Early history of development of boron neutron capture therapy of tumors.

The stable isotope 10B has a peculiarly marked avidity to capture slow neutrons whereupon it disintegrates into a lithium and a helium atom. These give up the 2.4 MeV of disintegration energy which they share within 5 and 9 microns of the 10B atom respectively. This means that the cell closest to the 10B atom bears the brunt of its atomic explosion. The objective of the tumor therapist is to find a carrier molecule for the boron atom which will concentrate in the tumor. Although a number of investigators saw the peculiar advantage of this selective tactic to achieve destruction of a species of unwanted cells, no success in animal studies was achieved until 1950. Sweet and colleagues found that the capillary blood-brain barrier keeps many substances out of the normal brain but that the gliomas had much less of such a barrier. He, Brownell, Soloway and Hatanaka in Boston together with Farr. Godwin, Robertson, Stickley. Konikowski and others at the Brookhaven. National Laboratory worked partially in collaboration and partly independently. We irradiated at 3 nuclear reactors several series of glioma patients with no long-term remission, much less a cure being achieved. Hatanaka on his return to Japan kept BNCT alive by treating a total of 140 patients with various brain tumors. Beginning in 1972, Mishima and colleagues have achieved useful concentrations of 10B-borono-phenylalanine, an analogue of the melanin precursor tyrosine, for BNCT of melanomas.

History of surgery for craniopharyngiomas.

Craniopharyngiomas, although histologically benign, are usually so intimately associated with the hypothalamus that total extirpation of these tumors was generally followed by death from hypotension and gross endocrine deficiencies. During the first half of the present century, those recording their tribulations include the famous names of Grant, Bailey, Bucy, Peet, Kahn, Olivecrona, Norlen, Sjöqvist, Rougerie and Northfield. Matson and Sweet were the first to achieve major reductions in mortality by giving massive doses of cortisone plus meticulous dissection, which took advantage of the reactive glial envelope which surrounds the great majority of these tumors.

Trigeminal facial pain: a model of peptides and monoamines in intracerebral cerebrospinal fluid.

A biochemical model of chronic trigeminal facial pain with elevated substance P (SP) and co-dysfunctional dopamine (DA), norepinephrine (NE) and purinergic systems is proposed. The serotonergic system is hypoactive as judged by low 5 hydroxyindoleacetic acid (5HIM). In distinction, intracerebral opioids may not be dysfunctional in facial pain as measured by normal levels of beta endorphin (BE). The neuropeptides somatostatin (SOM), cholecystokinin (CCK), met and leu-enkephalin (MENK, LENK) have very small picogram concentrations in these pain patients, but no definite conclusion can be reached on their role in trigeminal pain, alone or with monoamines, because of the small numbers, both sample size and concentrations. Interpretive obstacles to such human neurochemical studies suggest that future work might move to human clinical trials comodulating SP down, inhibitory peptides (SOM, CCK) up, and enhancing monoamine systems.

Distribution of 10B after infusion of Na210B12H11SH into a patient with malignant astrocytoma: implications for boron neutron capture therapy.

If a sufficient concentration of the stable isotope 10B is introduced into a neoplasm, radiation therapy can be effected by short-range heavy charged particles from the disintegration of 10B by slow neutrons. Brain tumors were irradiated postoperatively by Hatanaka and co-workers in Japan using a 1 to 2 hour intraarterial infusion of 10B-enriched Na2B12H11SH (Na210B12H11SH) before exposure of the tumor-bearing area of the brain to slow neutrons from a 100 kilowatt nuclear reactor. The clinical outcome of such boron neutron capture therapy has been favorably impressive in some patients, but its efficacy in brain tumors needs improvement. In our study, a terminally ill patient with malignant astrocytoma was infused intravenously with Na210B12H11SH for 25 hours. The postmortem distribution of 10B in unfixed, frozen, tumor-bearing brain and spinal cord tissues was studied by comparing representative cryostat sections of these specimens with neutron-induced heavy charged particle radiographs of the same sections. Preferential accumulation of 10B was observed in the tumor, with relatively little accumulation of 10B in the parenchyma of the central nervous system.

Percutaneous methods for the treatment of trigeminal neuralgia and other faciocephalic pain; comparison with microvascular decompression.

The treatment of trigeminal neuralgia by the minor percutaneous invasive procedures of selective thermal rhizotomy, glycerol injection, and balloon compression in the middle cranial fossa are compared with the open operations of compression in the middle fossa and MVD in the posterior fossa. A conservative end point for any one of the three percutaneous methods is recommended as the first invasive procedure in this disorder. The management of the facial pains in multiple sclerosis, cancer, posttraumatic and postherpetic pain, migrainous neuralgia (cluster headache), and vagoglossopharyngeal neuralgia is also discussed.

Conducted somatosensory evoked potentials during spinal surgery. Part 2: clinical applications.

In 27 patients undergoing laminectomy, spinal cord function was monitored by epidural bipolar recordings of conducted spinal somatosensory evoked potentials (SEP's) across the laminectomy site, with calculation of spinal conduction velocity (CV). In control cases without myelopathy, the CV remained relatively constant (+/- 3%) even during prolonged operations, despite markedly changing levels of anesthesia. Acute CV changes were detected intraoperatively in three cases: these patients displayed improvement after extramedullary (Case 1) and intramedullary decompression (Case 2), and deterioration after direct unilateral dorsal column injury (Case 3). These intraoperative CV alterations correlated postoperatively with changes in the neurological examination. Although a unilateral lesion confined to the dorsal column abolished the ipsilateral SEP in Case 3, complete anterior quadrant lesions did not consistently change the CV (Case 4). This further suggests that the SEP is generated entirely by ipsilateral dorsal column activation. Accurate measurement of this dorsal column conduction velocity across the operative field provides a very sensitive means of monitoring spinal cord function during operations for neurosurgical spinal lesions.

Cancer pain relieved by long-term epidural morphine with permanent indwelling systems for self-administration.

Clinical trials for abatement of intractable pelvic cancer pain were conducted in two patients, each electing surgical implantation of one of two indwelling catheter systems for administration of morphine into the spinal epidural space. Both systems, one consisting of a partially indwelling Broviac catheter, and the other, completely indwelling, consisting of a morphine reservoir connected to a shunt pump and on-off Hakim valve assembly, permitted the patients to return home where they could self-administer epidural morphine. Each patient reported that 2 mg of epidural morphine provided 8 to 12 hours of pain relief at a level of superior to their previous narcotic medication. On a regimen of 2 mg of epidural morphine administered twice daily, both patients experienced analgesia for 6 months, unaccompanied by alterations in sensory, motor, or cognitive functioning, and with a little drug tolerance reaction.

Central mechanisms of chronic pain (neuralgias and certain other neurogenic pain).

Almost all supratentorial intracranial lesions which may effectively control chronic pain in man are ineffective for acute pain. There are at least 10 sites at which lesions producing no somatic sensory loss have often stopped the peculiarly agonizing chronic pain of advanced cancer. They include: (a) inferior posteromedial or subcaudate (preinnominate) frontal white matter; (b) supracallosal portion of cingulum; (c) thalamotomy of centrum medianum and parafascicularis nuclei; (d) thalamotomy of linear parasagittal type separating connections between lateral specific and medial nonspecific sensory relay nuclei; (e) thalamotomy of pulvinar; (f) amygdalotomy; (g) frontothalamic tractotomy; (h) hypothalamotomy-posteromedial nuclei; (i) hypothalamotomy-periventricular nuclei; (j) hypophysectomy. It is indeed remarkable that such diversely situated lesions may many times be so successful. We understand poorly the mechanisms by which this control is often (though at times only temporarily) achieved. Hence, we are in real need of animal models to permit critical analysis. The problem of devising an ethically acceptable modus operandi is formidable. However, an ethicist who would demand that every time an experimental animal is showing some distress the experiment must be terminated, must also bear some responsibility for continuing disabling pain in hundreds of thousands of people.

Radical surgical treatment of craniopharyngioma.

There is evidence from this publication and those of Matson and colleagues that a determined effort at total excision of these tumors as the initial therapy is a tenable course of action. The main bases for this concept are: (1) that the dense gliosis characteristically intervening between these epithelial tumors and normal brain constitutes a margin of safety for the surgeon at least for the first several years such tumors are growing in the 3rd ventricle; (2) improved early diagnosis and better operative instruments, magnification, lighting, and technique are decreasing operative morbidity and mortality; and (3) new knowledge and new replacement therapy are reducing the burden of the metabolic and endocrine defects. Competing with this is the concept that rotationally delivered or even more precisely focused high energy photons and intracavitary beta-radiation have lower morbidity and mortality. The detailed and long term data on which to draw conclusions are not yet available. My medical colleagues and I are preparing case-by-case tables with all of the relevant facts to supply one component of the total picture.

Controlled thermocoagulation of trigeminal ganglion and rootlets for differential destruction of pain fibers: facial pain other than trigeminal neuralgia.

I describe the results of retrogasserian differential lidocaine block to aid in the selection of patients for a differential thermal lesion in the trigeminal ganglion and rootlets. This procedure temporarily duplicates the state of analgesia without anesthesia one seeks to make permanent with the radiofrequency heating. The results of this heating procedure are described in the treatment of 71 patients with facial pain of cancer, postherpetic, periodic migrainous neuralgia, acromegaly, trigeminal neuropathy, central pain, post-traumatic facial neuralgia, and atypical facial neuralgia.