RTOG Phase I study on fast neutron teletherapy for squamous cell carcinoma of the esophagus

From August, 1977, through January, 1981, the Radiation Therapy Oncology Group sponsored a Phase I study (RTOG 77-09) on the use of fast neutrons for treating inoperable squamous cell carcinomas of the esophagus. A total of 39 evaluable patients were treated with curative intent using either fast neutrons alone or in combination with low LET irradiation as part of a mixed beam fractionation scheme. Actuarial survival curves are presented for both the "neutrons alone" and the "mixed beam" treatment groups. There was no significant survival difference between these groups of patients. The projected survival at two years is less than 10%, which is comparable with megavoltage photon results for an unselected series of patients. The size of the primary lesion and the initial Karnofsky performance status were found to be the most important prognostic indications for prolonged survival. Sixteen of 39 patients were felt to have achieved local clearance of their tumor at some time during their follow-up with the median time until a local recurrence being 17 months. Treatment related complications and patterns of metastatic spread are discussed. In general, it appeared that the response of large tumors to neutron irradiation resulted in necrosis and fistula formation. In many cases this was accompanied by persistent/recurrent tumor within the high dose radiation volume.     

Slit grafting: the use of serrated island grafts in male and female-pattern alopecia

Successful aesthetic treatment of earlier thinning of scalp hair in men and women has necessitated the development of alternatives to traditional punch grafting. The hair-bearing "serrated island" remaining between two parallel rows of round donor sites can be removed and dissected to yield a large number of "serrated island grafts" and single-hair grafts. These miniature grafts, along with half grafts from bisected plugs, can be placed, in one or several sessions, into dozens to hundreds of small "slits" between the remaining hairs in patients with early or advanced thinning on the crown, vertex, or anterior scalp--hence the name "slit grafting." The versatility of this technique is demonstrated by its value for patients with dark hair and light skin, in repair work, in patients necessitating extensive vertex coverage, or in combination with alopecia reduction and traditional punch grafting. The finely tufted progressive growth from hundreds of these carefully placed slit grafts can thus counteract further hair loss in a variety of different situations.     

Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole.

Fluoromisonidazole (FMISO) has been shown to bind selectively to hypoxic cells in vitro and in vivo at radiobiologically significant oxygen levels. When labeled with the positron emitter fluorine-18 (F-18), its uptake in tissue can be detected quantitatively with high precision by positron emission transaxial tomography (PETT). This paper presents the first experiences with PETT imaging of [F-18]FMISO uptake in human malignancies, and describes the development of this technique as a tool for the non-invasive assessment of tumor hypoxia. Eight patients with selected cancers were imaged prior to primary radiotherapy, and 3 returned for follow-up scans, for a total of 11 imaging studies. Six of eight pre-radiotherapy studies revealed retention of [F-18]FMISO in tumors that significantly exceeded plasma concentrations by 2 hr after drug injection; all five patients with head and neck primaries had such "positive" scans. An analytic method for the interpretation of [F-18] FMISO PETT images is presented, defining hypoxic elements within a tumor volume as regions with a threshold regional tumor:plasma [F-18]FMISO ratio of greater than or equal to 1.4 by 2 or more hours after injection. Toward the end of a course of fractionated radiotherapy, three repeat studies in patients with initially positive scans showed no tumor accumulation of drug above the threshold ratio of 1.4, suggesting reoxygenation had occurred. Pharmacokinetic and dosimetry data support continued use of [F-18]FMISO as a safe hypoxia probe. Two imaging protocols have been developed for human studies; a long protocol allows for more complete biodistribution and dosimetry information, and a shorter protocol facilitates increased patient accrual by applying a simple, clinically expedient imaging procedure. When correlated with tumor outcome, [F-18]FMISO PETT imaging may be developed as a predictor of tumor response to conventional radiotherapy. The implications of this technique in addressing persistent questions of tumor hypoxia in human oncology is discussed.     

Cytokine expression in the brain during the acquired immunodeficiency syndrome.

The pathogenesis of central nervous system (CNS) disease in acquired immunodeficiency syndrome (AIDS) is poorly understood but may be related to specific effects of the immune system. Cytokines such as tumor necrosis factor and interleukin-1 may have toxic effects on CNS cells and have been postulated to contribute to the pathogenesis of the neurological complications of human immunodeficiency virus (HIV) infection. To characterize viral and immunological activity in the CNS, frozen specimens taken at autopsy from the cerebral cortex and white matter of HIV-seropositive and -seronegative individuals were stained immunocytochemically for mononuclear cells, major histocompatibility complex (MHC) antigens, HIV, astrocytes, and the cytokines interleukin-1 and -6, tumor necrosis factor-alpha and -beta, and interferon gamma. Levels of soluble CD4, CD8, and interleukin-2 receptor, as well as interferon gamma, tumor necrosis factor-alpha, beta 2-microglobulin, neopterin, and interleukin-6 and -1 beta were assayed in the cerebrospinal fluid and plasma of many of these individuals during life. The HIV-seropositive group included individuals without neurological disease, those with CNS opportunistic infections, and those with HIV encephalopathy. Perivascular cells, consisting primarily of macrophages with some CD4+ and CD8+ T cells and rare B cells, were consistently MHC class II positive. MHC class II antigen was also present on microglial cells, which were frequently positive for tumor necrosis factor-alpha. HIV p24 antigen, when present, was found on macrophages and microglia. Endothelial cells were frequently positive for interleukin-1 and interferon gamma and less frequently for tumor necrosis factor and interleukin-6. There were gliosis and significant increases in MHC class II antigen, interleukin-1, and tumor necrosis factor-alpha in HIV-positive patients compared to HIV-negative brains. Cerebrospinal fluid from most of the patients tested had increased levels of tumor necrosis factor, beta 2-microglobulin, and neopterin. There was no correlation in HIV-positive individuals between levels of cytokines and the presence or absence of CNS disease. These data indicate that there is a relative state of "immune activation" in the brains of HIV-positive compared to HIV-negative individuals, and suggest a potential role for the immune system in the pathogenesis of HIV encephalopathy.     

Aspirin usage and its influence on femoro-popliteal vein graft patency. The Femoro-popliteal Bypass Trial Participants.

As part of the Femoro-popliteal Bypass Trial patients undergoing femoro-popliteal vein bypass were randomised to aspirin 300 mg and dipyridamole 150 mg twice daily or identical placebo tablets. Blood was taken from a subgroup of 145 patients (mean age 66.3 years) with patent grafts at 6 months. Serum salicylate analysis revealed that of the 65 randomised to receive placebo 18 (28%) had evidence of salicylate in their sample (greater than 50 ng ml-1). Similarly, in those randomised to active treatment and considered to be good compliers 16/61 (26%) had no evidence of salicylate in their serum sample (less than 50 ng ml-1). Analysis of primary graft patency by "intention to treat" failed to detect a difference by life table, the risk being slightly higher in the group assigned to placebo (RR = 1.33, 95% confidence internal C.I. 0.64-2.78, p = 0.438). When comparing patients with no detectable serum concentration (less than 50 ng ml-1) with patients with serum salicylate over 50 ng ml-1 there was a significant difference in graft patency at 66 versus 83% respectively at 3 years (RR = 2.38, 95%C.I. 1.08-5.26, p = 0.024). When corrected for a number of possible risk factors this significant difference was maintained (RR = 2.78, 95%C.I. 1.15-6.67, p = 0.017). Although these findings are based on observational data they provide indirect evidence of an improvement in graft patency with aspirin. This result combined with the finding of a significant reduction in cardiovascular events in the main trial results support the use of aspirin and dipyridamole in patients undergoing femoro-popliteal vein bypass.     

Neurofilament redistribution in transected nerves: evidence for bidirectional transport of neurofilaments

Nerve fibers of the C57BL/6/Ola mouse exhibit very slow Wallerian degeneration following axotomy, thus allowing prolonged observation of mammalian axons separated from their cell bodies. The present study utilized teased-fiber preparations, silver histochemistry, immunocytochemistry, and electron microscopy to examine the distribution of axonal components in the distal stumps of axotomized sciatic nerves in C57BL/6/Ola mice. In examining nerve segments at varying intervals after nerve transection, we found no evidence of proximal-to-distal "emptying out" of the cytoskeleton, as would be predicted if the cytoskeleton in these transected nerves were undergoing anterograde transport as an assembled structure. Instead, we observed a gradual redistribution of cytoskeletal constituents over time, dominated by the progressive accumulation of neurofilaments at the severed ends of axons. In particular, there were massive accumulations at the proximal ends of the distal stumps. These results strongly suggest that, at least in transected nerve fibers, neurofilaments can be transported bidirectionally.     

Subclinical sensory neuropathy in late-onset restless legs syndrome

OBJECTIVE: To determine the prevalence of different forms of peripheral neuropathy in patients with restless legs syndrome (RLS) and correlate the findings with other clinical characteristics. BACKGROUND: RLS is characterized by a desire to move the extremities, often associated with paresthesias or dysesthesias, motor restlessness, worsening of symptoms with rest with relief by activity, and worsening of symptoms in the evening or night. The association between RLS and peripheral neuropathy remains controversial. The observation that many patients with small-fiber neuropathy also complain of RLS prompted this prospective case series. METHODS: Twenty-two consecutive patients with RLS were evaluated for evidence of large-fiber neuropathy (LFN) and small sensory fiber loss (SSFL). Results: In eight of the 22 (36%) patients, neuropathy was identified. Three patients had pure LFN; two had mixed LFN and SSFL; and three had isolated SSFL. The SSFL group had a later onset of RLS (p < 0.009), reported pain in their feet with RLS more frequently (p < 0.001), and tended to have no family history of RLS (p < 0.078). Patients with LFN did not have similar associations with age at onset, family history status, or presence of pain. CONCLUSION: The results suggest that two forms of RLS exist: one is triggered by painful dysesthesias associated with SSFL, has later onset, and no family history; and one without involvement of SSF, with an earlier onset age, positive family history for RLS, and no pain. The authors hypothesize that patients with the SSFL subtype of RLS will preferentially respond to neuropathic pain medications.     

Arsenic trioxide induces selective tumour vascular damage via oxidative stress and increases thermosensitivity of tumours.

It has previously been found that the anti-leukaemia agent Arsenic Trioxide (ATO) causes vascular shutdown in solid tumours and markedly sensitizes tumours to hyperthermia. The present study was designed to evaluate the mechanism of action and dose-dependence of ATO-induced thermosensitization in FSaII and SCK murine tumours. The role of oxidative stress was studied by observing ATO-induced vascular shutdown in vivo and ATO-induced endothelial cell adhesion molecule expression in vitro in the presence or absence of an anti-oxidant. It was found that a dose as low as 2 mg/kg ATO impaired vascular function, as estimated by 86Rb uptake, in the tumour. The degree of tumour growth delay induced by 1 h of hyperthermia at 42.5 degrees C, applied 2 h after ATO injection, was proportional to the dose of ATO administered. In addition, it was found that ATO can directly thermosensitize tumour cells in vitro. The development of massive tissue necrosis in the tumour was observed in the days after treatment, especially with the combination of ATO and heating. ATO-induced adhesion molecule expression in vitro was abolished when the anti-oxidant n-acetyl-cysteine (NAC) was introduced prior to exposure, while the addition of NAC in vivo partially blocked ATO-induced vascular shutdown. These results suggest that the expression of adhesion molecules by the vasculature due to oxidative stress contribute to the ATO-induced selective tumour vascular effects observed and that the clinical use of ATO to increase tumour thermosensitivity via direct cellular and vascular effects appears feasible.