13 PET/CT Imaging in Breast Cancer, Gastrointestinal Cancers, Gynecological Cancers and Lymphoma

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13 PET/CT Imaging in Breast Cancer,

Gastrointestinal Cancers, Gynecological Cancers and Lymphoma

Martin Allen-Auerbach, Johannes Czernin, and Christiaan Schiepers

M. Allen-Auerbach, MD; J. Czernin, MD;

C. Schiepers, MD, PhD

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, AR-144 CHS, Los Angeles, CA 90095-6942, USA

brown adipose tissue can be avoided (Goerres et al.

2003a; Cohade et al. 2003a). Because PET/CT provides the anatomical localization of mild or asym- metric hypermetabolic foci, images can be interpreted with a higher level of confidence, resulting in a reduced rate of false positive and false negative findings (Lardinois et al. 2003).

Since PET/CT only emerged as a clinical tool at the beginning of this millennium, studies evaluating the added value of PET/CT over PET are still limited. However, initial studies suggest that PET/

CT improves the accuracy of staging in lung cancer, colorectal cancer, head/neck cancer and lymphoma (Lardinois et al. 2003; Cohade et al. 2003b;

Schoder et al. 2004; Freudenberg et al. 2003).

This chapter reviews currently implemented PET/

CT imaging protocols and the current state and specific impact of PET/CT on the most common onco- logical indications other than head/neck and lung cancer (discussed in Chap. 12).

13.2

Imaging Protocols

13.2.1 PET/CT

No firm consensus regarding the optimal PET/CT acquisition and processing protocols has been established. Specific protocols depend upon several fac- tors. Firstly, differences in PET detector technology determine the duration of PET emission scanning.

For instance, because of its high sensitivity and light output (see Chap. 15) the LSO detector technology allows for very short imaging sequences (Halpern et al. 2004a). Similarly, the CT component deter- mines whether high quality, diagnostic CT studies can be performed. Multi-detector CT scanners are now standard in the radiology community. PET is a whole body imaging technique while CT tradition- ally provides limited views of head/neck, chest, and

CONTENTS

13.1 Introduction 215 13.2 Imaging Protocols 215 13.2.1 PET/CT 215

13.2.2 CT with Contrast Enhancement 216 13.2.3 Breathing Effects 218

13.3 Clinical Applications 218 13.3.1 Breast Cancer 218

13.3.2 Gastrointestinal Cancer 219 13.3.2 Lymphoma 221

13.3.2 Gynecological Malignancies 221 13.4 Conclusion 223

References 224

13.1

Introduction

The advantages of PET/CT over PET are discussed in Chaps. 6, 12, and 15. In brief, PET/CT Imaging com- bines simultaneous high quality molecular (PET) with anatomical information (CT) (Townsend et al.

2004). Because the CT data are used for attenuation correction, imaging time is reduced by at least 50%

(Halpern et al. 2004a). Thus, almost all patients can be imaged in arms-up position, which reduces motion artifacts.

The information provided by CT is important for several reasons. Hypermetabolic foci can be local- ized to specific anatomical structures. In addition, primary or metastatic lesions with low or no glucose metabolic activity might only be detectable by anatomic imaging. Areas of mildly and focally increased FDG uptake can result in ambiguous PET interpretations. Finally, misinterpretation of asym- metrical benign physiological activity in muscle or

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abdomen/pelvis. Since CT is used for attenuation correction a whole body CT needs to be acquired in each patient. Whereas a low dose CT is sufficient for attenuation correction, its diagnostic quality is limited. Therefore, most institutions acquire a higher dose CT, i.e. 130 kVp and 120 mAs, resulting in diagnostic quality images.

Based on studies in more than 4000 patients we believe that PET/CT imaging should not only include diagnostic PET but also diagnostic CT images for several reasons. Whereas FDG-PET is highly sensi- tive and quite specific for malignancy (Antoch et al.

2004) the anatomic information undoubtedly adds to the diagnostic accuracy, probably most importantly by improving the specificity of PET imaging.

In a group of 169 patients referred for staging of a mixture of neoplasms, we found a 12% improvement by PET/CT imaging over PET alone (Schiepers et al. 2003). Maximizing the information obtained by a single PET/CT scan will eventually lead to accep- tance of PET/CT as the comprehensive cancer-imaging tool of choice.

13.2.2

CT with Contrast Enhancement

Diagnostic CT studies frequently include intravenous and oral contrast, which significantly enhance the quality of the CT images. Intravenous contrast results in improved definition of anatomical structures, increased sensitivity for pathological lesion detection and better lesion characterization. The PET/CT community is divided as to whether and how much contrast is necessary for optimizing PET/CT imaging. Intravenous contrast certainly increases the complexity of patient scheduling, preparation and throughput. Furthermore, considerable skills are required from technologists to simultaneously perform high quality PET and contrast CT scans.

Frequently cited problems with attenuation correction secondary to the high density of the contrast material can lead to attenuation artifacts (Antoch et al. 2002; Halpern et al. 2004b). Thus, intravenous contrast studies require that interpreting physicians recognize these artifacts (Fig. 13.1).

Fig. 13.1. a Axial images of a 67-year-old female referred for re-staging of colon cancer, 2 years after curative resection. Left panel, CT image in the soft tissue window, with intra-venous contrast in the left subclavian region (white arrow). Second panel left, PET image with mildly increased uptake in the left subclavian area, related to over-estimation of the attenuation coefﬁ cients due to the contrast. Second panel from right, fused axial images, CT in gray scale and PET in color. Right panel, PET image not corrected for attenuation shows normal uptake in the left subclavian region. b Coronal PET image shows the mildly increased uptake (pseudo FDG uptake) in the left subclavian region (black arrow). c In the uncorrected image this is not present, indicat- ing that the “uptake” is an attenuation correction artifact

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b c

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At our institution, a joint read out of PET/CT images by radiologists and nuclear medicine physicians has been established. Most academic institutions have sub-specialties in radiology, and several radiologists are needed to report a whole body CT scan. Because of the requests of referring oncolo- gists and interpreting radiologists, we are adminis- tering contrast to all patients in whom there is no contraindication.

Our intravenous contrast protocol consists of 120 ml of Omnipaque 350 administered at a rate of 1.5–2 ml/s with a 45-s delay. For oral contrast, we use 900 ml of READY-CAT® with 2.1% barium sulfate, administered in three portions PO during the hour prior to imaging. This protocol results in satisfactory contrast enhancement and good image quality for the different body regions. Spe- cialized protocols (e.g. arterial and venous phase of the liver) cannot be obtained given the time constraints of scheduling and throughput. The advantage of having IV contrast enhancement is most apparent in patients with head and neck

cancer, where the differentiation between normal and abnormal glucose metabolic activity as well as the delineation of abnormal from normal anatomical structures can be very difficult. In the thorax the addition of IV contrast significantly enhances the evaluation of mediastinal structures, allowing for precise localization of increased FDG activity into specific lymph nodes and nodal stations. The enhancement of gastrointestinal tract with oral contrast allows the separation of soft tissue from bowel thus greatly facilitating the differentiation of physiological bowel activity from potentially abnormal activity within lymph nodes or other abdominal and pelvic structures. In our experience the attenuation artifacts caused by contrast are few, in most cases easily recognizable and usually caused by a bolus of IV contrast within the large thoracic veins (Antoch et al. 2002). The availability of non-attenuation corrected images further diminishes the problems caused by attenuation artifacts (Fig. 13.2).

Fig. 13.2. a Same patient as in Fig. 13.1 with similar layout. Axial images at the level of the superior vena cava. Note the hot spot on PET (black arrow on second panel from left), corresponding to contrast on CT (white arrow, left panel). The uncor- rected PET image is normal in this region (right panel). b Coronal PET images show that the hot focus in the superior vena cava region (black arrow) is induced by attenuation correction. c The uncorrected coronal image shows normal FDG uptake in this region of the thorax

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13.2.3

Breathing Effects

Conventional CT imaging of the chest and abdomen is performed during breath hold at maximal inspiration to achieve optimal visualization of the lung parenchyma and to avoid artifacts of structures affected by diaphragmatic motion. The short scan times achieved with modern CT scanners allow for such breath hold studies in most patients. PET imaging requires much longer acquisition times. We have established a weight-based protocol with PET image acquisition times usually ranging from 1 to 4 min per bed position (Halpern et al. 2004a). This results in an average PET/CT acquisition time of about 15 min.

The chest usually encompasses two bed positions, and would require a breath hold of at least 2 min for PET. Since a breath hold over such an extended period of time is impossible, patients are imaged during shallow breathing. To achieve optimal fusion, the CT images are also acquired during shallow breathing. The image artifacts resulting from respiratory motion have been described (Beyer et al. 2003;

Goerres et al. 2002, 2003b), are easily recognized and rarely cause significant problems for the interpretation of the studies. From a radiological point of view, the interpretation of the lung parenchyma and of structures adjacent to the diaphragm is significantly hampered by respiratory motion. Small sub-centimeter lung nodules are easily missed.

Since sub centimeter lesions frequently are below the resolution of PET imaging (Crippa et al. 2000), significant findings can be missed. Several studies have addressed the quest for an ideal breathing protocol. Although some of the proposed protocols can reduce the artifacts produced by respiratory motion, none of the protocols allows for optimal imaging of the lung parenchyma. A promising approach for the future appears to be the implementation of respiratory gating which in theory could provide optimal fusion together with high quality CT images not compromised by respiratory motion artifacts (Boucher et al. 2004).

It is to date unknown whether all patients need a whole body diagnostic CT study with intravenous contrast. For instance, the accuracy of PET for staging and restaging of lymphoma is very high.

The addition of non-contrast CT studies further enhances the diagnostic accuracy (Allen-Auer- bach et al. 2004). Contrast CT might provide no or very limited additional diagnostic value (Schaefer et al. 2003).

13.3

Clinical Applications

13.3.1 Breast Cancer

Mammography is the screening modality of choice for the detection of breast cancer. However, in women with dense or scarred breasts, mammographic assessment is severely limited and its sensitivity has been reported to be as low as 30% (Mandelson et al. 2000).

In addition, the specificity of mammography is low with more than 50% of biopsies performed for benign lesions (Orel et al. 1999). Given the fact that the overall sensitivity of PET and mammography are compa- rable (Noh et al. 1998; Scheidhauer et al. 1996) and that glucose metabolic activity of breast tissue is inde- pendent of breast density (Vranjesevic et al. 2003) PET can play an important role for screening women with dense or very dense, and scarred breasts.

The advent of PET/CT could provide additional information, by allowing precise anatomical localization of metabolic abnormalities and providing guidance for possible biopsy. FDG-PET is also helpful for detecting internal mammary node involvement and distant sites throughout the body (Schirrmeister et al. 2001). Nevertheless, certain problems remain.

The sensitivity for staging of axillary lymph nodes with PET is unsatisfactory as was demonstrated in a multicenter trial by Wahl et al. (2004) and a pro- spective study by Fehr et al. (2004). PET/CT might be helpful in determining the precise number of axillary lymph nodes involved, an important prognostic marker, which cannot be accomplished by PET alone. Tatsumi et al. (2003) reported additional information with PET/CT compared to PET in 17 of 48 patients with breast cancer and abnormal PET findings. Additional information was however provided for only a single axillary lesion. At this point it seems unlikely that PET/CT will be able to replace sentinel lymph node biopsy and axillary lymph node dissection for axillary lymph node staging. In the same study (Tatsumi et al. 2003) PET/CT provided additional information for characterizing correctly four internal mammary, three mediastinal and seven bone lesions. Detection and differentiation of internal mammary nodes from mediastinal or lung metastases is important for staging of disease as well as guidance for possible biopsy procedures.

In the evaluation of bone metastasis, osteolytic and bone lesions of a mixed type are readily detected by FDG-PET. However, sclerotic bone lesions are frequently negative (Cook et al. 1998; Gallowitsch et

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al. 2003). Fig. 13.3 illustrates the PET/CT images of such a patient. The identification of sclerotic bone lesions on the CT portion of the PET/CT might aid in directing further diagnostic imaging (bone scan, MRI) and treatment.

The overall effect of PET/CT on patient management was prospectively evaluated in a study by Buck et al. (2003) in 78 patients with suspected disease recurrence. As a result of improved detection and localization of lesions, PET/CT had a major impact on patient management in 36% of patients studied. The low sensitivity of PET for detection of breast cancer of the lobular and ductal in-situ type (Avril et al. 2001) is unlikely to be improved with the addition of CT since CT findings for these disease entities are non- specific and unlikely to improve overall sensitivity.

Data from our own institution by Fueger et al.

(2004) in a group of 60 patients referred for staging and restaging of breast cancer demonstrated a

considerable advantage of PET/CT over PET by correctly changing stage in 10% of patients (downstag- ing three patients and upstaging three). False negative PET studies were mostly due to sclerotic bone lesions. Whereas false positive PET studies in most cases were the result of non-specific muscle uptake as identified by PET/CT.

The role of PET/CT imaging in breast cancer is evolving. Clear advantages of PET/CT over PET alone have been demonstrated for restaging and for initial staging of axillary and internal mammary lymph node involvement, but not for primary diagnosis.

13.3.2

Gastrointestinal Cancer

The interpretation of FDG-PET images of the gastrointestinal tract is complicated by the frequently high

Fig. 13.3. a Axial CT slice (bone window), of a 53-year-old female with a history of breast cancer. Status post surgery and chemotherapy. Note the density in the vertebral body (white arrow), suspicious for metastasis. b Sagittal images show two lesions on CT in bone window (left, white arrow indicates T11), which have no increased uptake on PET (middle panel).

The right panel shows the fused image, CT in gray and PET in color. This ﬁ nding suggest sclerotic bone lesions

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b

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and sometimes focal physiological glucose metabolic activity of the bowel. These areas of increased FDG uptake represent normal gastrointestinal activity hypothesized to be either secondary to smooth muscle uptake related to peristalsis (Miraldi et al.

1998) or activity related to mucosal uptake (Jadvar et al. 1999). Normal ureteral and bladder activity can further complicate the assessment of FDG-PET scans of patients with gastrointestinal cancer. On the other hand, the evaluation with CT of patients previously treated with surgery or radiation can be difficult, because CT has a limited specificity in the characterization of soft tissue (such as presacral stranding) frequently representing scar tissue or necrotic residual masses.

Early PET literature suggests that the key advantage of PET imaging is related to its ability to determine extra-hepatic metastases (Schiepers et al.

1995; Rose et al. 1999). In addition, a superior performance of PET over CT with regards to identifying liver metastases has been reported (Schiepers and Hoh 2000). However, these studies were conducted when the CT technology was less advanced than it is

now. Initial data assessing the performance of PET/

CT over PET or CT alone are emerging.

Cohade et al. (2003c) reported an 11% increase in staging accuracy by PET/CT over PET alone in a retrospective study of 45 patients with colorectal cancer. Interestingly a positron emission source (⁶⁸Ge) instead of the available CT data was used for attenuation correction. Another study by Frances et al. (2003) comparing PET/CT to PET alone reported an impact on the surgical management in 24% of 21 patients with known colorectal cancer by PET/CT.

In a study of 45 patients with recurrent colorectal cancer performed at our institution (Kim et al. 2004) PET/CT detected more lesions than PET alone, lead- ing to a clinically relevant change of tumor stage in 9% of patients. A typical example of local recurrence is shown in Fig. 13.4.

Less information is available regarding the performance of PET/CT in patients with esophageal cancer. A study by Bar-Shalom et al. (2003) of 18 patients with esophageal cancer reported improved detection and characterization of 35% of suspicious sites in 89% of patients by PET/CT vs PET and CT.

Fig. 13.4. a A 72-year-old male, 6 months after anterior resection of an adeno-carcinoma of the rectum. He returned with abdominal pain and constipation. Axial images of the pelvis for CT (left), PET (middle), and fusion (right), show two foci of increased FDG uptake. A recurrence was seen at the site of anastomosis (arrowhead) and an affected lymph node right of the midline (white arrow). b Sagittal PET image shows the large pre-sacral recur- rence (arrowhead). An additional hyper-metabolic lymph node was found higher in the pelvis (black arrow). Note the hot bladder

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Image fusion altered patient management in 22% of the study group.

Mucinous colorectal and pancreatic cancers frequently do not exhibit increased FDG uptake. It is therefore likely that lesions potentially missed by PET alone could be detected and better classified by PET/CT. In a study that included 16 patients with a pancreatic mass who were studied prior to surgery (Tann et al. 2003) PET/CT correctly reclassified five lesions interpreted as indeterminate by PET alone.

However, the false negative rate in this study was not reduced by PET/CT.

The relatively high normal FDG activity in the liver frequently causes problems in the detection of malignant intrahepatic lesions. The availability of fused PET-CT images could help in the evaluation of patients with suspected hepatic malignancy since CT identifies hepatic lesions with a high sensitivity.

However, the benefit of image fusion in patients with hepatocellular carcinoma is less clear, since hepatocellular carcinomas rarely demonstrate increased FDG uptake (Khan et al. 2000).

Few studies have evaluated the role and advantage of PET/CT over PET in the monitoring of treatment response for gastrointestinal malignancies. In patients with gastrointestinal stromal tumors (GIST) PET is superior to CT in detecting early metabolic changes that are indicative of tumor response (van den Abbeele et al. 2002). A study by Antoch et al.

(2004) indicates that dual-modality PET/CT imaging compared to PET alone, or side-by-side PET and CT interpretation, detected more lesions on the baseline scans and demonstrated higher accuracy in determining tumor response after 1 month of treatment.

The role of PET/CT imaging of gastrointestinal malignancies can be summarized as follows. PET/CT improves the staging accuracy in colorectal cancer when compared to PET or CT alone. Initial studies suggest a similar advantage of PET/CT in patients with esophageal cancer while no clear benefits have been demonstrated for pancreatic and primary hepatic malignancies. The key advantage of PET/CT appears to be related to its increased specificity over PET alone.

13.3.2 Lymphoma

FDG-PET has proven to be a valuable tool for staging, restaging and prediction of response to chemotherapy in Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) (Cremerius et al. 1999; Kaplan 2002; Hoskin 2002; Bangerter et al. 1998; Jerusa-

lem et al. 1999; Filmont et al. 2003; Spaepen et al.

2001). The limited anatomical resolution of PET can, however, result in difficulties in the localization of extranodal disease that frequently occurs in NHL.

Lymph node lesions mistakenly placed into bone or lung for example, would lead to significant upstaging of disease. Frequently encountered benign entities with increased uptake, such as brown fat or non-specific muscle activity, pose a particular challenge in patients with lymphoma. For instance, FDG uptake in brown fat occurs more frequently in younger patients, an age group with high incidence of lymphoma. Thus, benign patterns can easily be confused with malignant hypermetabolic foci in these patients. The anatomical detail provided by the CT portion has therefore the potential of significantly improving the specificity and hence accuracy of lymphoma staging. This, in turn, would allow for improved treatment monitoring and appropriate adjustments of subsequent treatment.

In a study of 27 patients with HD and NHL by Freudenberg et al. (2003) restaging was altered in 11 % of patients by FDG-PET/CT compared to FDG-PET imaging alone. The same study reported a change in disease stage by PET/CT in 14% of patients when compared to side-by-side interpretation of FDG-PET and CT images.

A study at our own institution involving 73 patients with HD and NHL demonstrated a significant change in disease stage in 10% of patients by PET/CT compared to PET alone (Allen-Auerbach et al. 2004). Figure 13.5 shows a patient with wide- spread disease involvement.

Several questions with regard to the role of PET/

CT for imaging lymphoma are currently addressed.

For instance, given the high sensitivity of FDG- PET for lymphoma assessment, how much intravenous contrast is needed for the CT portion of the study? Initial studies suggest that PET/CT could be performed without intravenous contrast in these patients. Given the frequently low glucose metabolic rate in low-grade lymphoma, is PET/CT more sensi- tive than PET alone? Is PET alone sufficient for therapy monitoring or is PET/CT the modality of choice?

More studies in larger patient populations are needed to define the role of PET/CT in lymphoma.

13.3.2

Gynecological Malignancies

Some gynecological malignancies pose a considerable problem for PET imaging (Williams et al.

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2001). First, glucose metabolic activity can be low as is frequently the case for ovarian cancer. This is likely explained by the frequently cystic nature of these tumors in addition to special tumor features such as mucin production. Other tumors such as cervical cancer exhibit markedly increased FDG activity, but the close proximity to bowel, bladder and ureters can render the assessment of regional lymph node involvement difficult (Grigsby et al.

2001). It is important to realize that normal physiological activity is not only found in the urinary collecting system and bowel, but can also occur in the uterus and ovaries. As described by Lerman et al. (2004) premenopausal patients can demonstrate cycle dependent normal increase of FDG activity in the uterus and the ovaries. PET/CT provides a potential advantage by allowing the correct assignment

of hypermetabolic activity to normal and abnormal anatomical structures. False positive lesions are always possible as is shown in Fig. 13.6.

The value of PET/CT for evaluating gynecologic malignancies was examined by Israel et al. (2003) in 57 patients with cervical cancer (n=38), ovarian cancer (n=13) and endometrial cancer (n=6). PET/

CT led to management changes in 17 patients (30%) and added value to PET alone in 50% of the patients.

No diagnostic benefit of PET/CT over PET alone was reported by Cohade et al. (2003b) in 46 clinical patients with ovarian cancer. The accuracy of PET was 80% while that of PET/CT was 83%. However, a significant impact of PET/CT in patients with endo- metrial cancer (n=15) was observed by the same group with 12 of 49 lesions (24.5%) misdiagnosed or anatomically incorrectly placed by PET alone.

Fig. 13.5. a Extensive disease involvement in a 64-year-old woman with non-Hodgkin’s lymphoma. Restaging exam after bone marrow transplant. The left panel shows a cor- onal image of the torso in a more anterior cross-section than the right panel, depicting a slice through the posterior mediastinum. b Axial images at the level of the dome of the diaphragm (top row) and pelvis at the level of L4 (bottom row). The left column shows the CT, middle column PET, and right column the fused images with PET in color and CT in gray scale. Note the intense foci of hyper-metabolism

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Larger studies remain to be conducted to determine advantages of PET/CT over PET for specific gynecological cancers. Initial data strongly suggest that PET/CT will improve the performance of PET in patients with gynecological malignancies.

As was outlined by Wahl (2004), imaging of abdominal and pelvic cancer in the future will be almost exclusively done by PET/CT. This was based on the experience of the Johns Hopkins PET Center, where over 2700 studies were performed in a 2-year period.

13.4 Conclusion

PET/CT is rapidly evolving as the standard imaging procedure in oncology. PET/CT has several established advantages over PET alone. Image duration is reduced by about 50% resulting in improved image quality due to reduced patient motion. A comprehensive “one stop shop” whole body survey for cancer is convenient for patients and interpreting physicians. Shortened image acquisition times also

result in better utilization of the expensive equip- ment. Frequently these arguments are sufficiently compelling for the respective nuclear medicine and radiology departments to acquire this technology.

An increasing body of evidence is emerging that PET/CT leads to improved accuracy for detection, staging and restaging of cancer when compared to conventional PET.

Future studies will document the improved accuracy in larger and better defined patient populations.

Meanwhile the technology continues to develop at a rapid pace. PET/CT systems are now available whereby the number of CT detector slices varies from 1 to 64 and the PET technology ranges from standard to high – end systems. Improvements in PET detector technology will increase the sensitivity of PET for cancer detection. Respiratory gating will result in further improvements in image fusion and will permit exact identification of radiation targets.

PET/CT will play an ever-increasing role in biopsy planning by delineating viable tumor from necrosis or scar.

Issues that need to be addressed are largely related to the PET/CT acquisition protocols. How

Fig. 13.6. a Coronal image of a 38-year-old woman with a history of melanoma of the left conjunctiva. Status post resection, left neck dissection and left superﬁ cial parotidectomy. Referred for re-staging. An unsuspected focal hot spot was found in the left pelvis (arrow). b Axial images show the focus (PET, middle panel) to be related to a cystic structure (CT, left panel). The fusion image (right panel) dem- onstrates the exact location. Pelvic ultrasound and MRI conﬁ rmed that this lesion was a hemorrhagic ovarian cyst

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much CT is needed and how much intravenous contrast is required for diagnostic PET/CT? How can radiation exposure to patients be minimized? And finally and importantly, how should PET/CT studies be interpreted and reported? The need to have both radiologists and nuclear medicine specialists work- ing jointly on PET/CT image protocols and interpretation to provide patients and their physicians with the best possible service, is becoming increasingly evident.

By the end of 2004, 80% of all PET sales were PET/

CT with more than 350 systems installed worldwide.

Thus, PET/CT is here to stay and training require- ments for both nuclear medicine and radiology have to adapt to the new merger of molecular and anatomical imaging.

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