalacia (3 patients), and tumefactive encephalitis (1 patient). A laterality ratio of fMRI hemispheric dominance was compared with actual hemispheric dominance as verified by electrocortical stimulation, Wada testing, postoperative and posttreatment deficits, and/or lesion-induced deficits. fMRI activation maps were generated with cross-correlation (P < 0.001) or t test (P < 0.001) analysis. RESULTS: In 50 patients, a total of 85 functional areas were within 5 mm of the edge of a potentially resectable lesion. In 23 of these areas (27%), reduced fMRI signal in perilesional eloquent cortex in conjunction with preserved or increased signal in homologous contralateral brain areas revealed functional dominance opposite the side of the lesion. This suggested possible lesion-induced transhemispheric cortical reorganization to homologous brain regions (homotopic reorganization). In seven patients, however, the fMRI data were inconsistent with other methods of functional localization. In two patients with left inferior frontal gyrus gliomas and in one patient with focal tumefactive meningoencephalitis, fMRI incorrectly suggested strong right hemispheric speech dominance. In two patients with lateral precentral gyrus region gliomas and one patient with a left central sulcus AVM, the fMRI pattern incorrectly suggested primary corticobulbar motor dominance contralateral to the side of the lesion. In a patient with a right superior frontal gyrus AVM, fMRI revealed pronounced left dominant supplementary motor area activity in response to a bilateral complex motor task, but right superior frontal gyrus perilesional hemorrhage and edema subsequently caused left upper-extremity plegia. Pathophysiological factors that might have caused neurovascular uncoupling and facilitated pseudo-dominance at fMRI in these patients included direct tumor infiltration, neovascularity, cerebrovascular inflammation, and AVM-induced hemodynamic effects. Sixteen patients had proven (1 patient), probable (2 patients), or possible (13 patients) but unproven lesion-induced homotopic cortical reorganization. CONCLUSION: Lesion-induced neurovascular uncoupling causing reduced fMRI signal in perilesional eloquent cortex, in conjunction with normal or increased activity in homologous brain regions, may simulate hemispheric dominance and lesion-induced homotopic cortical reorganization.

Neurologic complications of bone marrow transplantation.

The various forms of HSCT are or will soon be accepted treatments for an ever-increasing number of hematologic and solid cancers. Attempts to reduce the mortality and morbidity of HSCT and at the same time preserve or increase its efficacy in tumor control include development of nonmyeloablative allogeneic stem-cell transplant strategies [208] and allogeneic laboratory research-enhancing graft acceptance [209,210]. Eventually, these efforts will reduce complication rates of HSCT, including neurologic complications. In the interim, the consultant neuro-oncologist or neurologist with a specific inteest in this field is faced with complex clinical syndromes, neuroradiologic imaging studies and neurophysiologic tests, and generally poorly understood pathophysiologic mechanisms. Prospective studies of HSCT patients in large transplantation centers using clinical registries are needed.

A cost-minimizing diagnostic methodology for discrimination between neoplastic and non-neoplastic brain lesions: utilizing a genetic algorithm.

RATIONAL AND OBJECTIVES: The purpose of this study was to make an improvement in the performance of a logistic regression model in predicting the presence of brain neoplasia with magnetic resonance spectroscopy data by using a new approach for logistic regression coefficient estimation. This new approach, termed cost minimizing (C-min), introduced by one of the authors (Chetty), uses the cost function for prediction outcomes to estimate model coefficients and the prediction decision rule. To do this requires use of a genetic algorithm. MATERIALS AND METHODS: Consecutive patients with suspected brain neoplasms or recurrent neoplasia referred for magnetic resonance spectroscopy were enrolled once a final diagnosis was established by histopathology or clinical course, laboratory data, and serial imaging. For the same magnetic resonance spectroscopy explanatory (input) variables, logistic regression models were constructed with conventional and C-min coefficient estimates, and sensitivity and specificity outcomes were compared at alternative probability threshold levels. RESULTS: The C-min approach dominated the conventional approach in 14 of 18 trials, in that C-min had either fewer of both false negatives and false positives, or it had the same number of one type, and less of the other type of diagnostic error. C-min was always less costly. CONCLUSION: The C-min approach to logistic or other regression model estimation may be a step forward in reducing the cost and, often, the errors of diagnostic (and treatment) processes. However, this new approach must be validated on larger and more varied datasets, and its statistical performance characteristics determined before it can be implemented as a practical clinical tool.

Semicontinuous low-dose-rate teletherapy for the treatment of recurrent glial brain tumors: final report of a phase I/II study.

PURPOSE: Semicontinuous low-dose-rate teletherapy (SLDR) is a novel irradiation strategy that exploits the increased radiosensitivity of glial cells in a narrow range of reduced dose rate. We present the final report of a prospective Phase I/II study testing the feasibility of SLDR for the treatment of recurrent gliomas. METHODS AND MATERIALS: Patients with previously irradiated recurrent gliomas were enrolled from November 1993 to March 1998. Patients received SLDR, delivered 6 to 8 hours/day at a dose rate of 40 to 50 cGy/hour for a total dose of 30 to 35 Gy given over 12 days using a modified cobalt-60 treatment unit. Acute central nervous system toxicity after SLDR treatment was the primary endpoint. Overall survival was a secondary endpoint. RESULTS: Twenty patients were enrolled (14 World Health Organization Grade 4 glioma, 5 Grade 2 glioma, 1 ependymoma). No patients developed ≥ Grade 3 central nervous system toxicity at 3 months without radiographic evidence of tumor progression. Overall survival after SLDR was 56% at 6 months, 28% at 12 months, and 17% at 24 months. One patient survived >48 months, and 1 patient survived >60 months after SLDR treatment. Re-resection before SLDR treatment significantly improved 1-year overall survival for all patients and patients with Grade 4 glioma. CONCLUSION: The delivery of SLDR is feasible in patients with recurrent gliomas and resulted in improved outcomes for patients who underwent re-resection. There were 2 long-term survivors (>48 months). This pilot study supports the notion that reduced dose rate influences the efficacy and tolerance of reirradiation in the treatment of recurrent gliomas.

The superior longitudinal fasciculus and speech arrest.

We present a 59-year-old woman with recurrent glioblastoma multiforme involving the left medial frontal and cingulate gyri. Diffusion tensor imaging (DTI) showed inferior-lateral tumor border proximity to the superior-medial (supracallosal) portion of the left frontal superior longitudinal fasciculus (SLF). Dissections of the tumor border contacting the dominant SLF caused speech arrests 8 times, with full recovery. At postoperative day 2, edema caused transient mild aphasia and paraphasic errors. Postoperative DTI showed an inferior-lateral resection cavity in immediate proximity to the supracallosal aspect of the left SLF. The case demonstrates excellent correlation between tumor border proximity to the dominant SLF shown at DTI and speech deficits caused by intraoperative dissections and postoperative edema. The case is the first to demonstrate speech arrest associated with lesion proximity to the supracallosal aspect of the SLF. Other SLF-related deficits are reviewed.

Noninvasive assessment of neoplastic angiogenesis: the role of magnetic resonance imaging.

The study of the effect of angiogenesis inhibitors on tumors is limited by our ability to assess their effect in vivo. Approaches that are currently employed have significant limitations. An ideal approach would employ a widely available noninvasive technology that can be used repeatedly to assess the antiangiogenic effect on the same lesions in a serial fashion. We describe here a specialized magnetic resonance imaging (MRI)-based technique that we employ in the study of angiogenesis of brain tumors. This technique, called relative cerebral blood volume (rCBV) mapping, is a noninvasive technique that adds just a few minutes to the conventional MRI study of a human brain tumor in the clinical setting. We hope that such a technique will serve as a model for developing new imaging techniques for the assessment of angiogenesis modulation in other tumor settings. We describe the technical basis and some examples of using rCBV mapping in neoplastic angiogenesis assessment, including a discussion of current limitations and future directions.

Intravoxel distribution of DWI decay rates reveals C6 glioma invasion in rat brain.

The hypothesis was tested that the intravoxel distribution of water diffusion rates, as measured with a stretched-exponential model of diffusion-weighted imaging (DWI), is a marker of brain tumor invasion. Eight rats underwent intracerebral inoculation of C6 glioma cells. In three rats, cells were labeled with a fluorescent dye for microscopy. One rat was inoculated with a saline solution, and five more rats were imaged without inoculation as controls. Five healthy uninoculated rats were also imaged. DWI was performed 14-15 days after inoculation, with diffusion-weighting factor b = 500 to 6500 sec/mm2, and the resulting signal attenuation was fitted with the stretched-exponential model. The heterogeneity index values were significantly lower (P < 0.05) in the peritumor ROI than in normal gray matter and significantly higher than in normal white matter. The distributed diffusion coefficient values were significantly lower than in normal white matter or normal gray matter. Fluorescence microscopy confirmed the presence of tumors in the peritumor region that could be histologically distinguished from the main tumor mass. There was no change in proton density or T2-weighted images in the peritumor region, making vasogenic edema unlikely as a source of contrast. It is therefore thought that the heterogeneity parameter alpha is a marker of brain tumor invasion.

Evaluation of photodynamic therapy near functional brain tissue in patients with recurrent brain tumors.

INTRODUCTION: Photodynamic therapy (PDT) involves the selective retention of a photosensitizer that upon activation with light mediates tumor cell destruction via the production of singlet oxygen. This study evaluates the toxicity of PDT and a new light-delivery device based on light-emitting diode (LED) technology in selected patients with brain tumors. METHODS: Twenty patients with recurrent malignant brain tumors received 22 treatments with PDT. Sixteen tumors were supratentorial and four tumors were infratentorial. Patients received IV Photofrin 24 h prior to light exposure starting at 0.75 mg kg(-1). Laser and LED arrays were used to deliver 100 J cm(-2) of light to the sensitized tumors. Fourteen patients received PDT with a laser-balloon adapter, two via interstitial optical fibers and five patients had LED based PDT. At the maximum Photofrin dose of 2.0 mg kg(-1) five patients received laser-balloon adapter light and five patients received LED light. In addition, three patients received LED light with 0.25 mg kg(-1) of Visudine, a benzoporphyrin derivative (BPD). Quantitative analysis of toxicity and time to progression was performed. RESULTS: Two patients had toxicity consisting of ataxia and facial weakness after treatment with interstitial fibers. Escalating doses of Photofrin were tolerated to the maximum dose of 2.0 mg kg(-1). BPD did not result in additional toxicity. PDT in the posterior fossa or near eloquent brain was tolerated using the LED or laser-balloon adapter. All patients had tumor responses as documented by MRI scan and the mean time to tumor progression after PDT was 67 weeks. CONCLUSION: PDT with LED balloon adapters (also tunable dye laser) has acceptable toxicity in brain tumor patients. Future studies using more effective photosensitizers could improve local recurrence control.