Hydrodynamics of the fast-start caridoid escape response in Antarctic krill, Euphausia superba.

Krill are shrimp-like crustaceans with a high degree of mobility and variety of documented swimming behaviors. The caridoid escape response, a fast-start mechanism unique to crustaceans, occurs when the animal performs a series of rapid abdominal flexions and tail flipping that results in powerful backward strokes. The current results quantify the animal kinematics and three-dimensional flow field around a free-swimming Euphausia superba as it performs the caridoid escape maneuver. The specimen performs a single abdominal flexion-tail flip combination that leads to an acceleration over a 42 ms interval allowing it to reach a maximum speed of 57.0 cm/s (17.3 body lengths/s). The krill's tail flipping during the abdominal closure is a significant contributor to the thrust generation during the maneuver. The krill sheds a complex chain of vortex rings in its wake due to the viscous flow effects while the organism accelerates. The vortex ring structure reveals a strong suction flow in the wake, which suggests that the pressure distribution and form drag play a role in the force balance for this maneuver. Antarctic krill typically swim in a low to intermediate Reynolds number (Re) regime where viscous forces are significant, but as shown by this analysis, its high maneuverability allows it to quickly change its body angle and swimming speed.

Stewart-Bluefarb syndrome: Report of five cases and a review of literature.

Stewart-Bluefarb syndrome is a rare angioproliferative disorder characterised by acroangiodermatitis associated with an underlying arteriovenous shunt. This condition should be differentiated from acroangiodermatitis of Mali classically described in association with chronic venous insufficiency. Patients with Stewart-Bluefarb syndrome typically present with lower leg pigmented macules, papules and plaques that can coalesce to form larger confluent patches of pigmentation. Recognition of Stewart-Bluefarb syndrome may be difficult or delayed as the cutaneous manifestations may resemble a variety of other dermatological conditions. Most commonly, acroangiodermatitis may be confused with Kaposi's sarcoma and the condition is often referred to as 'Pseudo-Kaposi's sarcoma'. Acroangiodermatitis may also resemble or coexist with pigmentation of chronic venous insufficiency. As seen in this report, acroangiodermatitis may also be clinically confused with the 'cavernous' form of a capillary malformation. Here, we describe five patients with Stewart-Bluefarb syndrome. In one female and two male patients the diagnosis was delayed as the acroangiodermatitis closely resembled other conditions. All underlying arterio-venous communications were initially diagnosed on duplex ultrasound and confirmed with magnetic resonance angiography. Four patients were found to have a congenital arterio-venous malformation while one was diagnosed with a post-thrombotic arterio-venous fistula. Management included observation and intervention using a variety of techniques including percutaneous or trans-catheter embolisation, endovenous laser, radiofrequency ablation and foam ultrasound guided sclerotherapy. This case series highlights the challenges involved in the diagnosis and management of Stewart-Bluefarb syndrome. Given the local and systemic sequelae of high flow shunts, correct diagnosis and early detection of the underlying arterio-venous abnormality is crucial in the long-term management of these patients and in preventing the associated complications.

Short-term autologous tumor cell lines for the active specific immunotherapy of patients with metastatic melanoma.

We established short-term cell lines for 108/170 (64%) patients with metastatic melanoma. Tumor cell numbers were expanded to 10(8), then cells were irradiated, aliquoted, and cryopreserved for clinical use. Vaccines have been used to treat 69 patients with clinical follow up for 33 who had measurable metastatic disease at the time vaccine therapy was initiated (METS), and 33 who had no evidence of disease (NED) at the time of vaccine therapy following surgical resection of metastases. The protocol called for a baseline test of delayed tumor hypersensitivity (DTH), three weekly injections, a repeat of the DTH test, then monthly injections for an additional 5 months. Objective tumor responses were noted in 3/26 (12%) patients who received a minimum of three vaccinations, one complete, and two partial, with survivals of 36, 46+, and 78+ months. Only 6/64 (9.4%) had a positive DTH (>10 mm) at baseline, including three METS, all of whom progressed within 4 months and died within a year, and three who are still NED after more than 5 years. Conversion of DTH from negative to positive was documented in 18/44 (41%) patients who were tested at week 0 and 4. At a median follow up of greater than 5 years, the median overall survival (OS) was 40 months for "NED" with a 5-year survival rate of 39%, and 8.6 months with a 5-year survival rate of 10% for "METS" The 18 patients who had conversion of their DTH had a median event-free survival (EFS) of 15.8 months and 5-year EFS of 32% compared to 4.2 months and 9% for the 26 non-converters (P=0.012, two-tailed, log-rank test). Among patients who were NED when treatment started, the 12 patients whose DTH converted had a median overall survival of 61.4 months with 5-year survival of 63% compared to 9.7 months and 0% for the 13 non-converters (P=0.0026). This treatment approach is feasible, produces minimal toxicity, and is associated with long-term survival in a significant subset of patients.

Treatment of kidney cancer with autologous tumor cell vaccines of short-term cell lines derived from renal cell carcinoma.

BACKGROUND: We established short-term cultures of autologous tumors from patients with renal carcinoma for use as active specific immunotherapy (i.e., autologous vaccine). METHODS: Between 9/91 and 9/99 the cell biology laboratory of the Hoag Cancer Center received 69 kidney tumor samples that had been surgically excised, including 43 primary tumors and 26 metastatic lesions. Efforts were made to establish short-term tumor cell cultures to use as autologous tumor cell vaccines. Prior to treatment, patients underwent a baseline skin test for delayed tumor hypersensitivity (DTH) and then received s.c. injections of 10 million irradiated tumor cells that were given with various adjuvants weekly x3 and then monthly x5. RESULTS: Cell lines were established for 55/69 patients (80%) including 36/43 (84%) from primary tumors and 19/26 (73%) from distant metastases. Vaccines were prepared for 41 patients; 27 were treated. At the time of this analysis, follow up data was available for 26 patients with a median follow up > 5 years. Treatment was well-tolerated. Of 10 patients who had no evident disease at the time of treatment, nine were alive 1-8 years later; 5/8 had conversion of their DTH test from negative to positive. For 16 patients with measurable metastatic disease at the time of treatment, there were no objective tumor responses; their median survival was 5.0 months. Among these 16 patients, only 1/8 DTH tests converted, but three had a positive baseline DTH test; one was previously treated with interleukin-2 and tumor infiltrating lymphocytes and two others were previously treated with autolymphocyte therapy. CONCLUSIONS: Vaccine therapy with short-term cultures of autologous tumor cells is feasible, well-tolerated and associated with conversion of DTH and long-term survival in patients who are free of disease at the time treatment is initiated. However, significant anti-tumor responses were not seen in patients with measurable disease at the time vaccine treatment was initiated.

Tumor localization by tumor infiltrating lymphocytes labeled with indium-111 in patients with metastatic renal cell carcinoma, melanoma, and colorectal cancer.

BACKGROUND: Adoptive immunotherapy with autologous tumor infiltrating lymphocytes (TIL) is a promising approach for cancer bio-therapy. One issue, however, is whether such cells actually migrate to sites of tumor after intravenous infusion. There have been several reports of tumor uptake of radiolabeled TIL in patients with metastatic melanoma, but efforts to visualize tumor with radiolabeled TIL in other tumor types reportedly have been unsuccessful. METHODS: Eight patients with metastatic cancer (5 renal, 2 melanoma, 1 colon) received an intravenous infusion of 2 to 100 billion autologous TIL, including 50 million TIL which had been conjugated to 500 microCi Indium-111, co-administered with interleukin-2 (IL-2). One patient received 1 gm/m2 of cyclophosphamide one day prior to TIL; seven patients received interferon alpha 2b for 4 days prior to receiving TIL. Total body gamma camera imaging, including single photon emission computerized tomography (SPECT), was performed at 24 and 48 hours. RESULTS: All eight patients had demonstrable uptake of 111-Indium-labeled TIL into one or more known sites of tumor. There were no known sites of tumor which were not imaged. Metastatic sites imaged included bone, brain, mediastinal and perihilar lymph nodes, lung and liver parenchyma, abdominal periaortic nodes, and a pelvic mass. One patient served as a negative control in that the TIL scan was negative at a time when she had no evident disease, but a few weeks later had a positive TIL scan which lead to a diagnosis of axillary recurrence. CONCLUSION: Uptake of radiolabeled TIL, whether CD8+ or CD4+, by metastatic renal cell carcinoma and other carcinomas was similar to that previously reported in melanoma. Pretreatment with cyclophosphamide was not a prerequisite for imaging, and TIL uptake did not predict tumor response.

Clinical experience with autologous tumor cell lines for patient-specific vaccine therapy in metastatic melanoma.

Because of their patient specificity and proliferative capacity, tumor cell lines established from autologous metastatic melanoma tumor samples may be an excellent immunogen for patient-specific vaccine therapy. Between October 1990 and July 1996, the Hoag Cancer Center cell biology laboratory received 136 fresh metastatic melanoma samples from 122 different patients. Tumor cell lines were successfully established for 92 of 136 samples (68%), for 87 of 122 patients (71%). Successful cultures were expanded to 10(8) cells (total culture time about 8 weeks), confirmed to be sterile, irradiated, and stored frozen in aliquots of 10(7) cells. Vaccines were prepared from 72 lines, and 62 vaccines were used in 57 different patients. Subcutaneous vaccination took place on weeks 1, 2 and 3, and then monthly for a total of 6 months. A delayed tumor hypersensitivity skin test (DTH) was administered at week zero and week 4. Various adjuvants were co-administered including BCG, alpha- or gamma-interferon, and GM-CSF. Patients were monitored for failure-free survival (FFS) and overall survival (OS) from the date of the first vaccination. Follow-up data is available for 52 patients, 27 who had no evident disease (NED) at the time of vaccination and 25 who had metastatic disease at the time of treatment. There were two partial responses which persisted 11.9 and 39.8+ months among the 25 patients who had detectable metastatic disease whün treatment was initiated (8%, 1 to 26%, 95%-Ci). Twenty patients had negative skin tests at week 0 and week 4; six were positive both times, and 13 converted their DTH from negative to positive, for a conversion rate of 13 of 33 (39%). Patients who received interferon-gamma and/or GM-CSF as an adjuvant had a higher rate of DTH conversion compared to patients who received other adjuvants (13 of 20 v 2 of 13, P = 0.003). For patients who were NED, nine of 19 (47%) converted their DTH test compared to four of 14 (29%) patients with metastatic disease (p = 0.33). For patients whose DTH converted from negative to positive after 3 weeks of vaccination, median FFS and OS were superior compared to patients whose DTH remained negative (19.4 v 4.0 months FFS, p = 0.0052 and 39.6 v 18.3 months OS, p = 0.0602). The autologous cell line approach to active specific immunotherapy is feasible for patients who have resectable foci of metastatic disease. Administration of such patient-specific vaccines improves survival for those patients who are NED at the time of vaccination and convert their DTH skin test, compared to those whose DTH test remains negative.