Effect of longitudinal-bending elliptical ultrasonic vibration assistance on electrosurgical cutting and hemostasis.

Electrosurgical devices are widely used for tissue cutting and hemostasis in minimally invasive surgery (MIS) for their high precision and low trauma. However, tissue adhesion and the resulting thermal injury can cause infection and impede the wound-healing process. This paper proposes a longitudinal-bending elliptical ultrasonic vibration-assisted (EUV-A) electrosurgical cutting system that incorporates an ultrasonic vibration in the direction of the cut by introducing an elliptical motion of the surgical tip. Compared with a solely longitudinal ultrasonic vibration-assisted (UV-A) electrosurgical device, the EUV-A electrode contacts the tissue intermittently, thus allowing for a cooler cut and preventing tissue accumulation. The experimental results reveal that the EUV-A electrode demonstrates better performance than the UV-A electrode for both anti-adhesion and thermal injury through in vitro experiments in porcine samples. The tissue removal mechanism of EUV-A electrosurgical cutting is modeled to investigate its anti-adhesion effect. In addition, lower adhesion, lower temperature, and faster cutting are demonstrated through in vivo experiments in rabbit samples. Results show that the EUV-A electrode causes lower thermal injury, indicative of faster postoperative healing. Finally, efficacy of the hemostatic effect of the EUV-A electrode is demonstrated in vivo for vessels up to 3.5 mm (equivalent to that of electrocautery). The study reveals that the EUV-A electrosurgical cutting system can achieve safe tissue incision and hemostasis.

A longitudinal-torsional mode ultrasonic needle for deep penetration into bone.

This work presents a longitudinal-torsional (L-T) composite mode ultrasonic needle device for deep bone penetration. The L-T needle is a geometrically modified version of an L-mode needle whose efficacy as a prototype ultrasonic bone biopsy device has been previously demonstrated by the authors. Finite element analysis (FEA) aided in the design of the L-T needle, with the aim of maximising the achievable torsional displacement while matching the longitudinal displacement achieved by the L-mode needle. Experimental modal analysis (EMA) of the fabricated ultrasonic device was used to identify the modal parameters and validate the FEA model. Harmonic analysis then provided an insight into how the inherent nonlinearities of the high-power transducer are affected by incorporating the geometrical features that degenerate the L mode into an L-T mode. High power characterisation shows that the longitudinal displacement amplitude of the L-T mode needle is larger than that of the L-mode needle. Comparative penetration tests in fresh Wistar rat skull were evaluated by investigating cell death and cell survival. The region of statistically significant cell death was small for both devices, with the combined axial and shear motion of the L-T device causing increased osteocyte necrosis within this region. Nevertheless, the results suggest a promising environment for post-operative healing. It is shown how this technology offers a potential technique for a surgical approach to the petrous apex, an application that requires a deep penetration into bone.

Limits and Opportunities for Miniaturizing Ultrasonic Surgical Devices Based on a Langevin Transducer.

Minimally invasive surgery offers opportunities for reduced morbidities, faster postoperative recovery, and reduced costs, and is a major focus of surgical device innovation. For ultrasonic surgical devices, which offer benefits of high precision, low force, and tissue selectivity in surgical procedures, there exist laparoscopic ultrasonic shears for minimally invasive surgeries that combine tissue cutting with vessel hemostasis and sealing functions. Another approach to laparoscopy that could enable new procedures, and increase the sites of surgeries that could be reached by an ultrasonic device, involves integrating a miniature ultrasonic tool with a flexible surgical robot. However, miniaturization presents challenges in delivering the ultrasonic vibrational energy required to cut hard and soft tissues, partly due to the concomitant small volume of piezoelectric material. This article aims to provide insights into the trade-offs between transducer size, volume of piezoceramic material, resonance frequency, and the achievable displacement amplitude of devices that, consistent with current ultrasonic surgical tools, are based on a bolted Langevin transducer (BLT) and tip. Different configurations of BLTs are studied, including a cascaded version, simple bar versions, and BLTs with different front mass geometries. Results show that a BLT with a larger number of piezoceramic rings exhibits a higher coupling coefficient [Formula: see text] but with the compromise of a lower mechanical Q and stronger nonlinear response at increasing excitation levels. Displacement amplitude is reduced considerably when a BLT is excited at a higher harmonic, where the PZT rings are maintained at a nodal plane, and the resonance frequency shift at increasing excitation levels increases significantly. The electromechanical and dynamic characteristics of a cascaded transducer excited in its third longitudinal mode (L3) are almost equivalent to a much shorter version of a BLT driven at the same frequency but in its first longitudinal mode (L1), showing that a cascaded BLT can be a realistic proxy for studying the dynamics of small BLT devices. A new figure of merit is proposed that is the product of Q , [Formula: see text], and gain, which [Formula: see text] accounts for the gain of cylindrical BLTs which is shown not to be unity. It also proves effective as it incorporates the key factors affecting the achievable displacement amplitude of a BLT, including for BLTs with gain profiles in the front mass. The order of highest to lowest amplitude of a series of six gain-profile BLTs matches the order estimated by the figure of merit. It is shown that a BLT with a stepped profile front mass can achieve displacement that has the potential to cut hard or soft tissue and exhibits the smallest shifts in resonance frequency at increasing excitation levels.

Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists.

Venetoclax has efficacy in patients relapsing after B-cell receptor pathway inhibitors (BCRis); however, because of the risk of tumor lysis syndrome (TLS), a 5-week dose ramp-up is required to attain the target dose. Patients relapsing after BCRis frequently have proliferative disease, requiring a faster time to target dose than this scheme allows. This limitation can potentially be overcome with rapid dose escalation (RDE). We analyzed 33 chronic lymphocytic leukemia patients who underwent venetoclax RDE after prior BTKi treatment. Median time to target dose was 9 days. Seventeen patients (52%) developed laboratory TLS, and 5 (15%) developed clinical TLS, all as a result of renal injury. TLS was seen in more patients with a higher initial tumor burden. TLS occurred at all dose levels, with most episodes occurring at the 50- and 100-mg doses. Most interestingly, a decrease in absolute lymphocyte count (ALC) from pre-venetoclax dose to 24 hours post-venetoclax dose of 10 × 103/µL was associated with an increased risk of TLS (hazard ratio, 1.32; P = .02), after controlling for venetoclax dose level. Venetoclax RDE with close in-hospital monitoring at experienced centers and in select patients is feasible. The rapidity with which ALC drops helps predict TLS and could help guide dose-escalation decisions.

Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia.

PURPOSE: The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy. PATIENTS AND METHODS: This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety. RESULTS: The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed. CONCLUSION: The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia.

Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.

BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia.

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.

Ultrasonic Needles for Bone Biopsy.

Bone biopsy is an invasive clinical procedure, where a bone sample is recovered for analysis during the diagnosis of a medical condition. When the architecture of the bone tissue is required to be preserved, a core-needle biopsy is taken. Although this procedure is performed while the patient is under local anaesthesia, the patient can still experience significant discomfort. Additionally, large haematoma can be induced in the soft tissue surrounding the biopsy site due to the large axial and rotational forces, which are applied through the needle to penetrate bone. It is well documented that power ultrasonic surgical devices offer the advantages of low cutting force, high accuracy, and preservation of soft tissues. This paper reports a study of the design, analysis, and test of two novel power ultrasonic needles for bone biopsy that operate using different configurations to penetrate bone. The first utilizes micrometric vibrations generated at the distil tip of a full-wavelength resonant ultrasonic device, while the second utilizes an ultrasonic-sonic approach, where vibrational energy generated by a resonant ultrasonic horn is transferred to a needle via the chaotic motion of a free-mass. It is shown that the dynamic behavior of the devices identified through experimental techniques closely match the behavior calculated through numerical and finite-element analysis methods, demonstrating that they are effective design tools for these devices. Both devices were able to recover trabecular bone from the metaphysis of an ovine femur, and the biopsy samples were found to be comparable to a sample extracted using a conventional biopsy needle. Furthermore, the resonant needle device was also able to extract a cortical bone sample from the central diaphysis, which is the strongest part of the bone, and the biopsy was found to be superior to the sample recovered by a conventional bone biopsy needle.

An ultrasonic orthopaedic surgical device based on a cymbal transducer.

An ultrasonic orthopaedic surgical device is presented, where the ultrasonic actuation relies on a modification of the classical cymbal transducer. All current devices consist of a Langevin ultrasonic transducer with a tuned cutting blade attached, where resonance is required to provide sufficient vibrational amplitude to cut bone. However, this requirement restricts the geometry and offers little opportunity to propose miniaturised devices or complex blades. The class V flextensional cymbal transducer is proposed here as the basis for a new design, where the cymbal delivers the required vibrational amplitude, and the design of the attached cutting insert can be tailored for the required cut. Consequently, the device can be optimised to deliver an accurate and precise cutting capability. A prototype device is presented, based on the cymbal configuration and designed to operate at 25.5kHz with a displacement amplitude of 30µm at 300V. Measurements of vibrational and impedance responses elucidate the mechanical and electrical characteristics of the device. Subsequent cutting tests on rat femur demonstrate device performance consistent with a commercial Langevin-based ultrasonic device and show that cutting is achieved using less electrical power and a lower piezoceramic volume. Histological analysis exhibits a higher proportion of live cells in the region around the cut site for the cymbal device than for a powered sagittal or a manual saw, demonstrating the potential for the ultrasonic device to result in faster healing.

Phase I dose escalation trial of the novel proteasome inhibitor carfilzomib in patients with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma.

The proteasome complex degrades proteins involved in a variety of cellular processes and is a powerful therapeutic target in several malignancies. Carfilzomib is a potent proteasome inhibitor which induces rapid chronic lymphocytic leukemia (CLL) cell apoptosis in vitro. We conducted a phase I dose-escalation trial to determine the safety and tolerability of carfilzomib in relapsed/refractory CLL or small lymphocytic lymphoma (SLL). Nineteen patients were treated with carfilzomib initially at 20 mg/m(2), then escalated in four cohorts (27, 36, 45 and 56 mg/m(2)) on days 1, 2, 8, 9, 15 and 16 of 28-day cycles. Therapy was generally well tolerated, and no dose limiting toxicities were observed. The most common hematologic toxicities were thrombocytopenia and neutropenia. All patients evaluable for response had stable disease, including patients with del17p13 and fludarabine-resistant disease. This trial shows acceptable tolerability and limited preliminary efficacy of carfilzomib in CLL and SLL.

Understanding nonlinear vibration behaviours in high-power ultrasonic surgical devices.

Ultrasonic surgical devices are increasingly used in oral, craniofacial and maxillofacial surgery to cut mineralized tissue, offering the surgeon high accuracy with minimal risk to nerve and vessel tissue. Power ultrasonic devices operate in resonance, requiring their length to be a half-wavelength or multiple-half-wavelength. For bone surgery, devices based on a half-wavelength have seen considerable success, but longer multiple-half-wavelength endoscopic devices have recently been proposed to widen the range of surgeries. To provide context for these developments, some examples of surgical procedures and the associated designs of ultrasonic cutting tips are presented. However, multiple-half-wavelength components, typical of endoscopic devices, have greater potential to exhibit nonlinear dynamic behaviours that have a highly detrimental effect on device performance. Through experimental characterization of the dynamic behaviour of endoscopic devices, it is demonstrated how geometrical features influence nonlinear dynamic responses. Period doubling, a known route to chaotic behaviour, is shown to be significantly influenced by the cutting tip shape, whereas the cutting tip has only a limited effect on Duffing-like responses, particularly the shape of the hysteresis curve, which is important for device stability. These findings underpin design, aiming to pave the way for a new generation of ultrasonic endoscopic surgical devices.

Maximization of the effective impulse delivered by a high-frequency/low-frequency planetary drill tool.

Ultrasonic tools are used for a variety of cutting applications in surgery and the food industry, but when they are applied to harder materials, such as rock, their cutting performance declines because of the low effective impulse delivered by each vibration cycle. To overcome this problem, a technique known as high-frequency/low-frequency (or alternatively, ultrasonic/sonic) drilling is employed. In this approach, an ultrasonic step-horn is used to deliver an impulse to a free mass which subsequently moves toward a drilling bit, delivering the impulse on contact. The free mass then rebounds to complete the cycle. The horn has time between impacts to build significant vibration amplitude and thus delivers a much larger impulse to the free mass than could be delivered if it were applied directly to the target. To maximize the impulse delivered to the target by the cutting bit, both the momentum transfer from the ultrasonic horn to the free mass and the dynamics of the horn/free mass/cutting bit stack must be optimized. This paper uses finite element techniques to optimize the ultrasonic horns and numerical propagation of the stack dynamics to maximize the delivered effective impulse, validated in both cases by extensive experimental analysis.

Consolidation therapy with subcutaneous alemtuzumab after fludarabine and rituximab induction therapy for previously untreated chronic lymphocytic leukemia: final analysis of CALGB 10101.

PURPOSE: To determine if alemtuzumab consolidation improves response rate and progression-free survival (PFS) after induction chemoimmunotherapy in previously untreated symptomatic patients with chronic lymphocytic leukemia. PATIENTS AND METHODS: Patients (n = 102) received fludarabine 25 mg/m(2) intravenously days 1 to 5 and rituximab 50 mg/m(2) day 1, 325 mg/m(2) day 3, and 375 mg/m(2) day 5 of cycle 1 and then 375 mg/m(2) day 1 of cycles 2 to 6; fludarabine plus rituximab (FR) administration was repeated every 28 days for six cycles. Three months after completion of FR, patients with stable disease or better response received subcutaneous alemtuzumab 3 mg day 1, 10 mg day 3, and 30 mg day 5 and then 30 mg three times per week for 5 weeks. RESULTS: Overall response (OR), complete response (CR), and partial response (PR) rates were 90%, 29%, and 61% after FR, respectively; 15% of patients were minimal residual disease (MRD) negative. Of 102 patients, 58 received alemtuzumab; 28 (61%) of 46 patients achieving PR after FR attained CR after alemtuzumab. By intent to treat (n = 102), OR and CR rates were 90% and 57% after alemtuzumab, respectively; 42% of patients became MRD negative. With median follow-up of 36 months, median PFS was 36 months, 2-year PFS was 72%, and 2-year OS was 86%. In patients achieving CR after FR, alemtuzumab was associated with five deaths resulting from infection (viral and Listeria meningitis and Legionella, cytomegalovirus, and Pneumocystis pneumonias), which occurred up to 7 months after last therapy. The study was amended to exclude CR patients from receiving alemtuzumab. CONCLUSION: Alemtuzumab consolidation improved CR and MRD-negative rates after FR induction but caused serious infections in patients who had already achieved CR after induction and did not improve 2-year PFS or survival.

Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia.

The use of nucleoside analog-based chemo-immunotherapeutic regimens over the last decade has significantly improved outcomes in patients with chronic lymphocytic leukemia (CLL). Nonetheless, virtually all patients with CLL relapse from chemoimmmunotherapy and current available therapies are not curative. Identifying therapies that effectively eliminate CLL cells and lack immunesuppression represent an exciting new therapeutic approach. IMiDs are a class of immunomodulating drugs that increase T-cell and NK-cell directed killing of tumor cells. The first generation molecule is thalidomide followed by a second generation molecule lenalidomide that lacks neurotoxicity and is being explored more extensively in clinical trials. Lenalidomide has been shown to benefit patients with multiple myeloma, myelodysplastic syndromes, and lymphoma. Initial reports in patients with relapsed and refractory CLL have shown promising responses. In a subset of patients with CLL complete responses have been noted. Subsequent studies, however, have suggested that this class of drug can also have serious and potentially life-threatening side effects including myelosuppression, tumor flare reaction and in a small subset of patients tumor lysis syndrome. Tumor flare with both thalidomide and lenalidomide appear to be disease specific to CLL and may reflect clinical manifestation of CLL tumor cell activation. As a consequence of these disease specific effects, the optimal safe dose of lenalidomide in CLL remains to be determined but appears to be lower than that tolerated in other B-cell malignancies. To date, biomarkers for response remain poorly defined and the relationship of clinical benefit to tumor flare is uncertain. This review examines the existing literature on the use of IMiDs in patients with CLL and provides suggestions for future research in this area.

A phase I/II dose escalation study of apolizumab (Hu1D10) using a stepped-up dosing schedule in patients with chronic lymphocytic leukemia and acute leukemia.

Apolizumab (Hu1D10), a humanized monoclonal anti- Human leukocyte antigen -DR beta-chain antibody, mediates apoptosis of chronic lymphocytic leukemia (CLL) cells in vitro. We conducted a phase I/II dose-escalation study of thrice-weekly apolizumab (1.5, 3.0, 5.0 mg/kg/dose) for 4 weeks in relapsed CLL. Two of six patients at 5.0 mg/kg/dose developed treatment-related dose-limiting toxicity (aseptic meningitis, hemolytic uremia). Other toxicities included infusion toxicity, urticaria, and headache. Eleven patients were enrolled in a phase I/II expansion to evaluate the maximum tolerated dose (MTD) of 3.0 mg/kg/dose. In total, 23 patients were enrolled (22 CLL, 1 ALL). Nineteen patients with CLL were treated at or above the MTD. One partial response was observed, and three patients had stable disease exceeding 6 months. Pharmacokinetic analysis demonstrated a dose-dependent C(max) increase and serum antibody accumulation after week 1 of therapy. Given the toxicity and lack of efficacy in this and other trials in lymphoma and solid tumors, further development of apolizumab was discontinued.

Effects of motexafin gadolinium in a phase II trial in refractory chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) cells are susceptible to oxidative stress. The expanded porphyrin, motexafin gadolinium (MGd), reacts with intracellular reducing metabolites and protein thiols to generate reactive oxygen species (ROS). A phase II trial administered MGd 5 mg/kg/day IV for 5 days every 3 weeks until disease progression to patients with previously treated CLL and small lymphocytic lymphoma. Thirteen patients (median age 66 years) with a median of four prior therapies (range 2-9) were enrolled. Modest anti-tumor activity was seen in three patients, with improvement in lymphocytosis, lymphadenopathy and/or splenomegaly, but no patient achieved a partial or complete response by NCI 96 criteria. Flow cytometry confirmed tumor uptake of MGd. Serial increase in AKT phosphorylation in patient samples following MGd treatment was not observed, suggesting intracellular generation of ROS was not optimal. Therefore, this schedule of administration achieved MGd uptake into primary tumor cells in vivo, but clinical activity was modest.

Computed tomography scans do not improve the predictive power of 1996 national cancer institute sponsored working group chronic lymphocytic leukemia response criteria.

PURPOSE: National Cancer Institute-sponsored Working Group (NCI-WG) response criteria for chronic lymphocytic leukemia (CLL) rely on physical examination, blood, and bone marrow evaluations. The widespread use of computed tomography (CT) scans has prompted many to advocate for the incorporation of this test into CLL response criteria. PATIENTS AND METHODS: In a retrospective review of 82 CLL patients treated at the Ohio State University (Columbus, OH), we compared CT assessed response using non-Hodgkin's lymphoma (NHL) response definitions with NCI-WG response. RESULTS: Responses by NCI-WG criteria included five complete responses (CRs), 32 partial responses (PRs), 21 patients with stable disease (SD), 17 patients with progressive disease (PD), and seven patients not assessable (NA). Responses by NHL-CT criteria included three CRs, 12 unconfirmed CRs (CRus), 16 PRs, 26 with SD, four with PD, and 21 NA. Using NCI-WG criteria, progression-free survival (PFS) was 27.3 months for CR and 11.4 months for PR. With NHL-CT criteria, PFS was 18.4 months for CR, 11.7 months for CRu, and 14.5 months for PR. In multivariate analysis, both NCI-WG and NHL-CT response correlated with PFS (P = .009 and .001, respectively). CONCLUSION: Current NCI-WG CLL response criteria are a significant predictor of PFS in previously treated CLL patients, with no additional benefit from the inclusion of CT scans. Although retrospective, these results highlight the importance of prospective validation of CT scans before routine inclusion in CLL response criteria.

Methods for reducing cutting temperature in ultrasonic cutting of bone.

Ultrasonic cutting is widely used in food processing applications to produce a clean and accurate cut. However, it is yet to be adopted as an instrument of choice in orthopaedic applications, mainly due to the high temperatures that can be generated at the cut site and the consequent requirement to use additional cooling. For example, if cutting temperatures above 55-60 degrees C are reached, particularly for sustained periods, bone necrosis can occur, compromising post-operative recovery. A recent study by the authors has shown that the thermal response in natural materials, such as wood and bone, is affected by the absorption of ultrasonic energy and conduction of heat from the cut site. In this paper the dependency of cutting parameters, such as blade tip vibration velocity, applied load, tuned frequency and coupling contact conditions, on the thermal response are reported and results show that it is possible to maintain cutting temperatures within safety limits by controlling the cutting parameters. A novel cutting blade design is proposed that reduces frictional heat generated at the cut site. Through a series of experimental investigations using fresh bovine femur it is demonstrated that the cutting temperature, and hence thermal damage, can be reduced by selecting appropriate cutting parameters and blade profile.

A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m(2); cohort II: 20 mg/m(2)) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m(2) chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL.

Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia.

PURPOSE: Fludarabine and cyclophosphamide is an effective combination but increases the risk of opportunistic infections due to depressed lymphocyte counts. In an attempt to preserve CD4 counts, we conducted a phase I, double-blind, placebo-controlled trial of recombinant interleukin-2 (IL-2) added to fludarabine and cyclophosphamide in patients with treatment-naive indolent lymphomas or chronic lymphocytic leukemia. EXPERIMENTAL DESIGN: Subcutaneous IL-2 (days 1-21 of each 28-day cycle) was combined with cyclophosphamide (600 mg/m2, day 8) and fludarabine (20 mg/m2, days 8-12) at four dose levels: 0.8, 1.0, 1.2, and 1.4 x 10(6) IU/m2/d. IL-2 dose was escalated in cohorts of four to six patients, with one patient per cohort receiving placebo. RESULTS: Twenty-three patients, median age 50, were enrolled, of whom 30% had chronic lymphocytic leukemia/small lymphocytic lymphoma and 52% had follicular lymphomas. The combination was generally well tolerated, with mainly hematologic toxicities. CD4 counts typically declined substantially during the early weeks of treatment and remained suppressed for months afterward. In the 18 evaluable patients who received IL-2, the mean absolute CD4 count was 999 cells/microL (range, 97-3,776) pretreatment, 379 cells/microL (range, 54-2,599) at day 14, and 98 cells/microL (range, 17-291) at end of treatment. In longitudinal linear models, the changes in CD4 counts were not significantly different across IL-2 dose levels. CONCLUSIONS: The addition of low-dose IL-2 to fludarabine and cyclophosphamide does not seem immunoprotective. New approaches are needed to reduce the cellular immunosuppression and infectious complications associated with purine analogues.