Quantitative Micro-Elastography Enables In Vivo Detection of Residual Cancer in the Surgical Cavity during Breast-Conserving Surgery.

Breast-conserving surgery (BCS) is commonly used for the treatment of early-stage breast cancer. Following BCS, approximately 20% to 30% of patients require reexcision because postoperative histopathology identifies cancer in the surgical margins of the excised specimen. Quantitative micro-elastography (QME) is an imaging technique that maps microscale tissue stiffness and has demonstrated a high diagnostic accuracy (96%) in detecting cancer in specimens excised during surgery. However, current QME methods, in common with most proposed intraoperative solutions, cannot image cancer directly in the patient, making their translation to clinical use challenging. In this proof-of-concept study, we aimed to determine whether a handheld QME probe, designed to interrogate the surgical cavity, can detect residual cancer directly in the breast cavity in vivo during BCS. In a first-in-human study, 21 BCS patients were scanned in vivo with the QME probe by five surgeons. For validation, protocols were developed to coregister in vivo QME with postoperative histopathology of the resected tissue to assess the capability of QME to identify residual cancer. In four cavity aspects presenting cancer and 21 cavity aspects presenting benign tissue, QME detected elevated stiffness in all four cancer cases, in contrast to low stiffness observed in 19 of the 21 benign cases. The results indicate that in vivo QME can identify residual cancer by directly imaging the surgical cavity, potentially providing a reliable intraoperative solution that can enable more complete cancer excision during BCS. SIGNIFICANCE: Optical imaging of microscale tissue stiffness enables the detection of residual breast cancer directly in the surgical cavity during breast-conserving surgery, which could potentially contribute to more complete cancer excision.

Handheld volumetric manual compression-based quantitative microelastography.

Compression optical coherence elastography (OCE) typically requires a mechanical actuator to impart a controlled uniform strain to the sample. However, for handheld scanning, this adds complexity to the design of the probe and the actuator stroke limits the amount of strain that can be applied. In this work, we present a new volumetric imaging approach that utilizes bidirectional manual compression via the natural motion of the user's hand to induce strain to the sample, realizing compact, actuator-free, handheld compression OCE. In this way, we are able to demonstrate rapid acquisition of three-dimensional quantitative microelastography (QME) datasets of a tissue volume (6 × 6 × 1 mm3 ) in 3.4 seconds. We characterize the elasticity sensitivity of this freehand manual compression approach using a homogeneous silicone phantom and demonstrate comparable performance to a benchtop mounted, actuator-based approach. In addition, we demonstrate handheld volumetric manual compression-based QME on a tissue-mimicking phantom with an embedded stiff inclusion and on freshly excised human breast specimens from both mastectomy and wide local excision (WLE) surgeries. Tissue results are coregistered with postoperative histology, verifying the capability of our approach to measure the elasticity of tissue and to distinguish stiff tumor from surrounding soft benign tissue.

Handheld probe for quantitative micro-elastography.

Optical coherence elastography (OCE) has been proposed for a range of clinical applications. However, the majority of these studies have been performed using bulky, lab-based imaging systems. A compact, handheld imaging probe would accelerate clinical translation, however, to date, this had been inhibited by the slow scan rates of compact devices and the motion artifact induced by the user's hand. In this paper, we present a proof-of-concept, handheld quantitative micro-elastography (QME) probe capable of scanning a 6 × 6 × 1 mm volume of tissue in 3.4 seconds. This handheld probe is enabled by a novel QME acquisition protocol that incorporates a custom bidirectional scan pattern driving a microelectromechanical system (MEMS) scanner, synchronized with the sample deformation induced by an annular PZT actuator. The custom scan pattern reduces the total acquisition time and the time difference between B-scans used to generate displacement maps, minimizing the impact of motion artifact. We test the feasibility of the handheld QME probe on a tissue-mimicking silicone phantom, demonstrating comparable image quality to a bench-mounted setup. In addition, we present the first handheld QME scans performed on human breast tissue specimens. For each specimen, quantitative micro-elastograms are co-registered with, and validated by, histology, demonstrating the ability to distinguish stiff cancerous tissue from surrounding soft benign tissue.

Bidirectional microwave and optical signal dissemination.

We describe a technique to disseminate highly stable microwave and optical signals from physically separated frequency standards to multiple locations. We demonstrate our technique by transferring the frequency stability performance of a microwave frequency reference to the repetition-rate stability of an optical frequency comb in a different location. The stabilized optical frequency comb becomes available in both locations for measurements of both optical and microwave signals. We show a microwave frequency stability of 4×10(-15) in both locations for integration times beyond 100 s. The control system uses only a standard Ethernet connection.

Complex direct comb spectroscopy with a virtually imaged phased array.

We demonstrate a simple interferometric technique to directly measure the complex optical transmittance over a large spectral range using a frequency-comb spectrometer based on a virtually imaged phased array. A Michelson interferometer encodes the phase deviations induced by a sample contained in one of its arms into an interferogram image. When combined with an additional image taken from each arm separately, along with a frequency-calibration image, this allows full reconstruction of the sample's optical transfer function. We demonstrate the technique with a vapor cell containing H13C14N, producing transmittance and phase spectra spanning 2.9 THz (∼23 nm) with ∼1 GHz resolution.

Coherent radio-frequency detection for narrowband direct comb spectroscopy.

We demonstrate a scheme for coherent narrowband direct optical frequency comb spectroscopy. An extended cavity diode laser is injection locked to a single mode of an optical frequency comb, frequency shifted, and used as a local oscillator to optically down-mix the interrogating comb on a fast photodetector. The high spectral coherence of the injection lock generates a microwave frequency comb at the output of the photodiode with very narrow features, enabling spectral information to be further down-mixed to RF frequencies, allowing optical transmittance and phase to be obtained using electronics commonly found in the lab. We demonstrate two methods for achieving this step: a serial mode-by-mode approach and a parallel dual-comb approach, with the Cs D1 transition at 894 nm as a test case.

Self-heterodyne interference spectroscopy using a comb generated by pseudo-random modulation.

We present an original instrument designed to accomplish high-speed spectroscopy of individual optical lines based on a frequency comb generated by pseudo-random phase modulation of a continuous-wave (CW) laser. This approach delivers efficient usage of the laser power as well as independent control over the spectral point spacing, bandwidth and central wavelength of the comb. The comb is mixed with a local oscillator generated from the same CW laser frequency-shifted by an acousto-optic modulator, enabling a self-heterodyne detection scheme. The current configuration offers a calibrated spectrum every 1.12 µs. We demonstrate the capabilities of the spectrometer by producing averaged, as well as time-resolved, spectra of the D1 transition of cesium with a 9.8-MHz point spacing, a 50-kHz resolution and a span of more than 3 GHz. The spectra obtained after 1 ms of averaging are fitted with complex Voigt profiles that return parameters in good agreement with expected values.

A quantitative mode-resolved frequency comb spectrometer.

We have developed a frequency-comb spectrometer that records 35-nm (4 THz) spectra with 2-pm (250 MHz) spectral sampling and an absolute frequency accuracy of 2 kHz. We achieve a signal-to-noise ratio of ~400 in a measurement time of 8.2 s. The spectrometer is based on a commercial frequency comb decimated by a variable-length, low-finesse Fabry Pérot filter cavity to fully resolve the comb modes as imaged by a virtually imaged phased array (VIPA), diffraction grating and near-IR camera. By tuning the cavity length, spectra derived from all unique decimated combs are acquired and then interleaved to achieve frequency sampling at the comb repetition rate of 250 MHz. We have validated the performance of the spectrometer by comparison with a previous high-precision absorption measurement of H13C14N near 1543 nm. We find excellent agreement, with deviations from the expected line centers and widths of, at most, 1 pm (125 MHz) and 3 pm (360 MHz), respectively.

Hermetic optical-fiber iodine frequency standard.

We have built an optical-frequency standard based on interrogating iodine vapor that has been trapped within the hollow core of a hermetically sealed kagome-lattice photonic crystal fiber. A frequency-doubled Nd:YAG laser locked to a hyperfine component of the P(142)37-0 I2127 transition using modulation transfer spectroscopy shows a frequency stability of 3×10(-11) at 100 s. We discuss the impediments in integrating this all-fiber standard into a fully optical-fiber-based system, and suggest approaches that could improve performance of the frequency standard substantially.

Nano-Kelvin thermometry and temperature control: beyond the thermal noise limit.

We demonstrate thermometry with a resolution of 80 nK/Hz using an isotropic crystalline whispering-gallery mode resonator based on a dichroic dual-mode technique. We simultaneously excite two modes that have a mode frequency ratio that is very close to two (±0.3 ppm). The wavelength and temperature dependence of the refractive index means that the frequency difference between these modes is an ultrasensitive proxy of the resonator temperature. This approach to temperature sensing automatically suppresses sensitivity to thermal expansion and vibrationally induced changes of the resonator. We also demonstrate active suppression of temperature fluctuations in the resonator by controlling the intensity of the driving laser. The residual temperature fluctuations are shown to be below the limits set by fundamental thermodynamic fluctuations of the resonator material.

High-performance iodine fiber frequency standard.

We have constructed a compact and robust optical frequency standard based around iodine vapor loaded into the core of a hollow-core photonic crystal fiber (HC-PCF). A 532 nm laser was frequency locked to one hyperfine component of the R(56) 32-0 (127)I(2) transition using modulation transfer spectroscopy. The stabilized laser demonstrated a frequency stability of 2.3×10(-12) at 1 s, almost an order of magnitude better than previously reported for a laser stabilized to a gas-filled HC-PCF. This limit is set by the shot noise in the detection system. We present a discussion of the current limitations to the performance and a route to improve the performance by more than an order of magnitude.

Second generation 50 K dual-mode sapphire oscillator.

Low-temperature, high-precision sapphire resonators exhibit a turning point in mode frequency-temperature dependence at around 10 K. This, along with sapphire's extremely low dielectric losses at microwave frequencies, results in oscillator fractional frequency stabilities on the order of 10(-15). At higher temperatures the lack of a turning point makes single-mode oscillators very sensitive to temperature fluctuations. By exciting two quasi-orthogonal whispering gallery (WG) modes in a single sapphire resonator, a turning point in the frequency-temperature dependence can be found in the beat frequency between the two modes. A temperature control technique based on mode frequency temperature dependence has been used to maintain the sapphire at this turning point and the fractional frequency instability of the beat frequency has been measured to be at a level of 4.3 X 10(-14) over 1 s, dropping to 3.5 X 10(-14) over 4 s integration time.

Spherical Bragg reflector resonators.

In this paper we introduce the concept of the spherical Bragg reflector (SBR) resonator. The resonator is made from multiple layers of spherical dielectric, loaded within a spherical cavity. The resonator is designed to concentrate the energy within the central region of the resonator and away from the cavity walls to minimize conductor losses. A set of simultaneous equations is derived, which allows the accurate calculation of the dimensions of the layers as well as the frequency. The solution is confirmed using finite-element analysis. A Teflon-free space resonator was constructed to prove the concept. The Teflon SBR was designed at 13.86 GHz and exhibited a Q-factor of 22,000, which agreed well with the design values. This represents a factor of 3.5 enhancement over a resonator limited by the loss-tangent of Teflon. Similarly, SBR resonators constructed with low-loss materials could achieve Q-factors of the order of 300,000.

High-Q whispering modes in empty spherical cavity resonators.

This work presents the study of high-order modes in spherical cavity resonators. In general there are resonant mode families, degenerate in frequency, that "whisper" around the spherical surface. We call these whispering spherical (WS) mode sets. Each set includes the well-known whispering gallery (WG) mode, which propagates like a ray around the azimuth. Also, we identify a new mode, which we label the whispering longitudinal (WL) mode. This mode propagates as a wave front along the longitudinal direction. The rest of the degenerate set propagates like a combination of the WG and WL modes. We show that transverse electric WS modes have high geometric factors, greater than 2000, which increase linearly with frequency. This is an order of magnitude greater than that of a TM010 cylindrical resonator. Also, Q-factors as high as 65,000 at 13.3 GHz were measured at room temperature.