Management of neuropathic pain following treatment for breast cancer in the absence of recurrence: a challenge for the radiation oncologist.

This report reviews various management options for treatment-induced neuropathic pain in breast cancer. First-line options include tricyclic antidepressants and anticonvulsant drugs. Opioids should be prescribed according to published guidelines. Second-line treatments include lignocaine, mexiletine and ketamine. Sympatholytic therapies are available to patients with features of chronic regional pain syndrome. Anti-inflammatory agents are used for neurogenic inflammation. Surgical interventions are considered for refractory neuropathic pain. Interdisciplinary management is appropriate when persisting pain causes physical and psychosocial disabilities.

Glycerol disrupts tight junction-associated actin microfilaments, occludin, and microtubules in Sertoli cells.

Intratesticular injections of glycerol have been shown to result in a marked and prolonged reduction of spermatogenesis, accompanied by increased permeability of the blood-testis barrier. Because the permeability of the blood-testis barrier is regulated by Sertoli cell tight junctions, and tight junction organization is regulated by the cytoskeleton, we undertook to examine the effects of glycerol treatment on cytoskeletal actin microfilaments and microtubules, and on the tight junction protein, occludin, in Sertoli cells. Adult rats received a single intratesticular injection of either saline (controls) or a 10% glycerol solution. At 24 hours and 7, 15, and 21 days after injection, testes were collected and prepared for routine histology, cryosectioning, or whole seminiferous tubule immunohistochemical staining; and the preparations were viewed by light and confocal microscopy. In saline-injected testes, Sertoli cells had a cytoskeletal and junctional organization that resembled that of normal testes. F-actin microfilaments, located in the basal region, were arranged in regular bundles or chords that circumscribed the perimeter of each Sertoli cell at the level of the tight junction. Occludin colocalized with tight junction-associated actin filament distribution and microtubules formed a geometric array associated with spermatogenic cells. In contrast, in glycerol-treated Sertoli cells, microfilament and microtubule organization and occludin distribution were partially or completely disrupted. From these results we conclude that glycerol treatment either directly or indirectly disrupts tight junction-associated F-actin and occludin and tubulin organization in rat Sertoli cells. Perturbation of the tight junction-associated proteins could explain the increase in permeability of the blood-testis barrier observed after glycerol treatment. Impaired spermatogenesis following glycerol treatment is likely a consequence of a leaky blood testis barrier and disrupted Sertoli cell cytoskeleton. Glycerol injections may serve as a useful tool in studying the relationship between cytoskeletal organization and the stabilization of Sertoli-Sertoli cell junctions.

The 300-kDa intermediate filament-associated protein (IFAP300) is a hamster plectin ortholog.

Plectin is a high-molecular-weight cytoskeleton-associated protein that was initially identified in intermediate filament (IF)-enriched fractions of rat C6 glioma cells. At the cellular level, plectin has been found to associate with IF networks and IF-associated structures that are involved in cell-cell and cell-substrate adhesions. IFAP300 is an IF-associated protein that was initially identified in hamster cells by a monoclonal antibody directed against a high molecular weight protein present in IF-enriched cytoskeletal preparations. Plectin and IFAP300 display similar distribution patterns within cells as determined by immunofluorescence. Based upon this and the finding that their biochemical properties are similar, it has been suggested that they may actually be orthologous proteins. In this paper we demonstrate that this is the case. Cloning and sequencing of most of the hamster plectin cDNA demonstrates that plectin is found in hamster cells and that its sequence is highly conserved between species. Using immunological cross-reactivity, epitope mapping, and immunoelectron microscopy, we show that IFAP300 is actually the hamster ortholog of plectin.

Peripheral nuclear matrix actin forms perinuclear shells.

Perinuclear actin shells have been reported in a variety of organisms. The shells have been identified by staining perinuclear material with fluorescently-labelled phalloidin, but have not been localized to a specific subcellular compartment at the ultrastructural level. We show here that the shells of 3T3 cells lie in the peripheral nuclear matrix. Nuclear shells and matrix actin in other parts of the nucleus are not usually detected by immunohistochemical staining because they are inaccessible to antibodies or to phalloidin. Immunohistochemical detection of nuclear actin is only possible during its deposition at the end of mitosis, or in interphase nuclei that have been extracted with detergent, digested with nucleases and washed with high salt buffers.

3T3 cells have nuclear invaginations containing F-actin.

Nuclear envelope invaginations occur in many kinds of cell. Double-labeling of 3T3 cells with Hoechst 33342 strain for DNA and phalloidin-rhodamine for F-actin, show that some nuclei appear to contain tangled knots of F-actin. Concanavalin A-fluorescein staining for membranes shows that the knots are continuations of the nuclear envelope. Although they contain F-actin, the knots appear by electron microscopy to be cytoplasmic invaginations lacking microfilaments. Since we have shown previously that nuclear-membrane associated actin forms perinuclear shells in 3T3 cells, we propose that nuclear knots also are composed of actin associated with the nuclear membrane. 3T3 nuclei also contain nuclear invaginations of a second kind. These invaginations lie perpendicular to the first type and lack F-actin.

Extracellular matrix regulates microfilament and vinculin organization in C6-glioma cells.

Since the extracellular matrix (ECM) has a role in regulating cell proliferation it has been hypothesized that unregulated growth of transformed cells results from an inability of cells to interpret the constraints on growth as dictated by the ECM. The most likely candidate to communicate the restraint on growth to the nucleus is the cytoskeleton because it is the only cytoplasmic structure to physically connect the nucleus and plasma membrane. The purpose of this study was to determine whether the cytoskeleton, specifically the microfilaments (MF), of the C6-glioma cell line possesses the ability to respond to changes in the ECM. The C6-glioma cell line was chosen as a model because it exhibits the characteristics of a tumor cell, both in vivo and in vitro. In this study cells were grown on bare glass, Matrigel, laminin and type IV collagen prior to staining with phalloidin tetramethylrhodamine B isothiocyanate or antibodies specific to vinculin to visualize MF and adhesion plaques, respectively. On the basis of MF orientation, network complexity and location of adhesion plaques, this study reports that the cytoskeletal arrangements of C6 cells grown on various substrates are distinctly different. Each distinct organization pattern may reflect a change of cell behavior promoted by the different culture conditions. The significance of this study is that it demonstrates that the process of transformation in C6-glioma cells has not interfered with the cells ability to recognize, interpret and adapt to changes in the ECM.

F-actin forms transient perinuclear shells at the mitosis-interphase transition.

Intermediate filaments and microtubules are known to be involved in establishing and maintaining nuclear shape. F-actin may also be involved in determining nuclear shape, since we have found it associated with reforming nuclei very briefly after cell division. We stained cells from vertebrate tissue cultures (3T3 and NRK-49F) and epidermal cells from an insect with rhodamine-phalloidin and Hoechst #33342 to localize F-actin in relation to the nucleus. We found that F-actin forms shells only around nuclei during reorganization in late mitosis and early interphase. We suggest that perinuclear F-actin shells may be generally present in eukaryotes, but that they are easily missed because of their delicacy and transience.

Surface doses from combined electron/photon fields in a radiotherapy.

Using mixed modality treatments of photon and electron beams, some skin sparing can be acquired whilst administering a safer dose to crucial structures such as the spine or lung. The combination of 6MV X-rays and 12MeV electron beams in the treatment of breast nodes is a clinical example where such treatments are beneficial. By weighting the photon and electron beams accordingly, the surface dose and dose at depth can be changed whilst not dramatically varying the depth at which the 90% dose level is maintained. In order to accurately predict near surface dose, build up results were obtained using TLD extrapolation, Markus parallel plate and Attix parallel plate ionisation chambers in a solid water phantom. This data was then used to predict surface dose due to different beam weights. Depending on the weightings given to the photon and electron beams, the surface dose and dose at depth varies. For example, when 6MV X-rays and 12MeV electrons are combined the percentage dose at surface and 20cm depth is 46%/23%, 54%/20%, 61%/15% for 60/40, 50/50 and 40/60 X-ray/electron weightings respectively. For these weightings, the depth of the 90% level remained at 30mm. From a clinical point of view this data is important, showing that the 90% level of radiation does not vary in depth significantly provided the ratio of photon/electron weights is kept within a range of 60/40 to 40/60. However by varying the weightings, the ability to control dose to skin in particular to produce the optimum level for both areas whilst still delivering the required tumour dose is obtained.

X-ray surface dose measurements using TLD extrapolation.

Surface dose measurements in therapeutic x-ray beams are of importance in determining the dose to the skin of patients undergoing radiotherapy. Measurements were performed in the 6-MV beam of a medical linear accelerator with LiF thermoluminescence dosimeters (TLD) using a solid water phantom. TLD chips (surface area 3.17 x 3.17 cm2) of three different thicknesses (0.230, 0.099, and 0.038 g/cm2) were used to extrapolate dose readings to an infinitesimally thin layer of LiF. This surface dose was measured for field sizes ranging from 1 x 1 cm2 to 40 x 40 cm2. The surface dose relative to maximum dose was found to be 10.0% for a field size of 5 x 5 cm2, 16.3% for 10 x 10 cm2, and 26.9% for 20 x 20 cm2. Using a 6-mm Perspex block tray in the beam increased the surface dose in these fields to 10.7%, 17.7%, and 34.2% respectively. Due to the small size of the TLD chips, TLD extrapolation is applicable also for intracavity and exit dose determinations. The technique used for in vivo dosimetry could provide clinicians information about the build up of dose up to 1-mm depth in addition to an extrapolated surface dose measurement.

Neutron therapy in Saudi Arabia: an overview and results of dose searching study in head and neck cancer.

The King Faisal Specialist Hospital and Research Centre is the only center in the Middle East that incorporates a neutron therapy facility. The neutron beam is produced by a cyclotron, which produces a beam by either a (d(15)+Be) or (p(26)+Be) reaction. The beam from the proton reaction is selected for therapy because of its superior physical characteristics. These were verified by an intercomparison conducted by the European Organization for Research on Treatment of Cancer (EORTC) Heavy Particle Therapy Group. Full beam data are presented. The first study in the neutron therapy Program is on the treatment of squamous cancers of the head and neck. This consists of two parts. Part I is a dose searching phase and Part II is a comparison of our current photon treatment versus neutrons using the neutron dose selected by Part I of the study. Results of the dose searching phase (Part I) are presented.

Neutron therapy for locally advanced head and neck squamous cell carcinoma: optimum dose search.

28 patients with locally advanced primary squamous cell carcinoma of the head and neck received neutron therapy and were randomized between two dose levels: 145 cGy n gamma x twelve fractions, three fractions per week (total 17.4 Gy n gamma). 155 cGy n gamma x twelve fractions, three fractions per week (total 18.6 Gy n gamma). Acute toxicity for skin, mucous membrane, salivary and subcutaneous tissues was graded using the EORTC/RTOG scoring system. Analysis indicates 17.4 Gy n gamma as "safe". A further twelve patients are to be assigned to the higher dose (18.6 Gy n gamma) before making a final dose selection.

Relative biological effectiveness (RBE) of p(26) + Be neutrons from the King Faisal Specialist Hospital and Research Centre CS-30 cyclotron measured by testis weight loss.

Testis weight loss of C3H and Swiss-Webster (SW) mice was used as endpoint to determine the relative biological effectiveness (RBE) of p(26) + Be fast neutrons with respect to Co-60 gamma irradiation. Percent weight loss versus dose curves showed two components. Comparing first component effects, the RBE was 3.4 (C3H) and 3.7 (SW); when the second component was used, the RBE was 2.6 and 2.7 (C3H), and 3.5 (SW). When percent weight loss was plotted versus log dose, parallel lines were obtained, giving an RBE of 3.9 and 4.1 (C3H), and 4.2 (SW). Results were compared with published values and RBE as a function of fast neutron energy was plotted. A good correlation was found. Discrepancies seem to be mostly due to the use of different baseline radiation. When a constant correction is made, most of the values fit a single line. The possibility of using this approach as a substitute for international comparisons is discussed.

Nasopharyngeal carcinoma in Saudi Arabia: a retrospective study of 166 cases treated with curative intent.

A retrospective review was performed of the medical records of 166 adult patients with biopsy-proven carcinomas of the nasopharynx treated with curative intent at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. All patients were treated between June 1975 and December 1985 using megavoltage therapy equipment. Most patients presented with advanced nodal disease: 23 patients (13.9%) were N0, 16 patients (9.6%) were N1, 29 patients (17.5%) were N2, and 98 patients (59%) were N3. The overwhelming majority of patients had nonkeratinizing lesions (158/166). At the time of analysis, mean follow-up time was 24.2 months (range 2-108). Actuarial curves are presented for local/regional control as a function of T-stage and N-stage and for survival and time to development of distant metastases as a function of N-stage. At 4 years local/regional control was 70% for T1 lesions, 59% for T2 lesions, 30% for T3 lesions, and 35% for T4 lesions. There was little correlation between local/regional control and N-stage being about 50% at 4 years for all nodal subgroups. Only six patients exhibited an isolated first failure in the regional nodes alone, whereas 60 patients failed initially at the primary site (either alone or in conjunction with a simultaneous nodal failure). The development of distant metastases correlated to some extent with nodal disease ranging from 20% at 4 years for T1/T2 N0 patients to 70% for patients who initially presented with N3 disease. Survival data was more difficult to obtain due to cultural biases in a medically unsophisticated patient population. True survival curves are bounded by calculating actuarial curves in two ways: death as the failure endpoint and death plus lost-with-active-disease as failure endpoints. In terms of the latter curves, at 4 years "survival" ranged from 39% for patients with T1/T2 N0 lesions to 23% for patients with N3 lesions.

Combined iridium 192 interstitial and external beam radiation therapy for the treatment of prostatic cancer.

Twenty-four patients with clinically palpable prostatic adenocarcinoma (stage B or C) were treated with a combination of interstitial radiation therapy and external beam radiation therapy following pelvic lymphadenectomy for accurate staging. Early results indicate a complete clinical response rate at 12 months of 77%, with a 4% complication rate (persisting rectal ulceration).