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Biomedical Optics Express

Biomedical Optics Express

  • Editor: Joseph A. Izatt
  • Vol. 3, Iss. 9 — Sep. 1, 2012
  • pp: 2142–2153
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Interlesion differences in the local photodynamic therapy response of oral cavity lesions assessed by diffuse optical spectroscopies

Daniel J. Rohrbach, Nestor Rigual, Erin Tracy, Andrew Kowalczewski, Kenneth L. Keymel, Michele T. Cooper, Weirong Mo, Heinz Baumann, Barbara W. Henderson, and Ulas Sunar  »View Author Affiliations


Biomedical Optics Express, Vol. 3, Issue 9, pp. 2142-2153 (2012)
http://dx.doi.org/10.1364/BOE.3.002142


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Abstract

Photodynamic therapy (PDT) efficacy depends on the local dose deposited in the lesion as well as oxygen availability in the lesion. We report significant interlesion differences between two patients with oral lesions treated with the same drug dose and similar light dose of 2-1[hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH)-mediated photodynamic therapy (PDT). Pre-PDT and PDT-induced changes in hemodynamic parameters and HPPH photosensitizer content, quantified by diffuse optical methods, demonstrated substantial differences between the two lesions. The differences in PDT action determined by the oxidative cross-linking of signal transducer and activator of transcription 3 (STAT3), a molecular measure of accumulated local PDT photoreaction, also showed >100-fold difference between the lesions, greatly exceeding what would be expected from the slight difference in light dose. Our results suggest diffuse optical spectroscopies can provide in vivo metrics that are indicative of local PDT dose in oral lesions.

© 2012 OSA

1. Introduction

2. Materials and methods

2.1 Patient characteristics and measurement protocol

The current report was generated from a Phase-I clinical trial of HPPH-mediated PDT for patients with oral lesions, the main objective of which was to determine the maximum tolerated light dose at a fixed drug dose of 4.0 mg/m2 [10

10. U. Sunar, D. Rohrbach, N. Rigual, E. Tracy, K. Keymel, M. T. Cooper, H. Baumann, and B. H. Henderson, “Monitoring photobleaching and hemodynamic responses to HPPH-mediated photodynamic therapy of head and neck cancer: a case report,” Opt. Express 18(14), 14969–14978 (2010). [CrossRef] [PubMed]

]. The patient treatment and measurement protocol was approved by the RPCI Institutional Review Board. The first patient (Patient-1) had a large carcinoma in situ (CIS) of the hard palate on the roof of the mouth and the second patient (Patient-2) had high grade dysplasia in a papilloma of the buccal mucosa (Fig. 1
Fig. 1 Diagram indicating the types and locations of the lesions in Patient-1 and 2, respectively. Patient-1 had a carcinoma in situ (CIS) of the hard palate on the roof of the mouth (Lesion A) and Patient-2 had high grade dysplasia in a papilloma of the buccal mucosa (Lesion B).
). For both patients, HPPH was administered intravenously (IV) 24 hours before optical measurements and PDT treatment, the light fluence rate was 150 mW/cm2 and the treatment wavelength was 665 nm, corresponding to the in vivo absorption peak of HPPH. The first patient was in the cohort that received 125 J/cm2 and the second patient was in the cohort that received 140 J/cm2. The light source for the PDT treatment was a Coherent dye laser pumped by an Argon ion laser (Spectra Physics), and the light was delivered by a single quartz lens fiber. The treatment beam was centered on the lesion with the beam diameter slightly larger than the lesion diameter such that the periphery of the lesion was also within the treatment field. The size of the treatment field was 3.5 cm for Patient-1 and 2.5 cm for Patient-2. For each patient, optical measurements were acquired from within the lesion (identified by the surgeon) and the surrounding periphery of the lesion. There are two time points in the measurements: pre-PDT (baseline) and post-PDT (just after the end of PDT). At each time point, five measurements were acquired within the lesion and three measurements from the periphery. Multiple measurements were obtained by positioning the hand-held probe at a slightly different location.

2.2 Diffuse optical spectroscopies

For DFS data analysis, background subtracted fluorescence signal was normalized with the reflectance data [32

32. J. Wu, M. S. Feld, and R. P. Rava, “Analytical model for extracting intrinsic fluorescence in turbid media,” Appl. Opt. 32(19), 3585–3595 (1993). [CrossRef] [PubMed]

]. Every four pixels (corresponding to 1.35nm) were binned and the mean and standard deviation for each bin were calculated. Fluorescence signal was assumed to be a linear combination of HPPH, tissue autofluorescence (Auto), and components of the heme pathway such as protoporphyrin IX (PpIX), precursors coproporphyrinogen and uroporphyrinogen (CpUp) and a photoproduct of PpIX (Photo) [33

33. J. C. Finlay, D. L. Conover, E. L. Hull, and T. H. Foster, “Porphyrin bleaching and PDT-induced spectral changes are irradiance dependent in ALA-sensitized normal rat skin in vivo,” Photochem. Photobiol. 73(1), 54–63 (2001). [CrossRef] [PubMed]

]: Ftissue=CHPPHFHPPH+CAutoFAuto+CPpIXFPpIX+CCpUpFCpUp+CPhotoFPhoto, where CHPPH, CAuto, CPpIX, CCpUp, and CPhoto are spectral amplitudes of HPPH, autofluorescence, PpIX, CpUp and photoproduct of PpIX, respectively. These last three fluorescence components were included because the fluorescence spectra of the patients (especially Patient-2) showed distinct porphyrin peaks at approximately 635 nm and 705 nm (Figs. 2(c) and 2(d)). These peaks correspond to the emission peaks of PpIX in vivo. The measured tissue fluorescence (Fdata) from 600nm to 770nm was fitted to the modeled tissue fluorescence (Fmodel) by minimizingχ2=i=1i=N((Fdata(i)Fmodel(i))/σ(i))2, where σ(i) is the standard deviation of each binned pixel. Here, one should note that extracted spectral amplitudes do not correspond to absolute concentrations, since raw fluorescence signal is affected by the optical properties, especially around 410 nm. HPPH fluorescence quantification can be improved by dividing the fitted HPPH amplitude (CHPPH) by the autofluorescence amplitude (CAuto) under the assumptions that the autofluorescence itself does not bleach and that both the HPPH and the autofluorescence intensities are equally affected by any changes in the optical parameters [34

34. A. Amelink, A. van der Ploeg van den Heuvel, W. J. de Wolf, D. J. Robinson, and H. J. Sterenborg, “Monitoring PDT by means of superficial reflectance spectroscopy,” J. Photochem. Photobiol. B 79(3), 243–251 (2005). [CrossRef] [PubMed]

].

2.3 Gel electrophoresis

For determining the cumulative photoreaction in each lesion, biopsies were taken from each lesion after pre- and post-PDT optical measurements for analysis. Briefly, the biopsies were homogenized in Radioimmuno-precipitation buffer and extracted proteins were separated on 6% SDS-polyacrylamide gels. These proteins were then transferred to reinforced nitrocellulose membranes (Optitran, Whatman) and allowed to react overnight with antibodies to STAT3 (Santa Cruz Biotechnology). Enhanced chemiluminescence (ECL) (Pierce Chemical) was performed to detect immune complexes. ECL images were recorded on X-ray films and pixel values at each band were determined using ImageQuant (Amersham Biosciences). Oxidative cross-linking induced by PDT was expressed as the percentage conversion of monomeric STAT3 into the dimeric complex I. Human hypopharyngeal carcinoma cells (FaDu), treated in vitro with 200 nanomol/ml HPPH and 3 J/cm2 of 665 nm light, were used as positive control.

3. Results and discussion

3.1 Pretreatment contrast and changes in blood flow index (BFI)

Figure 3
Fig. 3 Blood flow contrast. (a) Blood flow differences between lesion and periphery for the first patient. (b) Blood flow differences between lesion and periphery for the second patient. Pre-treatment blood flow contrast is significant for both patients. Blood flow changes for each lesion are also significant. Error bars are standard error, * represents statistical significance (p<0.05)
summarizes the results for blood flow index of the lesion and periphery for each patient. The Patient-1 had ~3.8 × higher blood flow in the lesion compared to Patient-2 (p<0.05). At pretreatment, Patient-1 showed ~4.4 × higher blood flow in the lesion compared to the surrounding periphery (p<0.001) and Patient-2 showed ~5.6 × lower blood flow in the lesion compared to periphery (p<0.002).

PDT induced changes in blood flow index for both patients but the changes in Patient-1 were more significant. Specifically, Patient-1 showed an ~83% decrease (p<0.001) and Patient-2 showed a ~59% decrease in the lesion (p<0.02). In both cases the periphery did not show a significant change (p>0.05).

3.2 Pretreatment contrast and changes in blood volume fraction and blood oxygen saturation

Figure 4
Fig. 4 Blood volume fraction (BVf) for lesion and periphery sites before and after treatment for (a) Patient-1 and (b) Patient-2. Blood oxygen saturation (StO2) for lesion and periphery sites before and after treatment for (c) Patient-1 and (d) Patient-2 . Error bars represent standard error.
summarizes the results for blood volume fraction (BVf(%)) and blood oxygen saturation (StO2(%)) of lesion and periphery for each patient. Patient-1 had 1.8 × higher blood volume fraction in the lesion compared to Patient-2. Patient-1 also had 2.6 × higher blood volume fraction (p>0.05) in the lesion compared to periphery, while Patient-2 had 1.8 × lower blood volume fraction in the lesion compared to periphery (p~0.02). PDT induced a reduction in blood volume faction from 2.5 (mean) to 1.9 (mean); however, this change was not statistically significant (p>0.05). The blood volume fraction in the lesion of Patient-2 did not change much but the periphery blood volume fraction showed an increase.

At pre-treatment, the blood oxygen saturation was ~74% in the lesion of Patient-1 and ~64% in the lesion of Patient-2 (p<0.005). When compared to surrounding periphery tissue, blood oxygen saturation did not show pretreatment contrast for Patient-1, but was 1.2 × lower (p<0.03) in the lesion for Patient-2. Blood oxygen saturation increased at post-PDT for Patient-1 but decreased for Patient-2, though these changes were not statistically significant (p>0.05).

3.3 Pretreatment contrast and changes in HPPH concentration

Figure 5
Fig. 5 Photosensitizer concentration (cHPPH [μM]) for lesion and periphery sites before and after treatment for (a) Patient-1 and (b) Patient-2. Error bars represent standard error, * represents statistical significance (p<0.05)
shows the baseline and changes in HPPH photosensitizer concentration for both patients as obtained by diffuse reflectance measurements. Lesion HPPH concentration in Patient-1 (Fig. 5(a)) and Patient-2 (Fig. 5(b)) was higher than periphery. Pre-treatment HPPH concentration in lesion for Patient-1 was 0.34 µM and for Patient-2 was 0.10 µM, demonstrating a 3.4-fold difference. The differences in HPPH content between the two patients may be due to differences in tissue/lesion type and site as well as the physiological state of the patients such as peripheral blood flow and anesthesia level, etc. We could not compare the HPPH levels in the peripheral blood since the sample for Patient-2 did not allow reliable analysis.

By comparing HPPH concentrations pre- and post-PDT, it is clear that PDT induced significant photobleaching of the photosensitizer. The measured HPPH concentration decreased in both lesions. Patient-1 showed a 52% decrease (p<0.007) in HPPH concentration in the lesion while Patient-2 showed a 39% decrease in HPPH concentration. Periphery values for Patient-1 showed a decrease trend but remained relatively constant for Patient-2 at post-PDT.

3.4 Pretreatment contrast and changes in fluorescence

As Figs. 6(a)
Fig. 6 Fitted fluorescence amplitudes before and after PDT. HPPH fluorescence for Patient-1 (a) and Patient-2 (b). Fluorescence ratio (HPPH/Autofluorescence (AF)) for Patient-1 (c) and Patient-2 (d). PpIX fluorescence for Patient-1 (e) and Patient-2 (f). Error bars represent standard error, * represents statistical significance (p<0.05)
and 6(b) indicate, the lesion of Patient-1 had much higher HPPH fluorescence level (1.13 ± 0.28) compared to the lesion of Patient-2 (0.15 ± 0.05). However, both levels were lower than their periphery values. The observed differences in fluorescence and reflectance measurements may be due to optical property differences between the lesions and peripheries at both excitation and emission wavelengths and differences in penetration depth; fluorescence signal originates from shallower tissue compared to reflectance signal. Normalizing with reflectance data partially corrects at the emission wavelength range [670-750] nm, but absorption and scattering effects at the excitation wavelength of ~410 nm are more pronounced. In this respect we have adapted our instrument recently to assess attenuation at ~410 nm as well as to excite the HPPH fluorescence at ~665 nm for improved quantification of HPPH fluorescence for our ongoing studies. The “apparent” HPPH fluorescence decreased in both lesions after PDT. The periphery of the lesion of Patient-1 showed a large decrease while the lesion of Patient-2 showed a significant decrease in HPPH fluorescence at post-PDT.

Figures 6(c) and 6(d) show the ratio of HPPH and autofluorescence amplitude. At pre-PDT, the “improved” HPPH fluorescence indicates slightly more fluorescence in both lesions than in the corresponding peripheries, though these differences were not statistically significant. At baseline, Patient-1 had 10.7 ± 1.2 and Patient-2 had only 2.0 ± 0.3 as fluorescence ratio level. Both lesions showed statistically significant reductions in ratio fluorescence: The level of Patient-1 decreased 52.7% and that of Patient-2 decreased 75.1%.

We plotted PpIX fluorescence in Figs. 6(e) and 6(f) as the main porphyrin fluorescence component. The lesion of Patient-2 had more PpIX fluorescence than that of Patient-1. The PpIX levels remained stable at post-PDT, any changes were not statistically significant. The other porphyrin fluorescence components (precursors coproporphyrinogen and uroporphyrinogen and photoproduct of PpIX) also did not show significant changes at post-PDT (data not shown).

Pretreatment values as well as PDT induced changes in these parameters can affect accumulated local dose. Table 2

Table 2. PDT-induced changes in extracted parameters for Patient-1 (P1) and Patient-2 (P2), BFI and HPPH/Auto were significant for both patients while changes in cHPPH were only significant for Patient-1.

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summarizes the changes in the quantified parameters caused by PDT. Changes in photosensitizer (photobleaching), blood flow and blood volume were significantly higher in Patient-1 (P1) than in Patient-2 (P2), but the changes in blood oxygen saturation were similar for both patients, though the trend showed different polarity: P1 showed an increase trend and P2 showed a decrease trend. Changes in blood flow index (BFI) and the ratio of HPPH to autofluorescence (HPPH/Auto) were significant for both patients while changes in CHPPHwere only significant for Patient-1.

Table 2 and Fig. 7
Fig. 7 STAT3 crosslinking for Patient-1 and Patient-2 with a human hypopharyngeal carcinoma cell line (FaDu) shown as a control.
display the STAT3 cross-linking for these two patients. We previously demonstrated that STAT3 cross-linking is a molecular measure of the accumulated local PDT dose and photoreaction [11

11. B. W. Henderson, C. Daroqui, E. Tracy, L. A. Vaughan, G. M. Loewen, M. T. Cooper, and H. Baumann, “Cross-linking of signal transducer and activator of transcription 3—a molecular marker for the photodynamic reaction in cells and tumors,” Clin. Cancer Res. 13(11), 3156–3163 (2007). [CrossRef] [PubMed]

,12

12. W. Liu, A. R. Oseroff, and H. Baumann, “Photodynamic therapy causes cross-linking of signal transducer and activator of transcription proteins and attenuation of interleukin-6 cytokine responsiveness in epithelial cells,” Cancer Res. 64(18), 6579–6587 (2004). [CrossRef] [PubMed]

]. As summarized in Table 2, Patient-1 had 35% cross-linking indicating a highly efficient photoreaction and accumulated PDT dose compared to Patient-2 which had only 0.3% cross-linking, demonstrating a ~100 fold difference in photoreaction between the patients.

In addition to the HPPH peak near 668 nm, fluorescence signals showed additional peaks near 630 nm for both patients with a much higher signal level for Patient-2. The major natural fluorophores in tissue include collagen, reduced nicotinamide adenine dinucleotide, and porphyrins [36

36. J. R. Lakowicz, Principles of Fluorescence Spectroscopy (Plenum, New York, 1983), pp. 14–18.

,37

37. M. Inaguma and K. Hashimoto, “Porphyrin-like fluorescence in oral cancer,” Cancer 86(11), 2201–2211 (1999). [CrossRef] [PubMed]

]. Compared to the others which mainly emit green fluorescence, porphyrins emit unique red fluorescence above 600 nm, and thus spectral analysis is highly suitable in discriminating porphyrin fluorescence. The porphyrins may be produced by the lesion itself, by microbial activity, or they may be products of cancer metabolites [37

37. M. Inaguma and K. Hashimoto, “Porphyrin-like fluorescence in oral cancer,” Cancer 86(11), 2201–2211 (1999). [CrossRef] [PubMed]

]. This natural red fluorescence has been widely observed in human cancer especially in necrotic and ulcerated lesions, and thus might be an indicator of challenge for effective PDT.

It is clear that diffuse optical spectroscopies can improve the pre-PDT tissue assessment by providing hemodynamic parameters and administrated drug (photosensitizer) concentration. The techniques are noninvasive and near-real time, allowing the collection of many measurements at the operating room, and thus have clear advantages compared to single biopsy sampling. However, for widely spread diseases that occur in the oral cavity, spectroscopic point measurements have limitations and imaging is a more desirable option. After image guidance, spectroscopic measurements can be performed to increase tissue specificity and sensitivity as well as to assess PDT-induced changes. Oral lesions are very challenging since they occur at diverse sites (e.g., tongue, gingiva, lip, palate, etc.) with very different optical properties. Each lesion needs to be investigated on a background of surrounding tissue. For this reason, we compared the lesion with respect to periphery. However, there are limitations to this approach wherein there were only three point measurements of the periphery. Compared to well-established solid tumors there is no well-defined “periphery” tissue that can be clearly demarcated by white-light examination. More sampling at the periphery can help reduce this sampling error. Thus, we will be doing more measurements in the periphery in our ongoing studies.

4. Conclusion

In summary, our results indicate that substantial heterogeneity exists in the physiology of oral lesions, affecting drug and oxygen delivery, and that these factors determine the effective PDT dose. We show that these factors can be monitored non-invasively in real time, which ultimately may improve treatment delivery. We acknowledge that sampling of the biopsy tissue and variation of the delivered dose can contribute to the variations in the local dose. It will be interesting to explore the predictive power of these noninvasive indices compared to STAT3 analysis of biopsies. A statistically valid number of patient measurements has potential to assist in this endeavor and will allow better discrimination of patients with respect to local dose as well as PDT induced changes.

Acknowledgments

This research is supported by RPCI Startup Grant (U. Sunar) and NCI CA55791 (B. W. Henderson).

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A. Amelink, A. van der Ploeg van den Heuvel, W. J. de Wolf, D. J. Robinson, and H. J. Sterenborg, “Monitoring PDT by means of superficial reflectance spectroscopy,” J. Photochem. Photobiol. B 79(3), 243–251 (2005). [CrossRef] [PubMed]

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OCIS Codes
(170.0170) Medical optics and biotechnology : Medical optics and biotechnology
(170.3660) Medical optics and biotechnology : Light propagation in tissues
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(170.6480) Medical optics and biotechnology : Spectroscopy, speckle

ToC Category:
Optical Therapies and Photomodificaton

History
Original Manuscript: June 6, 2012
Revised Manuscript: July 27, 2012
Manuscript Accepted: August 10, 2012
Published: August 16, 2012

Citation
Daniel J. Rohrbach, Nestor Rigual, Erin Tracy, Andrew Kowalczewski, Kenneth L. Keymel, Michele T. Cooper, Weirong Mo, Heinz Baumann, Barbara W. Henderson, and Ulas Sunar, "Interlesion differences in the local photodynamic therapy response of oral cavity lesions assessed by diffuse optical spectroscopies," Biomed. Opt. Express 3, 2142-2153 (2012)
http://www.opticsinfobase.org/boe/abstract.cfm?URI=boe-3-9-2142


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