This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs′) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.
Head and neck cancer accounts for 3 to 5% of all cancers in the United States. Primary or salvage surgeries are extensive and often lead to major head and neck defects that require complex reconstructions with local, regional, or free tissue transfer flaps. Knowledge of tissue blood flow (BF) changes after free tissue transfer may enable surgeons to predict the failure of flap thrombosis at an early stage. This study used our recently developed noncontact diffuse correlation spectroscopy to monitor dynamic BF changes in free flaps without getting in contact with the targeted tissue. Eight free flaps were elevated in patients with head and neck cancer; one of the flaps failed. Multiple BF measurements probing the transferred tissue were performed during and post the surgical operation. Postoperative BF values were normalized to the intraoperative baselines (assigning '1') for the calculation of relative BF change (rBF). The rBF changes over the seven successful flaps were 1.89 ± 0.15, 2.26 ± 0.13, and 2.43 ± 0.13 (mean ± standard error) respectively on postoperative days 2, 4, and 7. These postoperative values were significantly higher than the intraoperative baseline values (p < 0.001), indicating a gradual recovery of flap vascularity after the tissue transfer. By contrast, rBF changes observed from the unsuccessful flap were 1.14 and 1.34 respectively on postoperative days 2 and 4, indicating a less flow recovery. Measurement of BF recovery after flap anastomosis holds the potential to act early to salvage ischemic flaps.
Radiation therapy is a principal modality for head and neck cancers and its efficacy depends on tumor hemodynamics. Our laboratory developed a hybrid diffuse optical instrument allowing for simultaneous measurements of tumor blood flow and oxygenation. In this study, the clinically involved cervical lymph node was monitored by the hybrid instrument once a week over the treatment period of seven weeks. Based on treatment outcomes within one year, patients were classified into a complete response group (CR) and an incomplete response group (IR) with remote metastasis and/or local recurrence. A linear mixed models was used to compare tumor hemodynamic responses to the treatment between the two groups. Interestingly, we found that human papilloma virus (HPV-16) status largely affected tumor hemodynamic responses. For HPV-16 negative tumors, significant differences in blood flow index (BFI, p = 0.007) and reduced scattering coefficient (μs’, p = 0.0005) were observed between the two groups; IR tumors exhibited higher μs’ values and a continuous increase in BFI over the treatment period. For HPV-16 positive tumors, oxygenated hemoglobin concentration ([HbO2]) and blood oxygen saturation (StO2) were significant different (p = 0.003 and 0.01, respectively); IR group showed lower [HbO2] and StO2. Our results imply HPV-16 negative tumors with higher density of vasculature (μs’) and higher blood flow show poor responses to radiotherapy and HPV-16 positive tumors with lower tissue oxygenation level (lower StO2 and [HbO2]) exhibit poor treatment outcomes. Our diffuse optical measurements show the great potential for early prediction of radiotherapy in head and neck cancers.
Occlusion calibrations and gating techniques have been recently applied by our laboratory for continuous and absolute diffuse optical measurements of forearm muscle hemodynamics during handgrip exercises. The translation of these techniques from the forearm to the lower limb is the goal of this study as various diseases preferentially affect muscles in the lower extremity. This study adapted a hybrid near-infrared spectroscopy and diffuse correlation spectroscopy system with a gating algorithm to continuously quantify hemodynamic responses of medial gastrocnemius during plantar flexion exercises in 10 healthy subjects. The outcomes from optical measurement include oxy-, deoxy-, and total hemoglobin concentrations, blood oxygen saturation, and relative changes in blood flow (rBF) and oxygen consumption rate (rV˙O2). We calibrated rBF and rV˙O2 profiles with absolute baseline values of BF and V˙O2 obtained by venous and arterial occlusions, respectively. Results from this investigation were comparable to values from similar studies. Additionally, significant correlation was observed between resting local muscle BF measured by the optical technique and whole limb BF measured concurrently by a strain gauge venous plethysmography. The extensive hemodynamic and metabolic profiles during exercise will allow for future comparison studies to investigate the diagnostic value of hybrid technologies in muscles affected by disease.
Knowledge of tissue blood flow (BF) changes after free tissue transfer may enable surgeons to predict the failure of flap thrombosis at an early stage. This study used our recently developed noncontact diffuse correlation spectroscopy to monitor dynamic BF changes in free flaps without getting in contact with the targeted tissue. Eight free flaps were elevated in patients with head and neck cancer; one of the flaps failed. Multiple BF measurements probing the transferred tissue were performed during and post the surgical operation. Postoperative BF values were normalized to the intraoperative baselines (assigning “1”) for the calculation of relative BF change (rBF). The rBF changes over the seven successful flaps were 1.89±0.15, 2.26±0.13, and 2.43±0.13 (mean±standard error), respectively, on postoperative days 2, 4, and 7. These postoperative values were significantly higher than the intraoperative baseline values (p<0.001), indicating a gradual recovery of flap vascularity after the tissue transfer. By contrast, rBF changes observed from the unsuccessful flaps were 1.14 and 1.34, respectively, on postoperative days 2 and 4, indicating less flow recovery. Measurement of BF recovery after flap anastomosis holds the potential to act early to salvage ischemic flaps.
Significant drops in arterial blood pressure and cerebral hemodynamics have been previously observed during vasovagal syncope (VVS). Continuous and simultaneous monitoring of these physiological variables during VVS is rare, but critical for determining which variable is the most sensitive parameter to predict VVS. The present study used a novel custom-designed diffuse correlation spectroscopy flow-oximeter and a finger plethysmograph to simultaneously monitor relative changes of cerebral blood flow (rCBF), cerebral oxygenation (i.e., oxygenated/deoxygenated/total hemoglobin concentration: r[HbO 2 ]/r[Hb]/rTHC ), and mean arterial pressure (rMAP) during 70 deg head-up tilt (HUT) in 14 healthy adults. Six subjects developed presyncope during HUT. Two-stage physiological responses during HUT were observed in the presyncopal group: slow and small changes in measured variables (i.e., Stage I), followed by rapid and dramatic decreases in rMAP, rCBF, r[HbO 2 ] , and rTHC (i.e., Stage II). Compared to other physiological variables, rCBF reached its breakpoint between the two stages earliest and had the largest decrease (76±8% ) during presyncope. Our results suggest that rCBF has the best sensitivity for the assessment of VVS. Most importantly, a threshold of ∼50% rCBF decline completely separated the subjects from those without presyncope, suggesting its potential for predicting VVS.
Technologies currently available for the monitoring of electrical stimulation (ES) in promoting blood circulation and tissue oxygenation are limited. This study integrated a muscle stimulator with a diffuse correlation spectroscopy (DCS) flow-oximeter to noninvasively quantify muscle blood flow and oxygenation responses during ES. Ten healthy subjects were tested using the integrated system. The muscle stimulator delivered biphasic electrical current to right leg quadriceps muscle, and a custom-made DCS flow-oximeter was used for simultaneous measurements of muscle blood flow and oxygenation in both legs. To minimize motion artifact of muscle fibers during ES, a novel gating algorithm was developed for data acquisition at the time when the muscle was relaxed. ES at 2, 10, and 50 Hz were applied for 20 min on each subject in three days sequentially. Results demonstrate that the 20-min ES at all frequencies promoted muscle blood flow significantly. However, only the ES at 10 Hz resulted in significant and persistent increases in oxy-hemoglobin concentration during and post ES. This pilot study supports the application of the integrated system to quantify tissue hemodynamic improvements for the optimization of ES treatment in patients suffering from diseases caused by poor blood circulation and low tissue oxygenation (e.g., pressure ulcer).
Peripheral artery disease (PAD) is a common condition with high morbidity. While measurement of tissue oxygen saturation (S t O 2 ) has been demonstrated, this is the first study to assess both S t O 2 and relative blood flow (rBF) in the extremities of PAD patients. Diffuse optics is employed to measure hemodynamic response to treadmill and pedal exercises in 31 healthy controls and 26 patients. For S t O 2 , mild and moderate/severe PAD groups show pronounced differences compared with controls. Pre-exercise mean S t O 2 is lower in PAD groups by 9.3% to 10.6% compared with means of 63.5% to 66.2% in controls. For pedal, relative rate of return of S t O 2 to baseline is more rapid in controls (p<0.05 ). Patterns of rBF also differ among groups. After both exercises, rBF tend to occur at depressed levels among severe PAD patients compared with healthy (p<0.05 ); post-treadmill, rBF tend to occur at elevated levels among healthy compared with severe PAD patients (p<0.05 ). Additionally, relative rate of return to baseline S t O 2 is more rapid among subjects with reduced levels of depression in rBF (p=0.041 ), even after adjustment for ankle brachial index. This suggests a physiologic connection between rBF and oxygenation that can be measured using diffuse optics, and potentially employed as an evaluative tool in further studies.
The dual-wavelength diffuse correlation spectroscopy (DCS) flow-oximeter is an emerging technique enabling simultaneous measurements of blood flow and blood oxygenation changes in deep tissues. High signal-to-noise ratio (SNR) is crucial when applying DCS technologies in the study of human tissues where the detected signals are usually very weak. In this study, single-mode, few-mode, and multimode fibers are compared to explore the possibility of improving the SNR of DCS flow-oximeter measurements. Experiments on liquid phantom solutions and in vivo muscle tissues show only slight improvements in flow measurements when using the few-mode fiber compared with using the single-mode fiber. However, light intensities detected by the few-mode and multimode fibers are increased, leading to significant SNR improvements in detections of phantom optical property and tissue blood oxygenation. The outcomes from this study provide useful guidance for the selection of optical fibers to improve DCS flow-oximeter measurements.
This study investigates a method using novel hybrid diffuse optical spectroscopies [near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS)] to obtain continuous, noninvasive measurement of absolute blood flow (BF), blood oxygenation, and oxygen consumption rate (O2) in exercising skeletal muscle. Healthy subjects (n = 9) performed a handgrip exercise to increase BF and O2 in forearm flexor muscles, while a hybrid optical probe on the skin surface directly monitored oxy-, deoxy-, and total hemoglobin concentrations ([HbO2], [Hb], and THC), tissue oxygen saturation (StO2), relative BF (rBF), and relative oxygen consumption rate (rO2). The rBF and rO2 signals were calibrated with absolute baseline BF and O2 obtained through venous and arterial occlusions, respectively. Known problems with muscle-fiber motion artifacts in optical measurements during exercise were mitigated using a novel gating algorithm that determined muscle contraction status based on control signals from a dynamometer. Results were consistent with previous findings in the literature. This study supports the application of NIRS/DCS technology to quantitatively evaluate hemodynamic and metabolic parameters in exercising skeletal muscle and holds promise for improving diagnosis and treatment evaluation for patients suffering from diseases affecting skeletal muscle and advancing fundamental understanding of muscle and exercise physiology.
A noncontact diffuse correlation spectroscopy (DCS) probe has been developed using two separated optical paths for the source and detector. This unique design avoids the interference between the source and detector and allows large source-detector separations for deep tissue blood flow measurements. The noncontact probe has been calibrated against a contact probe in a tissue-like phantom solution and human muscle tissues; flow changes concurrently measured by the two probes are highly correlated in both phantom (R2 = 0.89, p<10−5) and real-tissue (R2 = 0.77, p<10−5, n = 9) tests. The noncontact DCS holds promise for measuring blood flow in vulnerable (e.g., pressure ulcer) and soft (e.g., breast) tissues without distorting tissue hemodynamic properties.
Arterial revascularization in patients with peripheral arterial disease (PAD) reestablishes large arterial blood supply to the ischemic muscles in lower extremities via bypass grafts or percutaneous transluminal angioplasty (PTA). Currently no gold standard is available for assessment of revascularization effects in lower extremity muscles. This study tests a novel near-infrared diffuse correlation spectroscopy flow-oximeter for monitoring of blood flow and oxygenation changes in medial gastrocnemius (calf) muscles during arterial revascularization. Twelve limbs with PAD undergoing revascularization were measured using a sterilized fiber-optic probe taped on top of the calf muscle. The optical measurement demonstrated sensitivity to dynamic physiological events, such as arterial clamping/releasing during bypass graft and balloon inflation/deflation during PTA. Significant elevations in calf muscle blood flow were observed after revascularization in patients with bypass graft (+48.1 ± 17.5%) and patients with PTA (+43.2 ± 11.0%), whereas acute post-revascularization effects in muscle oxygenation were not evident. The decoupling of flow and oxygenation after revascularization emphasizes the need for simultaneous measurement of both parameters. The acute elevations/improvements in calf muscle blood flow were associated with significant improvements in symptoms and functions. In total, the investigation corroborates potential of the optical methods for objectively assessing the success of arterial revascularization.
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