Biomedical subjects
Publications and source records attributed to M R Pfeffer.
A prospective analysis of olfaction was performed in 21 patients receiving cisplatin. A reduction in olfactory function was noted in only one patient. Hearing impairment was documented in nine patients, none of whom had impaired sense of smell. We conclude that cisplatin has no major deleterious effect on olfactory function at doses which cause hearing impairment.
BACKGROUND: This prospective trial examined the feasibility, toxicity, and effectiveness of early locoregional radiotherapy after high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk American Joint Committee on Cancer (AJCC) Stage II-III and locally advanced breast carcinoma. METHODS: One hundred forty-seven consecutive patients with high-risk and locally advanced breast carcinoma were included in the current study. All patients received induction chemotherapy with a doxorubicin-based therapy, which was consolidated with high-dose cyclophosphamide, carboplatin, and thiotepa followed by autologous stem cell support. Within 50 days of the transplant, the patients were treated with locoregional radiotherapy that included the chest wall or breast, the axilla and supraclavicular area, and the internal mammary chain. The volume of lung included in the treatment volume was kept to a minimum. The central lung distance of the tangential fields ranged from 0.6-2.0 cm (mean, 1.1 cm). Tamoxifen was given based on receptor status. RESULTS: One hundred forty-six of 147 patients received the planned treatment. Only six patients had a delay in the initiation of radiotherapy, and another 16 patients had delays during radiotherapy. Leukocyte and platelet toxicities during radiotherapy were not life-threatening and blood counts thereafter returned to normal. Grade 2 (according to National Cancer Institute Common Toxicity Criteria) skin toxicity occurred in 22% of patients and Grade 3 skin toxicity occurred in 6% of patients. Radiation pneumonitis was reported to occur in 5 patients (< 4%). After a median follow-up of 36 months from diagnosis (range, 6-64 months), there were no long-term organ toxicity and no secondary malignancy reported. No treatment-related deaths were reported. Three patients (< 3%) developed locoregional recurrence. CONCLUSIONS: Locoregional radiotherapy after high-dose chemotherapy and autologous stem cell transplantation appears to be feasible and can be delivered safely within 10 weeks of transplantation. The short-term and long-term toxicity are reported to be low, with good local control.
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.
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.
BACKGROUND: Pain is one of the most feared consequences of cancer and is experienced by up to 80% of patients with head and neck carcinoma (HNC). Pain in terminal HNC patients is common and often defined as severe. This study evaluated the effectiveness of the World Health Organization (WHO) analgesic ladder in the treatment of a cohort of terminal HNC patients. METHODS: The authors prospectively evaluated 62 consecutive terminal HNC patients admitted to the Chaim Sheba Medical Center Tel Hashomer Hospice or the general hospital. Data pertaining to tumor origin, spread, treatment, and results were defined. Pain was assessed with the McGill Pain Questionnaire, using a 10-point visual analogue scale (VAS) and a body map. Pain was diagnosed according to cause and type. Treatment was selected according to the guidelines provided in the WHO analgesic ladder. RESULTS: Only 10 patients suffered from pain that was not locoregional. The results of the VAS score were available in the first reading in all patients with pain (n = 48), with a mean of 4.7 (standard deviation [SD] +/- 2.0). A mean second VAS score obtained 72 hours after the first was 1.9 (SD +/- 1.1). The difference between the two scores was statistically significant (P < 0.001). A third score was available for only 6 patients, with a mean of 1.6. Only 2 patients did not experience improvement of pain after 72 hours of treatment; both of these patients had bony involvement with tumor. Thirty-one patients (65%) were diagnosed with pain of nociceptive origin; these patients were categorized as having actual nociceptive pain (22), nociceptive nerve pain (6), or referred pain to the ear (3). Nonnociceptive pain of neuropathic origin was noted for only 6 patients (12.5%). Pain that could not be well defined but was responsive to opioid analgesic treatment was noted for 11 patients. A different form of non-cancer-related pain was noted for only one patient. CONCLUSIONS: Patients were treated for pain according to the WHO analgesic ladder. They received adequate narcotic analgesics and supportive measures that allowed significant reduction of pain in nearly all cases, with acceptable side effects.
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.
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.
Explore the source record for details and available documents.
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.
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.
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.
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.
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.
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.
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.
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).
The potential beneficial effects of partial lung shielding were investigated in 44 patients conditioned by whole body radiotherapy as part of the conditioning for bone marrow transplantation (BMT). The first 23 patients were irradiated with fractionated total body irradiation (TBI) to a total dose of 12 Gy. In the second series of 21 patients a 50% transmission lung shield was utilized following 6 Gy TBI. This treatment was combined in the second group with four fractions of 1.5 Gy total lymphoid irradiation (TLI), given in 2 d. The rate of idiopathic interstitial pneumonitis (IP) was 26% in the first group, compared to none in the second.