Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer.

BACKGROUND: Women who carry germ-line mutations in BRCA1/2 are at very high risk of developing breast and ovarian cancer. Breast conserving therapy is associated with a similar risk of ipsilateral cancer recurrence in BRCA carriers compared with non-carriers. However, the risk of subsequent contralateral breast cancer in carriers is markedly increased. Therefore, mastectomy of the diseased breast along with risk reducing mastectomy of the contralateral breast is often advocated for BRCA carriers who are treated for early breast cancer. Yet, many BRCA carriers forgo this option for fear of harmful effects and choose breast conserving treatment and observation instead. In Israel, BRCA-associated breast cancer is relatively common. Accordingly, a national protocol was devised for this enriched population. PATIENTS AND METHODS: In this Institutional Review Board-approved phase II trial, the option of prophylactic irradiation to the contralateral breast, in addition to standard loco-regional treatment, was offered to BRCA carrier patients treated for early breast cancer who declined contralateral mastectomy. The primary end point was contralateral breast cancer. RESULTS: Between May 2007 and October 2017, 162 patients were enrolled. Eighty-one patients opted for standard loco-regional treatment including surgery and radiation to the involved side (control arm) and 81 patients chose additional contralateral breast irradiation (intervention arm). At a median follow-up of 58 months, 10 patients developed contralateral breast cancer in the control arm at a median of 32 months, as compared with 2 patients in the intervention arm who developed contralateral breast cancer 80 and 105 months after bilateral breast irradiation (log-rank P = 0.011). CONCLUSIONS: Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset. CLINICAL TRIAL: Phase II, comparative two-arm trial (NCT00496288).

Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo.

EMT-6 murine mammary tumors were made resistant to cis-diamminedichloroplatinum (II) (CDDP), carboplatin, cyclophosphamide (CTX), or thiotepa in vivo by treatment of tumor-bearing animals with the drug during a 6-month period. In spite of high levels of in vivo resistance, no significant resistance was observed when the cells from these tumors were exposed to the drugs in vitro. The pharmacokinetics of CDDP and CTX were altered in animals bearing the respective resistant tumors. The resistance of all tumor lines except for the EMT-6/thiotepa decreased during 3 to 6 months in vivo passage in the absence of drugs. These results indicate that very high levels of resistance to anticancer drugs can develop through mechanisms that are expressed only in vivo.

Addition of 2-nitroimidazole radiosensitizers to cis-diamminedichloroplatinum(II) with radiation and with or without hyperthermia in the murine FSaIIC fibrosarcoma.

We have examined the ability of misonidazole (MISO) or etanidazole (ETA) to improve the antitumor efficacy of cisplatin (CDDP), hyperthermia, and radiation in the FSaIIC murine fibrosarcoma. A growth delay of about 25 days was produced with CDDP (5 mg/kg) and hyperthermia (43 degrees C, 30 min) prior to radiation (3 Gy daily for 5 days) on day 1. The addition of MISO (1 g/kg) on day 1 resulted in a tumor growth delay of about 28 days. The addition of ETA at 0.5 g/kg or 1 g/kg resulted in tumor growth delays of about 33 and 43 days, respectively. Tumor cell survival assay showed that MISO was additive with CDDP either at 37 degrees C or with hyperthermia (43 degrees C, 30 min). In contrast, ETA at both 0.5 g/kg and 1 g/kg was dose modifying over the CDDP dosage range at 37 degrees C or 43 degrees C. Analysis of tumor cell killing in Hoechst 33342 selected bright (presumably oxic) and dim (presumably hypoxic) tumor cell subpopulations demonstrated that the addition of MISO to the CDDP trimodality regimen increased killing in the dim cell subpopulation, while the addition of ETA increased tumor cell killing in both subpopulations, although the greater effect was in the dim cell subpopulation. These results indicate that ETA may add to the efficacy of the CDDP trimodality in the clinic and may be of value as a chemosensitizer with CDDP.

Interaction with hyperthermia of tetrachloroplatinum(II)(Nile blue)2 and tetrachloroplatinum(II)(neutral red)2 in EMT6 murine cells and the murine FSaIIC fibrosarcoma.

Complexes of the tetrachoroplatinum(II) dianion with positively charged nuclear dyes were prepared in an effort to produce agents which gain ready access into the nucleus and become very cytotoxic at clinically relevant hyperthermia temperatures. Pt(Nile blue)2 and Pt(neutral red)2 are complexes of tetrachloroplatinum(II) with two closely related p-quinonediamine dyes. Pt(Nile blue)2 and Pt(neutral red)2 were only moderately cytotoxic to exponentially growing normally oxygenated or hypoxic EMT6 cells in vitro at pH 7.40 and 37 degrees C. At pH 7.40 and 42 degrees C and especially at 43 degrees C, however, Pt(Nile blue)2 became far more cytotoxic. At pH 6.45 Pt(Nile blue)2 became more toxic toward hypoxic cells (cell kill of 3.5 logs at 500 microM, 42 degrees C for 1 h). Pt(neutral red)2 became much more cytotoxic at pH 6.45 and 42 degrees C or 43 degrees C compared to pH 7.4, and the cell kill observed was similar in both euoxic and hypoxic cells (3 logs at pH 6.45, 43 degrees C with only 100 microM). Tumor cell survival studies in the FSaIIC murine fibrosarcoma demonstrated that both drugs killed in a dose-dependent log-linear manner. Hyperthermia treatment (43 degrees C, 30 min) immediately after either drug resulted in a dose modifying effect. The tumor growth delay produced by Pt(Nile blue)2 (100 mg/kg) was 4.6 days and by Pt(neutral red)2 (100 mg/kg) was 3.8 days. Both drugs were markedly improved by hyperthermia (tumor growth delay 1.4 days for hyperthermia; tumor growth delay 10.9 days for Pt(Nile blue)2 and 8.0 days for Pt(neutral red)2. Intracellular platinum levels were approximately 200 times higher after exposure of EMT6 cells to 25 microM of Pt(Nile blue)2 or Pt(neutral red)2 for 1 h at 37 degrees C than after exposure to the same concentration of cis-diamminedichloroplatinum(II). Treatment of cells with the drugs at 42 degrees C (1 h) resulted in no change in platinum levels with cis-diamminedichloroplatinum(II), but with Pt(Nile blue)2 and Pt(neutral red)2 an increase of 2- to 3-fold was found. Since previous work has shown that both of these complexes are active radiosensitizing agents, these new drugs seem quite well suited for further development as antitumor agents for use against solid tumors alone and in conjunction with hyperthermia and/or radiation therapy.

Interaction of PtCl4(Fast Black)2 with hyperthermia.

We are developing complexes of negatively charged PtCl4 with positively charged nuclear dyes as new antitumor agents for use alone and in conjunction with hyperthermia and/or radiation. Elemental analysis has shown that the complex PtCl4(Fast Black)2 is a tight ion pair. In experimentally growing EMT6 cells in vitro, PtCl4(Fast Black)2 killed cells in a log-linear manner which increased as the temperature of the exposures was increased from 37 to 42 degrees C or 43 degrees C. In addition, cell kill was also increased under conditions of low pH (6.45), especially in hypoxic cells treated at elevated temperature. Measurement of intracellular platinum levels after exposure to 25 microM cisplatin or PtCl4(Fast Black)2 demonstrated that platinum levels were between 170- and 200-fold higher after exposure to PtCl4(Fast Black)2. In vivo studies in the FSaIIC murine fibrosarcoma showed, again, that PtCl4(Fast Black)2 killed in a log-linear manner. Treatment of tumors placed in the thigh with 43 degrees C, 30-min hyperthermia immediately following i.p. injection of PtCl4(Fast Black)2 was dose modifying. One hundred mg/kg of PtCl4(Fast Black)2 produced a 4.6-day tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min hyperthermia immediately following i.p. injection of PtCl4(Fast Black)2 was does modifying. One hundred mg/kg of PtCl4(Fast Black)2 produced a 4.6-day tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min hyperthermia (growth delay for hyperthermia alone was 1.4 days), and 500 mg/kg produced a 5.6-day delay which increased to 11.0 days with hyperthermia. In contrast, cisplatin (5 mg/kg) produced a 4.4-day delay which increased to 5.9 days with hyperthermia. PtCl4(Fast Black)2 was well tolerated by animals, and the maximally tolerated dose was approximately 650 mg/kg. This new complex appears quite active as an antitumor agent alone and in conjunction with hyperthermia, and, since other studies have shown it to interact positively with radiation, this agent seems a very appropriate candidate for further development as a clinical anticancer drug.

Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy.

Thirty-one (23%) of 137 patients treated for leptomeningeal metastases (LM) achieved a sustained off-therapy response of at least 6 months' duration following treatment by a standard protocol. Of the 31 patients, equal distribution was found among various tumors: lymphoma, 13/44 (29%); breast carcinoma, 10/51 (20%); and other tumors, 8/42 (19%). Neuroimaging of the neuraxis disclosed subarachnoid deposits in 70%, with unexpected findings in 55%. At withdrawal of therapy, all 13 patients with lymphomas had achieved a complete response, and for those with the other tumors, 61% had a partial response. Off-therapy relapse was unrelated to the type of attained response and occurred in nine patients (29%) after a median time of 12 months. Five patients obtained a second prolonged response, mainly by systemic therapy. All eight patients who received only systemic therapy for their LM responded to treatment, four with a complete response. All others received both systemic and intra-CSF treatment and maintained a systemic response. Delayed complications occurred in 58%, with leukoencephalopathy equally affecting patients exposed and patients not exposed to cranial irradiation. The median survival of the whole group was 23 months. We conclude that in LM (lymphomas excluded), a partial response is compatible with a prolonged off-therapy response. Since LM may respond to systemic treatment, the role of intra-CSF therapy, with its associated complications, deserves a prospective reevaluation.

Successful chemotherapy of recurrent intracranial germinoma with spinal metastases.

A recurrent CNS germinoma with subependymal and spinal metastases was treated by combination of cis-platinum, bleomycin, and vinblastine, resulting in disappearance of intracranial and spinal tumor. Second intracranial relapse responded again to the same combination chemotherapy. Response of spinal metastases to this combination chemotherapy has not been reported previously.

Radiation-induced changes in the profile of spinal cord serotonin, prostaglandin synthesis, and vascular permeability.

PURPOSE: To investigate the profile of biochemical and physiological changes induced in the rat spinal cord by radiation, over a period of 8 months. METHODS AND MATERIALS: The thoraco-lumbar spinal cords of Fisher rats were irradiated to a dose of 15 Gy. The rats were then followed and killed at various times afterward. Serotonin (5-HT) and its major metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed as well as prostaglandin synthesis. Microvessel permeability was assessed by quantitative evaluation of Evans blue dye extravasation. RESULTS: None of the rats developed neurologic dysfunction, and histologic examination revealed only occasional gliosis in the ventral white matter at 240 days after irradiation. Serotonin levels were unchanged at 2, 14, and 56 days after radiation but increased at 120 and 240 days in the irradiated cord segments when compared to both the nonirradiated thoracic and cervical segments (p < 0.01) and age-matched controls (p < 0.03). The calculated utilization ratio of serotonin (5-HIAA/5-HT) remained unchanged. Immediately after radiation (at 3 and 24 h) an abrupt but brief increase in the synthesis of prostaglandin-E2 (PGE2), thromboxane (TXB2), and prostacyclin [6 keto-PGF1 alpha (6KPGF)] was noted, which returned to normal at 3 days. This was followed after 7 and 14 days by a significant fall off in synthesis of all three prostaglandins. Thereafter, at 28, 56, 120, and 240 days, escalated production of thromboxane followed, while prostacyclin synthesis remained markedly reduced (-88% of control level at 240 days). Up to 7 days after radiation the calculated TXB2/6KPGF ratio remained balanced, regardless of the observed abrupt early fluctuations in their rate of synthesis. Later, between 7 and 240 days after radiation, a significant imbalance was present which became more pronounced over time. In the first 24 h after radiation, a 104% increase in microvessel permeability was observed which returned to normal by 3 days. Normal permeability was maintained at 14 and 28 days, but at 120 and 240 days a persistent and significant increase of 98% and 73% respectively above control level was noted. CONCLUSIONS: Radiation induces severe impairment in microvessel function even in the histologically unaffected spinal cord, and alters the secretory phenotype of various cell systems in the central nervous system.

The interaction of cisplatin plus etoposide with radiation +/- hyperthermia.

The addition of concurrent etoposide and cisplatin to radiation +/- hyperthermia was evaluated in the murine FSaIIC fibrosarcoma tumor system. Tumor growth delay (TGD) demonstrated that when the drugs were tested with radiation (3 Gy daily X 5) plus (43 degrees X 30 min) local hyperthermia, cisplatin/hyperthermia/radiation (TGD approximately 25 days) was significantly more effective than etoposide/hyperthermia/radiation (TGD approximately 14 days). The addition of etoposide to cisplatin/hyperthermia/radiation, however, yielded a significantly longer growth delay (approximately 34 days). Tumor cell survival studies demonstrated that hyperthermia (43 degrees C, 30 minutes) was dose modifying for etoposide cytotoxicity (dose modifying factor approximately 2.0 as determined by comparisons of the slopes of the curves). The addition of etoposide to cisplatin modified cisplatin killing only slightly at 37 degrees C or 43 degrees C. Considerable additional cell kill was observed over a range of radiation doses with cisplatin, hyperthermia, and etoposide added singly or in combination, especially at the lowest radiation dose tested (5 Gy), but essentially no dose modification was observed. Evaluation of Hoechst 33342 dye-selected tumor subpopulations demonstrated that cisplatin, etoposide, radiation (10 Gy), etoposide plus radiation, and cisplatin plus radiation killed significantly fewer dim (presumably hypoxic) cells than bright (presumably normally oxygenated) cells. Hyperthermia killed more dim than bright cells. The combination of hyperthermia with cisplatin and radiation, however, resulted in approximately 5-fold lesser kill in dim cells, and the addition of etoposide increased this differential to 6.4-fold. These results indicate that etoposide adds small but measurable antitumor effects when used with cisplatin alone or with cisplatin in combination with radiation +/- hyperthermia (especially at lower radiation fraction sizes).

Cellular and secretory mechanisms related to delayed radiation-induced microvessel dysfunction in the spinal cord of rats.

PURPOSE: This study aimed to investigate long-term, radiation-induced changes in microvessel permeability, the profile of the vasoactive mediators endothelin and nitric oxide, and the response of specific cell systems in the irradiated spinal cord of rats. METHODS AND MATERIALS: The thoracolumbar spinal cords of Fischer rats were irradiated to a dose of 15 Gy, and the rats were sacrificed at various times afterward. Endothelin levels and nitric oxide-synthase (NOS) activity were assayed in extracts of spinal cords. Microvascular permeability and the effect of treatment with recombinant human manganese superoxide dismutase (r-hMnSOD) were assessed quantitatively. Immunohistochemistry evaluated astrocytes, microglia, vascular basal membrane, and neurofilaments. RESULTS: None of the rats developed neurologic dysfunction. Endothelin levels were significantly reduced at 18 h after irradiation and markedly attenuated after 10 days (p < 0.007). Thereafter, endothelin levels returned to normal values at 56 days after radiation and escalated to markedly high levels after 120 and 180 days (p < 0.002). NOS activity remained very low throughout the period of follow-up and failed to counterbalance the shifts in endothelin levels. Treatment with r-hMnSOD had no effect on normal vascular permeability but it abolished the abnormally increased permeability measured at 18 h after radiation and again after 120 and 180 days. Standard microscopic evaluation failed to reveal abnormalities in the irradiated spinal cord, but immunohistochemical staining showed a progressive increase in the number of microglial cells per field after 120 and 180 days (p < 0003). A similar increase in the number of astrocytic cells per field was noted after more than 180 days, but an earlier short lasting peak was also noted at 14 days after radiation. No abnormalities were found in blood vessel configuration, density, diameter, and basal membrane staining, or in the neurofilaments. CONCLUSION: Marked imbalance in the regulatory function of endothelium-derived mediators of the vascular tone is present after radiation therapy probably inducing chronic vasoconstriction. This imbalance favors localized procoagulation that may enhance the consequent loss of function measured as increased permeability. Microglial proliferation may account for continuous release of superoxide that may enhance disruption of normal permeability. The latter is corrected by SOD treatment. Astrocytic proliferation may present a response to the mitogenic effect of endothelin and to microglial-derived paracrine effect of cytokines.

A phase I-II trial of cisplatin, hyperthermia and radiation in patients with locally advanced malignancies.

A Phase I-II trial testing the addition of systemic cisplatin (CDDP) to local hyperthermia and radiation was conducted to determine the dose of cisplatin that is tolerable once weekly for 6 weeks and to estimate the therapeutic potential of this trimodality combination in patients with locally advanced malignancies. Cisplatin at 20 mg/m2 (4 patients), 30 mg/m2 (8 patients), and 40 mg/m2 (12 patients) was given rapidly (over 5-10 min) i.v. after prehydration with 1 liter of normal saline. After approximately two-thirds of the cisplatin dose had been delivered, microwave hyperthermia was begun and continued for 60 min; the target minimum tumor temperature was 43 degrees C. Following hyperthermia, a 400 cGy fraction of radiation was delivered to the tumor. On other days during the treatment weeks, additional 200 cGy fractions were given to total doses of 6,000-6600 cGy in patients with full radiation tolerance or 2400-3600 cGy in patients with limited radiation tolerance. The 24 patients in this trial had a median age of 57 years and the predominant sites/tumor types were head and neck/squamous cell carcinoma (9) and chest wall/breast adenocarcinoma (9). Seventeen of the 24 treated tumors (70%) had previously been irradiated. Eighteen patients (75%) had received prior chemotherapy and nine patients (38%) had previously been treated with cisplatin. Bone marrow suppression was dose limiting in patients heavily pretreated with chemotherapy and chest wall radiation. No significant toxicities were observed at the 20 and 30 mg/m2 dose levels, but 5 of the 12 patients (42%) treated at 40 mg/m2 required modification of the cisplatin dose because of blood count suppression in four patients and mild renal dysfunction in one patient. Each of the patients with bone marrow suppression, however, had been heavily pretreated except for one patient with thrombocytopenia due to hypersplenism. Nausea and vomiting were mild with use of a standard, multiagent antiemetic regimen. Twelve patients (50%) attained a complete regression (CR) and 12 patients (50%) a partial regression (PR). Complete regression appeared to correlate with small tumor volumes (115 cc for CR versus 199 cc for PR patients) and higher tumor temperatures (4.6 average minimum equivalent minutes at 43 degrees C in CR versus 2.0 min in PR patients). Local toxicities included second degree burns in 12 patients (50%) and third degree burns in 6 (25%), but all burns healed in 4-12 weeks without surgical intervention.(ABSTRACT TRUNCATED AT 400 WORDS)

Somatostatin-receptor scintigraphy of subcutaneous and thyroid metastases from bronchial carcinoid.

We present a case of bronchial carcinoid tumor with multiple metastases in the retina, subcutaneous tissues and thyroid gland. These metastatic lesions were detected by 111In-pentetreotide scintigraphy 15 yr after removal of the primary tumor. The extensive metastatic involvement documented on scintigraphy spared the patient unnecessary total thyroidectomy and directed the attention of the primary physician to previously unknown and potentially more important foci of metastatic disease.

Effect of acidic pH on radiosensitization of FSaIIC cells in vitro by misonidazole, etanidazole, or cis-diamminedichloroplatinum (II).

Because acidic regions may coexist with hypoxic regions in solid tumors, we have studied the effect of acidic extracellular pH on the abilities of misonidazole, etanidazole, and cis-diaminedichloroplatinum(II) (CDDP) to radiosensitize hypoxic FSaIIC cells in vitro. For 1-h exposures to misonidazole prior to and during irradiation, the sensitizer enhancement ratios (SERs) were 2.10 +/- 0.18 at 1 mM drug and 2.50 +/- 0.16 at 5 mM drug at pH 7.40 but only 1.90 +/- 0.14 and 2.30 +/- 0.14, respectively, at pH 6.45. For etanidazole the SERs at pH 7.40 at 1 and 5 mM drug were 1.90 +/- 0.13 and 2.40 +/- 0.18, respectively, but only 1.25 +/- 0.13 and 1.70 +/- 0.17, respectively, at pH 6.45. The decrease in the SERs for both 2-nitroimidazole compounds was statistically significant (P less than 0.01). When CDDP at concentrations of 1 and 5 microM was tested, SERs of 1.30 +/- 0.15 and 1.60 +/- 0.18, respectively, were observed at pH 7.40, and the increase was not significant at pH 6.45 (1.35 +/- 0.15 and 1.80 +/- 0.19, respectively). The cellular levels of misonidazole, etanidazole, and CDDP did not vary significantly at the environmental conditions tested. These results demonstrate that pH is a potentially important variable in the action of hypoxic cell radiosensitizing drugs and suggest that future evaluations of such agents should test the effects of pH.

Interaction of platinum complexes of thiazin and xanthene dyes with hyperthermia.

In an attempt to develop platinum-containing drugs for use with hyperthermia that would be relatively nontoxic at 37 degrees C but would become very cytotoxic at 42 degrees or 43 degrees C, several nuclear dyes were complexed to the tetrachloroplatinum(II) dianion (PtCl4) at a ratio of 2:1. The cytotoxicity of PtCl4 complexes of three thiazin dyes (thionin, azure B, and methylene blue), the xanthene dye pyronin Y, and the thiazole dye thioflavin was examined in exponentially growing euoxic and hypoxic EMT6 cells in vitro at 37 degrees, 42 degrees, and 43 degrees C and at pH 7.40 and 6.45. Of the thiazin dye complexes, the cytotoxicity of Pt(methylene blue)2 was most enhanced at hyperthermic temperatures. Both Pt(pyronin Y)2 and Pt(thioflavin)2 also became markedly more cytotoxic at 42 degrees and 43 degrees C at pH 6.45 vs pH 7.40. In vivo tumor excision assays in the FSaIIC fibrosarcoma showed that with each of the thiazin dye-platinum complexes, hyperthermia enhanced cell kill [most effectively on Pt(methylene blue)2] but was not dose-modifying. For both Pt(pyronin Y)2 and Pt(thioflavin)2, however, administration of 43 degrees C, 30-min hyperthermia to the tumor immediately after i.p. drug injection was dose-modifying. Tumor growth delay studies in the FSaIIC tumor system demonstrated that, as with the in vitro studies, Pt(pyronin Y)2 and Pt(methylene blue)2 were most enhanced by hyperthermia [tumor growth delay increased by 4.8- and 3.0-fold, respectively, vs only 1.3-fold for cisplatin (CDDP)]. Examination of intracellular platinum levels after exposure of EMT6 cells to 25 microM of drug for 1 h at 37 degrees and 42 degrees C and at pH 7.40 and 6.45 showed that each platinum-dye complex achieved platinum levels that were 100-600 times higher at 37 degrees C and pH 7.40 than those obtained using CDDP. The platinum levels for each drug dropped markedly when exposure took place at pH 6.45. Exposure at 42 degrees C only moderately increased platinum levels in cells exposed to these drugs. Thus, for several of these drugs the level of cytotoxicity observed was in great part independent of the intracellular platinum levels achieved. Pt(pyronin Y)2 is an effective drug for use with hyperthermia, and further studies using this combination with and without radiation are under way.

Adriamycin, vinblastine and mitomycin C as second-line chemotherapy in advanced breast cancer.

Thirty-six evaluable patients with metastatic measurable breast carcinoma previously treated with CMF or CMFVP were given second-line chemotherapy with Adriamycin, vinblastine, and mitomycin C (AVM), as follows: Adriamycin 20 mg/m2 and vinblastine 6 mg/m2 by i. v. push on days 1, 8, and 15, and mitomycin C 10 mg/m2 i. v. on day 1, every 6 weeks. Ten patients (28%) achieved partial remission (PR) lasting a median of 10 months, and eight patients (22%) experienced improvement of a lesser level than PR. An additional nine patients (25%) had disease stabilization; in the remaining nine patients (25%), persistent disease progression was observed. The median survival from the onset of AVM was 7 months for all patients; patients with PR survived a median of 13 months. Myelotoxicity was substantial and frequently interfered with the optimal administration of AVM, especially in patients with skeletal metastases; four patients were hospitalized with leukopenia and fever; all recovered promptly; one death was probably related to thrombocytopenia and CNS bleeding. Our results with AVM are similar to the average response rate published in the literature with the use of Adriamycin as a single agent in previously treated patients with advanced breast cancer.

Antibiotic therapy for infected Ommaya reservoir systems.

The major complication of prolonged use of a permanently implanted Ommaya reservoir system is bacterial infection, encountered in 3 to 15% of patients. The best therapeutic approach to ventriculitis and meningitis occurring in the presence of this device is still a subject of debate. We reviewed our experience in 66 consecutive patients receiving intraventricular therapy via the Ommaya reservoir for leptomeningeal metastases or for subacute sclerosing panencephalitis. Eight episodes of infection occurred during the period of treatment, and all of them responded to systemic antibiotics with or without intraventricular treatment. Removal of the Ommaya reservoir was avoided, and therapy via the device for the underlying disease was resumed as soon as the infection was controlled. No relapse of infection occurred during a minimal follow-up of 40 days. On the basis of our experience and review of the literature, we challenge the concept that the Ommaya device, as a foreign body, must be removed to treat such infections successfully.

Pain in the neck after neck dissection.

BACKGROUND: Reports of disability after neck dissection have been directed toward shoulder dysfunction and pain. We could find no report addressing the issue of pain localized to the actual operative site. We have conducted a combined prospective and retrospective study of pain in patients undergoing neck dissection. METHODS: Eighty-eight disease-free patients were evaluated in 3 groups for neck pain. One group was followed up prospectively for 1 to 8 months after surgery, and 2 retrospective groups were followed up for more than 2 years or for 6 months to 2 years. Pain was assessed by a body map and visual analog scale. RESULTS: None of 31 patients followed up for more than 2 years reported neck pain. Four of 27 patients followed up for 6 to 24 months had pain, with a mean visual analog scale score of 3.7. Seventy percent of the prospective group of 30 patients had pain during the first postoperative week, and only 1 patient had pain persisting for more than 2 months. Shoulder pain and disability after radical neck dissection were encountered in all groups, comparable with the incidence reported in the literature. No postoperative neuromas were found. CONCLUSIONS: Chronic pain localized to the operative site is an uncommon occurrence even after radical neck dissection. Chronic pain in the shoulder region may follow radical neck dissection, whereas modified neck dissection is usually a painless procedure.

Incidence of secretory otitis media following maxillectomy.

OBJECTIVE: The purpose of this investigation was to determine the incidence and characteristics of secretory otitis media after maxillectomy procedures. STUDY DESIGN: Retrospective chart analysis was performed with the cases of 49 patients who underwent maxillectomy for tumor in the Departments of Otolaryngology-Head and Neck Surgery and Oral and Maxillofacial Surgery between the years 1990 and 1996. RESULTS: In 10 patients (20%), secretory otitis media manifested itself from 1 week to 6 months after surgery; 1 patient developed a central perforation with chronic otitis media. Nearly one third of patients who underwent total maxillectomy had secretory otitis media. Six patients (8 ears) required insertion of ventilation tubes. CONCLUSIONS: Patients undergoing total and partial maxillectomies are prone to occurrences of secretory otitis media. Insertion of ventilation tubes easily resolves the problem. Preoperative and routine postoperative patient follow-up should always include otoscopy and audiometry, and tympanometry should be performed when warranted.

Ethics and the oncologist.

The physician who treats cancer patients is particularly exposed to ethical problems in his daily routine. These ethical dilemmas occur at almost every stage of the cancer patient's treatment from diagnosis through treatment to the final stages of his or her illness. Several of the ethical questions in the treatment of these patients are discussed, particularly the issues of disclosing the diagnosis of cancer to the patient, the place of mutilative surgery and other aggressive modalities in cancer treatment, and the ethics of randomized clinical trials. Awareness of these problems and open discussion will help the oncologist to treat his or her patient in the best possible way.