Brain Lymphatics: Rediscovery and New Insights into Lymphatic Involvement in Diseases of Human Brains.

The brain's lymphatic system is comprised of a glymphatic-meningeal-cervical lymphatic vessel pathway. The study of its mechanism and pathophysiology in neurodegenerative disease has been one of the most exciting topics in basic and translational neuroscience of the last decade. However, while there has been some debate about when the meningeal lymphatics were discovered, it cannot be denied that studies in preclinical models and humans in this century represent a monumental step forward in our understanding of how the brain removes metabolic waste, the role this system plays in neurodegenerative disease, and, most importantly, its potential as a novel therapeutic target. This is a summary of the history, functional anatomy, and role of the brain's lymphatics in neurodegenerative disease.

Rotational magneto-acousto-electric tomography (MAET): theory and experimental validation.

We present a novel two-dimensional (2D) MAET scanner, with a rotating object of interest and two fixed pairs of electrodes. Such an acquisition scheme, with our novel reconstruction techniques, recovers the boundaries of the regions of constant conductivity uniformly well, regardless of their orientation. We also present a general image reconstruction algorithm for the 2D MAET in a circular chamber with point-like electrodes immersed into the saline surrounding the object. An alternative linearized reconstruction procedure is developed, suitable for recovering the material interfaces (boundaries) when a non-ideal piezoelectric transducer is used for acoustic excitation. The work of the scanner and the linearized reconstruction algorithm is demonstrated using several phantoms made of high-contrast materials and a biological sample.

Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma.

A data base study of 610 patients with recurrent or metastatic renal cell carcinoma was conducted in order to identify clinical characteristics that are prognostic for survival in patients with this disease. Multivariate analysis identified initial Eastern Cooperative Oncology Group performance status (0 versus 1 versus 2 versus 3), time from initial diagnosis (greater than 1 year versus less than or equal to 1 year), number of metastatic sites (0,1 versus greater than 1), prior cytotoxic chemotherapy (no versus yes), and recent weight loss (no versus yes) as important indicators of survival. Closer examination of the resulting model indicated that patients can easily be separated into five prognostic subgroups, the subgroups being defined by a simple function of the number of risk factors present [Eastern Cooperative Oncology Group performance status 1, recent diagnosis (less than or equal to 1 year), greater than 1 metastatic site, recent weight loss, and prior cytotoxic chemotherapy each counting as a single risk factor; and Eastern Cooperative Oncology Group performance status 2 and 3 counting as 2 and 3 risk factors, respectively]. Median survival for each of the five risk groups was 12.8, 7.7, 5.3, 3.4, and 2.1 months, respectively.

Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma.

PURPOSE: Alkylating agents have modest activity in advanced urothelial carcinoma. Ifosfamide (IFX) is an agent as yet unstudied in advanced urothelial carcinoma. Despite recent advances in the treatment of this disease, there continues to be a need to identify new active agents and their toxicity spectra. Here we report results from the use of IFX in this population. PATIENTS AND METHODS: Ambulatory patients with advanced urothelial carcinoma were treated with IFX 3,750 mg/m2 and mesna 2250 mg/m2 both intravenously (IV) daily for 2 days every 3 weeks. Significant renal and CNS toxicity required a dose change of IFX to 1,500 mg/m2 IV with mesna 750 mg/m2 IV for 5 days every 3 weeks. Doses were modified for hematologic, renal, and CNS toxicity. RESULTS: Of 56 eligible patients entered onto the study, 26 received the 2-day schedule and 30 were treated on the 5-day regimen. All patients had progressive disease following prior systemic chemotherapy. There were five complete responses (CRs) and six partial responses (PRs) for an overall response rate of 20% (exact 95% confidence interval [CI], 10% to 32%). Renal and CNS toxicity was severe before the change in schedule, but manageable after the change. Major identified toxicities were gastrointestinal, myelosuppressive, renal, and CNS. There were four early deaths to which treatment probably contributed, but were multifactorial in etiology. CONCLUSION: IFX has significant activity, but also major toxicity in a heavily cisplatin-pretreated cohort with advanced urothelial carcinoma. A modification of dose and/or schedule from that described should be considered in future trials. Combination regimens using this agent should be explored.

Clodronate. A randomized study in the treatment of cancer-related hypercalcemia.

Malignancy-associated hypercalcemia is a common and recalcitrant problem. Current modes of therapy are often ineffective or prohibitively toxic. Clodronate disodium is a diphosphonate capable of inhibiting bone resorption resulting in a hypocalcemic effect. In this randomized, placebo-controlled study, we investigated the effect of hydration only (Rx-1) vs the effect of hydration plus either intravenously administered clodronate disodium, 4 mg/kg of body weight per day for three days (Rx-2) or intravenously administered clodronate disodium, 12 mg/kg of body weight given once only (Rx-3). By the third day of observation, Rx-2 produced a significant 2.8 mg/dL (0.70 mmol/L) reduction in serum calcium levels, whereas Rx-1 and Rx-3 did not produce a significant hypocalcemic effect when compared with baseline values. There were no toxicities observed. Intravenously administered clodronate appears to be an excellent agent for the acute treatment of malignancy-associated hypercalcemia.

Maintenance etidronate in the prevention of malignancy-associated hypercalcemia.

Normocalcemic patients with cancer who had been successfully treated for an episode of hypercalcemia were enrolled in a randomized, multisite, double-blind, placebo-controlled trial designed to determine the efficacy of maintenance oral etidronate in preventing the recurrence of moderate to severe hypercalcemia (serum calcium level, greater than 11.5 mg/dL [greater than 2.87 mmol/L]). Ten (40%) of 25 etidronate-treated patients and 17 (46%) of 37 placebo-treated patients had recurrence of hypercalcemia within 150 days. Although patients taking etidronate had a longer time to the development of hypercalcemia (median, 55 days vs 28 days), this was not significantly different from the control group. The high attrition rate in this trial from hypercalcemia and other malignancy-related causes represents a major difficulty in conducting studies with agents that may require prolonged administration before producing a therapeutic effect.

A phase II trial of melphalan or thioguanine in the treatment of patients with advanced renal cell cancer.

Sixty-one ambulatory patients with advanced or unresectable renal carcinoma were treated with either melphalan (41 patients) or thioguanine (20 patients). Two objective partial responses were observed in the melphalan cohorts for a response rate of 4.9% (exact 95% confidence interval, 1-17%). No patients treated with thioguanine responded. One patient died of hemorrhage on the melphalan arm. There were no treatment-related deaths on the thioguanine arm. Other than the one death, there were no unexpected or irreversible toxicities. Myelosuppression was the most frequent toxicity. These agents have no meaningful activity in the treatment of advanced renal cell carcinoma.

Four-dimensional ultrasound current source density imaging of a dipole field.

Ultrasound current source density imaging (UCSDI) potentially transforms conventional electrical mapping of excitable organs, such as the brain and heart. For this study, we demonstrate volume imaging of a time-varying current field by scanning a focused ultrasound beam and detecting the acoustoelectric (AE) interaction signal. A pair of electrodes produced an alternating current distribution in a special imaging chamber filled with a 0.9% NaCl solution. A pulsed 1 MHz ultrasound beam was scanned near the source and sink, while the AE signal was detected on remote recording electrodes, resulting in time-lapsed volume movies of the alternating current distribution.

Thrombocytopenia and pancreatic carcinoma.

More and more physicians are finding increasing evidence of carcinoma-related immune-mediated platelet destruction. Such is the case of the patient with carcinoma of the exocrine pancreas associated with profound thrombocytopenia that follows. The patient died before studies could be completed. However, well-recognized causes of drug reactions, DIC, chemotherapy and marrow infiltration were able to be excluded. Although anti-platelet antibodies weren't isolated in the serum, the patient's response to steroids and its similarity to other cases with evidence of carcinoma-related immune-mediated platelet destruction makes this process most likely in the case presented.

Acute tumor lysis syndrome with choriocarcinoma.

A 52-year-old man with retroperitoneal nodal, lung, and liver metastases from choriocarcinoma received chemotherapy with etoposide, cisplatin, and bleomycin. Within 48 hours of starting treatment, he had hypotension, hypoxemia, and anuria. Laboratory values showed hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and metabolic acidosis. He was placed on mechanical ventilation, and hemodialysis was instituted, with marked improvement in renal function. A second, shortened course of chemotherapy with carboplatin and etoposide was given 21 days later. However, on hospital day 48, the patient died of progressive pulmonary insufficiency and cardiac arrest. This represents the first reported case of acute tumor lysis syndrome after systemic chemotherapy for advanced nonseminomatous germ cell cancer.

Trimetrexate in advanced hormone-refractory prostate cancer. An ECOG phase II trial.

The antitumor activity and toxicity of trimetrexate (TMTX) was evaluated in measurable, hormone-refractory, advanced prostate cancer patients. Patients were required to have an ECOG performance status < 3, bidimensionally measurable disease, serum creatinine < or = 1.5 mg/dL, normal bone marrow function, and adequate hepatic function. Prior non-hormonal systemic therapy, active infection, third space effusions were exclusion criteria. TMTX 12 mg/m2 daily for five days (8 mg/m2 for patients with any prior radiation therapy or age > or = 75 years) was administered every 3 weeks. There were no responses in the 18 eligible patients. Median time to treatment failure and median survival were 6 and 20 weeks, respectively. Myelosuppression was the most frequent toxicity observed and was mild to severe in all but 4 patients. Two patients whom experienced life-threatening reversible leukopenia and grade 4 thrombocytopenia developed in 2 further patients. Non-hematologic toxicity was also reversible and was mild to severe. TMTX at this dose and schedule is inactive in advanced, hormone-refractory prostate cancer.

Trimetrexate in advanced renal cell carcinoma. An ECOG phase II trial.

Thirty-four chemotherapy-naive, ambulatory patients with advanced renal cell cancer were treated with the non-classical antifol trimetrexate at the intravenous dose of 12 mg/m2 daily x 5 every three weeks (8 mg/m2 qd x 5 for greater than 30% bone marrow previously irradiated). One patient experienced a partial response lasting 24 weeks for a response rate of 3% (exact 95% CI, 0.1 to 15.3%). Toxicity was manageable and primarily myelosuppression, gastrointestinal, and mucosal. Trimetrexate has little activity in advanced renal cell carcinoma at this dose and schedule.

A phase II trial of amonafide, caracemide, and homoharringtonine in the treatment of patients with advanced renal cell cancer.

Forty-eight previously untreated, ambulatory patients with advanced or unresectable renal carcinoma were treated with either amonafide (17 patients), caracemide (17 patients), or homoharringtonine (14 patients). No objective responses were observed in any of the treatment cohorts. Amonafide and caracemide were well tolerated with no unexpected toxicities. One patient each died of pulmonary thromboembolism and sepsis with severe metabolic acidosis on the homoharringtonine arm. An additional 4 patients experienced grade 4 complications including myelosuppression, neurologic dysfunction, and respiratory failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced renal cell carcinoma.

An Eastern Cooperative Oncology Group phase II trial of trimetrexate in the treatment of advanced urothelial carcinoma.

BACKGROUND: Trimetrexate is an antifol that differs from methotrexate in ways that may be clinically important. Because methotrexate has activity in advanced bladder cancer, this trial was initiated. METHODS: Ambulatory patients with advanced urothelial carcinoma were treated with the nonclassic antifol trimetrexate at the intravenous dose of 8 mg/m2 daily for 5 consecutive days every 3 weeks (4 mg/m2 daily for 5 consecutive days for patients with creatinine levels greater than 1.6 mg/dl). RESULTS: Of the 48 patients in the study, one had a complete response and seven had partial responses, for an overall response rate of 17% (exact 95% confidence interval, 7-30%). The response rate in patients who had received prior methotrexate was 18%, suggesting lack of complete cross-resistance. Toxicity was manageable and primarily mucosal, gastrointestinal, and myelosuppressive. CONCLUSIONS: Trimetrexate has as much activity as other single agents in advanced urothelial carcinoma. Combination therapy, possibly with cisplatin, platinum analogs, or other antifols, using trimetrexate should be studied.

Topotecan in previously treated advanced urothelial carcinoma: an ECOG phase II trial.

BACKGROUND: [corrected] Chemotherapeutic agents are playing an increasing role in the management of urothelial carcinoma. Despite recent advances in the treatment of this disease there continues to be a need to identify new active agents and their toxicity spectra. Topotecan is an agent as yet unstudied in bladder cancer. METHODS: Ambulatory patients with progressive advanced urothelial carcinoma following prior systemic chemotherapy were treated with topotecan 1.5 mg/m2 intravenously (i.v.) daily for 5 days every three weeks for 6 cycles. Doses were modified for leukopenic fever, thrombocytopenic bleeding, and any grade 3 or 4 (NCI common toxicity criteria) toxicity. RESULTS: Forty-four eligible patients entered the trial. There were 4 partial responses for an overall response rate of 9.1% (exact 95% two-stage binomial CI, 2.9% to 25.5%). Major identified toxicities were gastrointestinal and myelosuppression. There were no treatment-related deaths. CONCLUSIONS: Topotecan at this dose and schedule has minimal activity in previously treated patients with advanced urothelial carcinoma. Toxicities can be severe but are manageable.

Comparison of 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma.

BACKGROUND: The authors conducted a randomized Phase III trial of three treatment regimens for patients with residual, nonmeasurable, intra-abdominal metastatic disease after undergoing resection for primary colorectal carcinoma. METHODS: To be eligible for this study, patients had to be both free of other malignancies and capable of starting their therapy within 3-6 weeks after surgery. They were required to have an Eastern Cooperative Oncology Group performance status < 3; to be chemotherapy, radiation, and immunotherapy naïve; to have adequate bone marrow, renal, and hepatic function; and to provide written, informed consent. The patients were divided into two cohorts: patients with no demonstrable hepatic metastasis (Group A) and patients with hepatic metastasis (Group B). RESULTS: The 229 patients in Group A were randomized to receive either 5-fluorouracil (5-FU) (n = 116 patients) or 5-FU with levamisole (n = 113 patients). The median survival (15.4 months and 15.3 months, respectively, for Groups A and B) was virtually identical. The two groups also were similar in terms of time to treatment progression, which was 7.9 months for group that received 5-FU alone 7.7 months for the group that received levamisole with 5-FU. The 168 patients in Group B with hepatic metastasis underwent a three-way randomization: 5-FU alone (n = 60 patients), 5-FU with levamisole (n = 54 patients), and 5-FU with hepatic irradiation (n = 54 patients). The median overall survival for the three treatment arms were similar, with 17.3 months for the group that received 5-FU alone, 16 months for the group that received 5-FU with levamisole, and 14.4 months for the group that received hepatic irradiation in addition to 5-FU: The time to treatment failure was 6.7 months, 6.8 months, and 8.3 months, respectively, for the three groups. The toxicity experienced by patients was as expected with the regimens, and no differences were observed between any of the treatment groups. The primary toxicities were hematologic and gastrointestinal. There was one treatment-related death due to adult respiratory distress syndrome, which occurred on the first day of the fourth cycle of 5-FU and levamisole. Other Grade 4 toxicities included nine patients with Grade 4 leukopenia, one patient with Grade 4 sepsis, and one patient with Grade 4 gastrointestinal toxicity, including blood loss and diarrhea. CONCLUSIONS: This study showed no treatment advantage for any of the combined modalities over 5-FU alone in this group of patients with intra-abdominal, nonmeasurable disease.

PALA versus streptozotocin, doxorubicin, and MeCCNU in the treatment of patients with advanced pancreatic carcinoma.

Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were allocated to one of two treatment regimens: 35 received PALA (1250 mg/m2 daily x 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m2 i.v. daily x 5, doxorubicin 45 mg/m2 i.v. on day 1 and 22, and methyl CCNU 60 mg/m2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer.

A phase I/II investigation of trioxifene mesylate in advanced breast cancer. Clinical and endocrinologic effects.

Tamoxifen and trioxifene are antiestrogens that appear to have different endocrine effects when tested in rats. Whereas tamoxifen has considerable clinical activity, trioxifene is a new antiestrogen with undefined clinical activity. Thirty-six patients were treated with graded doses of trioxifene. The low-dose group (0.5 to 12 mg/m2 twice daily) had a 21% response rate in 24 subjects, and the high-dose group (40 to 100 mg/m2 twice daily) had a 33% response rate in 12 patients (P = 0.13). The time to treatment failure was 67 days and 178 days for the low- and high-dose groups, respectively. Toxicities were non-dose dependent; those of moderate frequency included leukopenia (41%) and nausea (31%). Tamoxifen reduced both prolactin and inducible growth hormone (GH). Trioxifene, although reducing prolactin, differed from tamoxifen in that an increase in inducible GH occurred. Furthermore, a striking dose-dependent decrease in luteinizing hormone and lesser decrease in follicle-stimulating hormone occurred only in the trioxifene-treated patients. This implies an intrinsic estrogenic action of trioxifene in man. Trioxifene is no more efficacious than tamoxifen and has more toxicity.

Phase I study of vinblastine and verapamil given by concurrent iv infusion.

Overcoming resistance to chemotherapy is an important goal in cancer treatment. In many systems, resistance to anthracyclines and vinca alkaloids correlates with a diminished intracellular content of drug. In P388 leukemia and Ehrlich ascites tumor, an active outward transport of anthracyclines and vinca alkaloids occurs. Calcium channel blockers, such as verapamil, inhibit this active outward transport and increase intracellular content of vinblastine and anthracyclines in cells resistant to vinca alkaloids and anthracyclines, respectively. We report a phase I trial of vinblastine (1.5 mg/m2 daily as iv continuous infusion X 5 days) in 17 patients and concurrent verapamil in escalating doses. Verapamil was administered as a loading dose (0.02-0.1 mg/kg) followed by a maintenance infusion (0.036-0.18 mg/kg/hour) for 5 1/2 days with continuous cardiac monitoring. There was no apparent augmentation of vinblastine toxicity when vinblastine and verapamil were given concurrently. ECG change was the dose-limiting toxicity. At 0.12 mg/kg/hour, five of nine patients developed first-degree heart block (mean P-R interval, 0.32 seconds; range, 0.23-0.52 seconds). Junctional rhythms were noted in two of 17 patients. Reversible nonspecific T-wave changes were seen in four of 17 patients. Blood pressure and left ventricular ejection fractions (ultrasonic) were not altered. Five of 17 patients had wbc count nadirs less than 2000/mm3, and two of 17 patients had platelet count nadirs less than 100,000/mm3. Four patients experienced neurotoxicity. A mean vinblastine concentration of 2.2 ng/ml (0.55 nM) and a mean verapamil concentration of 290 ng/ml (0.45 microM) were achieved with the concurrent 5-day infusion. The tolerable levels of verapamil obtained appear to be less than those which were reported to inhibit vinblastine efflux in vitro. Additional in vitro experiments at the tolerable doses of vinblastine and verapamil are recommended.

A phase II study of interleukin-2 with and without beta-interferon in the treatment of advanced renal cell carcinoma.

BACKGROUND: Biologic response modifiers have activity in renal cell carcinoma. The combination of interleukin-2 (IL-2) and beta-interferon (B-IFN) is synergistic in vitro. This trial was initiated to determine the efficacy of IL-2 alone and with B-IFN in advanced RCC. METHODS: Ambulatory patients with advanced RCC were randomly allocated to either IL-2 6 x 10(6) units/M2 intravenously (IV) three days a week for four weeks or IL-2 5 x 10(6) units/M2 IV plus B-IFN 6 x 10(6) units/M2 IV three days a week for 4 weeks. This induction phase was followed by a maintenance phase of the same drugs and doses administered for two weeks out of every four. RESULTS: 84 patients were entered onto this phase II trial with 75 considered eligible for response and survival. Toxicity is reported for the 81 patients on whom data was received, irrespective of eligibility. The overall response rate (RR) was 9.3% (7/75). Of the 3 responses in the IL-2 arm (RR = 8.3%), one was a complete response. 4 patients in the IL-2 + B-IFN arm (RR = 10.3%) achieved a partial response. Median survival was estimated to be 8.4 months for patients given IL-2 and 8.0 months for patients given the IL-2 and B-IFN combination. Multivariate analysis of survival data identified initial performance status, metastases of > 1 site, and weight loss as being important prognostic factors for survival. There were 2 lethal and 3 life threatening toxicities with the IL-2 treatment. While there were no lethal toxicities on the combination arm, there were 4 life threatening toxicities. CONCLUSIONS: The results of this study indicate that further investigation of IL-2 with or without B-IFN at this dose and schedule as treatments for renal cell carcinoma is probably not warranted.