Richard L. Goldberg

Prognostic Significance of Defective Mismatch Repair and BRAF V600E in Patients with Colon Cancer

Purpose: Colon tumors with defective DNA mismatch repair (dMMR) have a well-characterized phenotype and accounts for ∼15% to 20% of sporadic colon cancer as well as those colon cancer patients with Lynch syndrome. Although the presence of dMMR seems to be a favorable prognostic marker, data suggest that these patients do not respond as well to adjuvant chemotherapy. Experimental Design: In this study, we examined the prognostic significance of tumor MMR deficiency and the presence of a specific mutation in BRAF (V600E) in a group of patients (n = 533) who participated in a randomized prospective clinical trial through the North Central Cancer Treatment Group. Results: Tumors with dMMR were found to be associated with higher tumor grade (P = 0.001), proximal location (P < 0.0001), and improved overall and disease-free survival (P = 0.05 and 0.04, respectively). Among all cases examined, evaluation of the BRAF V600E mutation status revealed no statistically significant differences in either disease-free or overall survival. Patients were then grouped into four categories for further analysis: dMMR/BRAF(−), dMMR/BRAF(+), pMMR/BRAF(−), and pMMR/BRAF(+). The dMMR/BRAF(−) group had a significantly improved overall survival (5-year overall survival of 100% versus 73%, P = 0.002) compared with all others. The remaining three groups had very similar survival outcomes. An additional cohort of tumors previously classified as having dMMR were also tested for the BRAF V600E alteration. Results remained significant (P = 0.006) when the two groups were combined for analysis. Conclusions: Overall, these data suggest that the underlying molecular etiology of those tumors having dMMR may influence the disease outcome in these patients.

End Points in Advanced Colon Cancer Clinical Trials: A Review and Proposal

Colorectal cancer accounts for the death of more than 55,000 individuals in the United States each year. 1 The vast majority of these patients receive systemic chemotherapy with one or more of several agents presently approved for treatment in this setting. Given the relatively recent and rapid identification of new active therapeuticsforpatientswithadvancedcolorectalcancer,thealgorithm for patient management is undergoing a similarly rapid evolution. The traditional paradigm, dating from the initial use of fluorouracil in the 1960s, dictated that patients receive continuous systemic therapy until disease progression or unacceptable toxicity.Thistreatmentmodelhasgenerallybeenappliedtotherapeutic clinical trials and forms the foundation on which the currently accepted intermediate end points designed to assess the efficacy of new agents (eg, progression-free survival [PFS]) are based. The high level of activity of newer regimens and a particular element of treatment with the agent oxaliplatin are challenging these standard paradigms. Although highly effective when used in combination with fluorouracil, oxaliplatin is associated with a cumulative sensory neuropathy that occurs at clinically significant levels after approximately 5 months (approximately 850 mg/m 2 total dose) of therapy. 2 This adverse event generally precludes long-term continuous therapy with this agent. In other tumor types (eg, lung, ovary), the use of platinum therapy has resulted in preplanned, fixed therapeutic windows of 4 to 6 months. Similar approaches are beginning to be explored in colorectal cancer, driven primarily by the desire to obviate or at least mitigate neurotoxicity. In addition, as three-, four-, and five-drug regimens become more common and a majority of patients respond to treatment (or at least establish stable disease), in many cases, toxicityexceedstolerablelimitsbeforetheeffectivenessofaregimenis fully exploited. A recent study reported in abstract form may serve as an example of this phenomenon. 3 In this investigation, bevacizumab did not seem to improve the PFS of oxaliplatin-based regimens to the extent expected based on prior trials. 4 A possible

Modeling of piezoelectric multilayer ceramics using finite element analysis

For medical ultrasound imaging, 2-D array transducers have greater versatility than linear arrays. Unfortunately, the tiny array elements in a 2-D array have poor signal-to-noise ratio (SNR). We have previously shown that SNR is increased in 2-D array transducers made from piezoelectric multilayer ceramics. Conventional one-dimensional models provide accurate results when comparing multilayer ceramic performance relative to single layer transducers. However, these models are not accurate when comparing simulations directly to measurements. Because multilayer ceramics have a complex structure, a 3-D model, such as finite element analysis, is needed for accurate simulations. We modeled four arrays that were previously fabricated: a single layer and multilayer 1 MHz, 2-D array element, and a single layer and multilayer 2.25 MHz, 1.5-D array element that can focus and steer in azimuth but only steer in the elevation dimension. We compared the simulated and measured impedance plots for each transducer. The finite element analysis plots accurately predicted the impedance for each vibration mode. On the other hand, the one dimensional KLM transmission line model could simulate only the thickness mode vibrations and the results were inaccurate compared to measurements. We also simulated the transmit output pressure for the 2.25 MHz arrays and compared the results to measurements. The simulated pressure vs. time plots and their spectra were accurate when compared to measurements. Finally, we obtained a series of images that show the impulse response vibrations for the 2.25 MHz, arrays. These animations show the vibration modes in the complex multilayer ceramic structure. Measurements were not available to confirm the animations. Our results show that finite element analysis in three dimensions is a valuable tool to predict the performance of multi-layer transducers.

Update on 2-D array transducers for medical ultrasound

l 1/2 -D and 2-D arrays offer a myriad of new imaging modalities and benefits when compared to the linear array. However, with added benefits come many problems and challenges and l 1/2 -D and 2-D arrays are no exception. The authors give possible solutions to a number of these challenges. The increase in transducer channels needed in a 1 1/2 -D and 2-D array can be reduced using a sparse periodic or sparse random array. The complexity of the fabrication is overcome using a multilayer flexible connector designed and fabricated using microelectronic techniques. The low SNR of 1 1/2 -D and 2-D arrays can be circumvented with the application of multi-layer ceramic elements to optimize the SNR given a specific transmit and receive configuration. In addition, optoelectronic transmitters allow for the reduction in size and increase in flexibility of the transducer cable because of the use of fiber optics. With the reduction in the number of channels, improvement in transducer fabrication, and increase in transducer SNR, l 1/2 -D and 2-D arrays will be accepted as viable replacements for the linear arrays of today.

Changes in cochlear mechanics during vocalization: evidence for a phasic medial efferent effect.

The mustached bat, Pteronotus p. parnellii, has a finely tuned cochlea that rings at its resonant frequency in response to an acoustic tone pip. The decay time (DT) and frequency of these damped oscillations can be measured from the cochlear microphonic potential (CM) to study changes in cochlear mechanics. In this report, we describe phasic changes that occur in synchrony with communication sound vocalizations of the bat. Three animals with chronically implanted electrodes were studied. During the experiments, 1-2 ms tone pips were emitted from a speaker every 200 ms. This triggered a computer analysis of the resulting CM to determine the DT and cochlear resonance frequency (CRF) of the ringing. The time relative to vocalizations was determined by monitoring the output of a microphone placed near a bats mouth. Similar results were obtained from all three bats tested. In a representative case, the average DT was 2.33 +/- 0.25 ms while the bat was quiet, but it decreased by 46% to 1.26 +/- 0.75 during vocalizations, which indicates a greater damping of the cochlear partition. Sometimes, DT started decreasing immediately before the bat vocalized. After the end of a vocalization, the return to baseline values varied from rapid (milliseconds) to gradual (1-2 seconds). The CRF also changed from baseline values during vocalization, although the amount and direction of change were not predictable. When gentamicin was administered to block the action of medial olivocochlear (MOC) efferents, DT reduction was still evident during vocalization but less pronounced. We conclude that phasic changes in damping occur in synchrony with vocalization, and that the MOC system plays a role in causing suppression. Since suppression can begin prior to vocalization, this may be a synkinetic effect, mediated by neural outflow to the ear in synchrony with neural outflow to the middle ear muscles and the muscles used for vocalization.

Hybrid multi/single layer array transducers for increased signal-to-noise ratio

In medical ultrasound imaging, two-dimensional (2-D) array transducers are necessary to implement dynamic focusing in two dimensions, phase correction in two dimensions and high speed volumetric imaging. However, the small size of a 2-D array element results in a small clamped capacitance and a large electrical impedance, which decreases the transducer signal-to-noise ratio (SNR). We have previously shown that SNR is improved using transducers made from multi-layer PZT, due to their lower electrical impedance. In this work, we hypothesize that SNR is further increased using a hybrid array configuration: in the transmit mode, a 10 /spl Omega/ electronic transmitter excites a 10 /spl Omega/ multi-layer array element; in the receive mode, a single layer element drives a high impedance preamplifier located in the transducer handle. The preamplifier drives the coaxial cable connected to the ultrasound scanner. For comparison, the following control configuration was used: in the transmit mode, a 50 /spl Omega/ source excites a single layer element, and in the receive mode, a single layer element drives a coaxial cable load. For a 5/spl times/102 hybrid array operating at 7.5 MHz, maximum transmit output power was obtained with 9 PZT layers according to the KLM transmission line model. In this case, the simulated pulse-echo SNR was improved by 23.7 dB for the hybrid configuration compared to the control. With such dramatic improvement in pulse-echo SNR, low voltage transmitters can be used. These can be fabricated on integrated circuits and incorporated into the transducer handle.

A pilot study assessing social support among cancer patients enrolled on clinical trials: a comparison of younger versus older adults

Purpose: This study tested the logistical feasibility of obtaining data on social support systems from cancer patients enrolled on clinical trials and compared the social support of older adults (age ≥65) and younger adults (<50 years of age) with cancer. Methods: Patients had to be eligible for a phase II or phase III oncology clinical trial and enter the study prior to treatment. Patients filled out the Lubben Social Network Scale (LSNS) at baseline. The Symptom Distress Scale (SDS) and single-item overall quality of life (QOL) Uniscale were assessed at baseline and weekly for 4 weeks. Results: There was no significant difference in overall mean Lubben social support levels by age. Older patients had more relatives they felt close to (85% versus 53% with 5 or more relatives, P = 0.02), heard from more friends monthly (84% versus 53% with 3 or more friends, P = 0.02), less overall symptom distress (P = 0.03), less insomnia (P = 0.003), better concentration (P = 0.005), better outlook (P = 0.01), and less depression (P = 0.005) than younger patients. Conclusions: Younger subjects reported worse symptoms, a smaller social support network, and fewer close friends and relatives than older subjects. Having someone to discuss decisions and seeing friends or relatives often was associated with longer survival.

Colon Cancer in Older Adults

Colorectal cancer (CRC) is a common malignancy in the elderly. Randomized trials have demonstrated that adjuvant and palliative chemotherapy for CRC improves survival and quality of life. Unfortunately, there is a lack of evidence-based data about elderly patients to guide decisions regarding therapy. Clinical trials have generally excluded the vulnerable elderly population commonly seen in practice and included the robust elderly, who seem to benefit from chemotherapy as much as younger patients. The existing literature consists of pooled datasets from large studies and a few small dedicated trials on chemotherapy and its toxicity in elderly patients with CRC. We present illustrative data in this article and summarize our recommendations for managing the disease in elderly patients in a variety of clinical circumstances.

Multilayer 2-D array transducers with integrated circuit transmitters and receivers: a feasibility study

In 2-D arrays, the elements have poor signal-to-noise ratio (SNR) because their small size results in a small clamped capacitance and a large electrical impedance near resonance. The SNR can be increased using multi-layer PZT transducers. It is hypothesized that further improvements in pulse-echo SNR are obtained using a hybrid array in the following configuration: in the transmit mode, 10 Ω electronic transmitters exciting 10 Ω multi-layer elements, and in the receive mode, single layer elements driving high impedance pre-amplifiers. A sparsely sampled array was modeled, operating at 7.5 MHz. According to simulations, pulse-echo SNR was improved by 40 dB in the hybrid configuration compared to the control. An experimental feasibility study was also performed using a 2.25 MHz transducer. The measurements were consistent with the simulations. The dramatic improvement in SNR for the hybrid configuration allows for new implementations of the transmit and receive circuitry

Loading and knee flexion after stroke: Less does not equal more.

It is believed that force feedback can modulate lower extremity extensor activity during gait. The purpose of this research was to determine the role of limb loading on knee extensor excitability during the late stance/early swing phase of gait in persons post-stroke. Ten subjects with chronic hemiparesis post-stroke participated in (1) seated isolated quadriceps reflex testing with ankle loads of 0-0.4Nm/kg and (2) gait analysis on a treadmill with 0%, 20% or 40% body weight support. Muscle reflex responses were recorded from vastus lateralis (VL), rectus femoris (RF), and vastus medialis (VM) during seated testing. Knee kinematics and quadriceps activity during late stance/early swing phase of gait were compared across loading conditions. Although isolated loading of the ankle plantarflexors at 0.2Nm/kg reduced VM prolonged response (p=0.04), loading did not alter any other measure of quadriceps excitability (all p>0.08). During gait, the use of BWS did not influence knee kinematics (p=0.18) or muscle activity (all p>0.17) during late stance/early swing phase. This information suggests that load sensed at the ankle has minimal effect on the ipsilateral quadriceps of individuals post-stroke during late stance. It appears that adjusting limb loading during rehabilitation may not be an effective tool to address stiff-knee gait following stroke.