Pennsylvania Hospital, Philadelphia, Pennsylvania, USA

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1 The Oncologist Cancer Medicine: Case Discussion Cancer of Unknown Primary: Changing Approaches. A Multidisciplinary Case Presentation from the Joan Karnell Cancer Center of Pennsylvania Hospital DAVID M. MINTZER, MICHAEL WARHOL, ANNE-MARIE MARTIN, GARY GREENE Pennsylvania Hospital, Philadelphia, Pennsylvania, USA Key Words. Cancer of unknown primary Cancer of unknown origin Immunohistochemistry Molecular genetics Microarray PET scan LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe the newer pathologic techniques for defining the site of origin of unknown primary cancers, including immunohistochemistry and molecular genetic techniques. 2. List the subsets of patients with unknown primary cancers most likely to achieve long-term survival with appropriate therapies. 3. Explain how the newer radiologic techniques such as MRI and PET scanning can help to localize unknown primary cancers. CME Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Cancer of unknown primary is a common clinical syndrome, accounting for 2%-5% of cancer patients. A representative case is presented. This heterogenous group of disorders includes entities such as poorly differentiated carcinoma of unknown primary, adenocarcinoma of unknown primary, neuroendocrine carcinoma of unknown primary, squamous cell carcinoma of unknown primary, poorly differentiated (not otherwise specified) cancer of unknown primary, and melanoma of unknown primary. It is crucial to identify those treatment-responsive presentations of unknown primary with the greatest potential for long-term survival. This discussion emphasizes newer approaches to the diagnosis and treatment of unknown primary cancer, including advances in pathology with immunoperoxidase and molecular genetic techniques, positron emission tomography, and published chemotherapeutic trials. With the increased sophistication of pathologic and radiologic techniques, the frequency of unknown primary cancers will likely continue to decline. Further, as newer and more targeted therapies for specific types of cancer are identified, the previously held nihilism regarding the search for and identification of the primary may become less supportable. The Oncologist 2004;9: CASE PRESENTATION A 49-year-old female presented with swollen lymph nodes in her left neck. She felt well without any active systemic or localizing symptoms. She had a history of an early cervical cancer treated 15 years previously with cryosurgery and cone resection without known recurrence. Correspondence: David M. Mintzer, M.D., Joan Karnell Cancer Center, 230 West Washington Square, 2nd Floor, Philadelphia, Pennsylvania 19106, USA. Telephone: ; Fax: ; dmmonc@aol.com Received September 5, 2003; accepted for publication December 16, AlphaMed Press /2004/$12.00/0 The Oncologist 2004;9:

2 Mintzer, Warhol, Martin et al. 331 She had undergone a benign right breast biopsy 3 years previously. Her past medical history was notable for mitral valve prolapse, tonsillectomy, and appendectomy. She had quit smoking 6 years previously, with a 15 pack-year history. Her family history was positive for colon cancer in her mother. She was on no regular medications and had no allergies. On physical exam, there were multiple palpable firm nodes measuring 1-2 cm in the lower left cervical and medial left supraclavicular areas. The remainder of her physical examination was negative. CBC, chemistry panel, and chest x-ray were negative. A biopsy of the left lower cervical nodes revealed poorly differentiated carcinoma. Further workup included a computerized tomography (CT) scan of the chest, abdomen, and pelvis, which confirmed the left supraclavicular adenopathy and also showed adenopathy in the upper mediastinum. Ear, nose, and throat evaluation revealed no evident primary lesion on fiberoptic endoscopy. Mammograms were negative. Breast magnetic resonance imaging (MRI) showed no suspicious lesions. Pelvic examination showed no evidence of pathology. Upper and lower endoscopies of the gastrointestinal (GI) tract were negative. Positron emission tomography (PET) scanning revealed uptake in the lower left neck, upper mediastinum, and right hilum, but nowhere else. PATHOLOGY REVIEW AND DISCUSSION Michael Warhol, M.D. A left scalene node biopsy was received. Within the lymph node there were punched out areas representing metastatic tumor (Fig. 1). Higher powered imaging revealed undifferentiated cells that were not forming any recognizable structures (Fig. 2). So while they were not telling us what they were, even undifferentiated cells can be characterized as to size and shape. An internal measuring stick for size is a lymphocyte. These particular tumor cells were many times bigger than lymphocytes; hence, they were large cells. Their shape was round; in particular, their nuclei were round to oval and had at least one, and in certain cases many, prominent nucleoli. So this was a large round cell tumor. Large round cell tumors are usually either undifferentiated carcinoma, large cell lymphoma, or amelanotic melanoma. There were certain clues on routine staining that suggested that this was probably a carcinoma. The cells were cohesive with prominent cell borders, with clustering and a punched out appearance. These are not features of lymphoma. Lymphoma and melanoma tend to have interdigitating cell membranes that, at the resolution of a light microscope, appear indistinct. Distinct cell membranes are suggestive of carcinoma. Immunohistochemistry (IHC) is the current method of choice for the classification of undifferentiated tumors [1]. Different antigens characterize different cell types, with certain antigens present in epithelial tumors, others in lymphoid tumors, and still others in melanomas. The antigens used are specific for only one cell type. Antibodies are colorless, so to identify the antibody, a detection system such as peroxidase enzymes is necessary. These reduce a substrate and produce a brown color at the site of antibody localization. Intermediate filaments, which form part of the cell cytoskeleton, are particularly useful antigens in identifying cells of origin. Keratins are a family of intermediate filaments that characterize epithelial tissue. The tumor in this case stained strongly with antikeratin antibodies, indicating that it was a carcinoma. Ideally, one would like organ-specific antigens, that is, antigens that are present only in a particular organ. Such antigens do exist; prostate-specific Figure 1. Photomicrograph of the scalene node. The lymph node architecture is disrupted by punched out areas of palestaining metastatic carcinoma (hematoxylin and eosin staining, magnification = 40 ). Figure 2. A higher power view of the metastatic tumor. The tumor cells have large, round, vesicular nuclei with prominent nucleoli. There is abundant pale-staining cytoplasm. Cell membranes are distinct (hematoxylin and eosin staining, magnification = 200 ).

3 332 Karnell Cancer Center Unknown Primary antigen and prostatic acid phosphatase are found only in the prostate. They have a sensitivity of about 95% and are very effective diagnostic tools. Obviously, prostate antigens are not relevant in this case. The gross cystic disease fluid protein or Brst-1 antigen is reasonably characteristic of breast cancer [2]. This antigen, however, only has a sensitivity of about 50%, so it is not expressed in about half of all breast cancers. Hormone receptors, such as estrogen and progesterone receptors, can also be relatively specific for tumors like breast and endometrial cancer, but they also can be found in smooth muscle. The keratin proteins, a family of approximately 23 different polypeptides, are emerging as relatively organ-specific antigens. They are both acidic and basic polypeptides, varying in molecular weight from kda. In vivo, keratin peptides exist in pairs. Two basic polypeptides match with two acidic polypeptides to form a keratin tetramer. These different pairs are given different numbers. The distribution of keratins varies among the different types of epithelium. Squamous epithelium contains different keratins from glandular epithelium. Particularly useful keratins include CK7 and CK20 [3, 4] (Table 1). The tumor in this patient was positive for CK7 (Fig. 3) and negative for CK20. So, as shown in Table 1, in the context of the relevant clinical information, ovarian carcinoma and mesothelioma were not considerations. Endometrial carcinoma was not a consideration clinically and Table 1. Patterns of expression of the keratins CK7 and CK 20 in epithelial malignancies CK7 + CK20 + Transitional cell carcinoma Pancreatic carcinoma Ovarian mucinous adenocarcinoma Merkel cell carcinoma CK7 + CK20 Breast carcinoma Non-small cell lung carcinoma Ovarian serous carcinoma Mesothelioma Endometrial carcinoma Pancreatic carcinoma CK7 CK20 Hepatocellular carcinoma Renal cell carcinoma Prostate carcinoma Squamous carcinoma Neuroendocrine carcinoma CK7 CK20 + Colorectal carcinoma From Wang et al. [3] and Chu et al. [4]. Figure 3. The scalene node stained with antikeratin 7, using the immunoperoxidase technique. Note the strong diffuse staining of the tumor cells (immunoperoxidase stain, magnification = 100 ). neither was pancreatic carcinoma. So we were left with breast cancer and lung cancer as likely possibilities. Now, in addition to being CK7 + and CK20, the tumor was also carcinoembryonic antigen (CEA) positive. CEA is relatively nonspecific, but it is present frequently in colorectal, nonsmall cell lung, hepatocellular, and mucinous carcinomas (Table 2). In this particular case, the negative CK20 ruled out colorectal carcinoma. Hepatocellular carcinoma was not a clinical consideration and neither was mucinous carcinoma. So the combination of CK7 positivity and CEA positivity indicates that the tumor in this case was consistent with a lung primary. In summary, this patient had a poorly differentiated cancer. The presence of keratin staining established that it was an epithelial tumor. The presence of a particular type of keratin, specifically CK7, in conjunction with the presence of CEA suggested that the most likely primary site was lung. We could not exclude breast as a primary, but it is relatively uncommon for breast to be strongly CEA positive. It should be emphasized that the results of IHC staining are but one piece of the puzzle, and that these results must Table 2. CEA staining in carcinoma of unknown primary CEA-positive tumors Colorectal carcinoma Non-small cell lung carcinoma Hepatocellular carcinoma Mucinous adenocarcinomas CEA-negative tumors Renal cell carcinoma Prostate carcinoma Endometrial adenocarcinoma Mesothelioma

4 Mintzer, Warhol, Martin et al. 333 be interpreted in the appropriate context. Although extremely helpful, tissue antigens such as CK7 and CK20 themselves rarely specifically identify a primary site. But, as with this case, they can help suggest a primary site through the process of elimination. Also important to remember is that, by definition, tumors are abnormal and, therefore, may not completely mimic the phenotype of their corresponding normal tissue. MOLECULAR GENETIC ANALYSIS IN UNKNOWN PRIMARY CANCER A.M. Martin, Ph.D. While molecular genetic analysis was not performed in the case presented here, I review some published results and the potential utility of such analyses in the classification of cancers of unknown primary. Pathologists classify tumors according to the sites in which they arise and by their morphologies; however, this method of classification can be imprecise. As reviewed above, further analysis relies on the use of IHC techniques to determine the expression of specific molecular markers (proteins). However, even with IHC techniques, limitations exist due to subjectivity, interobserver variation, and the paucity of specific and reliable measurable molecular markers. Standard cytogenetic techniques have also been reported to be occasionally helpful in the classification of unknown primary cancer [5, 6]. Recent technologic advances allow for the simultaneous analysis of genes and their products. Previously, scientists had only been able to conduct specific genetic studies, one gene at a time. However, with the publication of the human genome sequence and the development of DNA microarray technology, we can now study thousands of genes at one time. This greatly enhances the capacity to study every gene in the human genome, identifying and quantifying changes that occur during the course of tumorigenesis. DNA arrays consist of thousands of short strands of DNA sequences (oligonucleotides), identical to the sequences of normal genes, which are assembled systematically onto the surface of a glass slide [7]. These slides can hold more than 20,000 different oligonucleotides representing more than 20,000 different genes. RNA isolated from the test sample (tumor) and a reference sample (normal adjacent tissue) are reverse-transcribed to cdna, then each sample is labeled with a different fluorescent dye. The fluorescent samples are hybridized to the DNA array, and the resulting fluorescence intensities indicate gene activity (Fig. 4). Finally, mathematical algorithms are employed to arrange (cluster) differences in gene expression between different samples. While DNA array expression profiling is arduous for cancer gene discovery, it is, nonetheless, an awesome tool for describing gene expression differences between cancerous and normal cells. Thus, it will help to identify therapeutic targets based on gene expression differences as well as to define new molecular genetic characteristics for tumor sets. The use of DNA microarray technologies has been demonstrated to identify genetic characteristics of various adenocarcinomas [8-12], and the results of these studies are helpful in cases where the adenocarcinoma is of unknown origin. Giordano et al. studied gene expression profiles of 154 primary adenocarcinomas of the lung, colon, and ovary [13]. Using high-density oligonucleotide arrays with 7,129 gene probe sets, they demonstrated comprehensive expression profiles of 57 lung, 51 colon, and 46 ovarian adenocarcinomas. Following statistical analysis, 152/154 of the adenocarcinomas could be classified in an organ-specific manner. Su et al. also reported the use of gene expression signatures in the molecular classification of carcinomas, finding gene subsets that predicted the site of origin for 90% of 175 carcinomas [14]. Finally, Dennis et al. used hierarchical clustering of public expression data from serial analyses of gene expression to identify candidate tumor markers with characteristic patterns and genes predictive for individual primary sites [15]. These findings are both interesting and encouraging, as they confirm what pathologists already suspected as far as histopathological similarities and differences in epithelialderived tumors are concerned. Furthermore, these studies demonstrate that gene-expression profiles are useful in the reclassification of tumors and can define organ-specific Figure 4. DNA array technology. Tumor cdna and normal cdna are labeled with different fluorescent dyes. The labeled cdnas are hybridized to DNA arrays containing oligonucleotides representing known genes. The fluorescence intensity is analyzed using statistical algorithms, and color intensities are assigned to the ratios of gene expression.

5 334 Karnell Cancer Center Unknown Primary gene expression profiles. Some caution may be needed, however, before assuming that cancers of unknown primary, with their atypical clinical presentations, will have the same molecular genetics of cancers of known primary origin. Despite these advances, it is unlikely that gene expression analysis will become the gold standard for pathological diagnostic purposes, but instead, it will provide a means for identifying new tumor-specific markers that can be identified using IHC in formalin-fixed paraffin-embedded tissue. To this end, the goal for pathology diagnostics is to use these new technologies to identify tumor-specific protein panels that can be classified based on their expression patterns. Then, tumors can be further characterized and compared simultaneously with a large number of similar tumor samples using tissue microarrays and IHC techniques, ultimately subclassifying them according to their molecular genetic and protein profiles. In summary, the combination of DNA and tissue-array technologies will greatly facilitate the ability of pathologists to conduct high-throughput validation of tumors. This ultimately will provide a more comprehensive approach to tumor classification and may result in more specific treatment regimens for patients. PET SCANNING IN UNKNOWN PRIMARY CANCER Gary Greene, M.D. PET is a noninvasive nuclear medicine examination used primarily for the detection of tumors. The patient is injected with a glucose analogue that is radioactive ( 18 F fluoro-d-glucose [FDG]). This radiotracer travels preferentially to malignant tumors, most of which show increased glucose metabolism. The 18 F FDG emits a positron within the tumor mass, which then combines with an electron, causing emission of two 511 kev gamma photons. These annihilation photons travel 180 degrees apart from each other. A positron camera is used to detect the photons and construct tomographic cross-sectional images, similar to CT and MRI, which show up as focal hot areas, similar to other nuclear medicine exams. While oncologic PET imaging is approved for the detection and/or staging of lung, breast, esophageal, colorectal, and head and neck cancers, and lymphoma, melanoma, and the solitary pulmonary nodule, several series have reported results in the search for the unknown primary. Recent series have reported the utility of PET imaging in patients specifically with cervical lymph node presentations [16-22] as well as in other sites [23-26]. Those studies indicate that PET imaging can detect an unknown primary tumor in 20%-60% of patients when conventional workups have failed to do so. Further experience is still needed to assess how informative and useful PET scans can be in the clinical management of unknown primary patients and whether PET should be considered in all or just selected patients. The particular patient discussed here presented with left scalene nodes and a CT scan that was positive for pretracheal and precarinal adenopathy. The subsequent PET scan also clearly showed right paratracheal uptake and right hilar uptake as well as confirming disease in the neck within the posterior cervical chain and the left supraclavicular region. In this case the results were consistent with but not diagnostic of a lung primary. CLINICAL APPROACH TO THE PATIENT AND THERAPY David M. Mintzer, M.D. The literature is replete with excellent reviews on the approach to the patient with cancer of unknown primary [27-31]. It cannot be overemphasized that the initial approach is a careful history, physical exam, and review of the pathology with a workup directed toward sites suggested by this initial evaluation. What may be debated is where and how far to go after that. Early studies emphasized the futility, expense, and delay caused by extensive workups in search for the unknown primary. In the past, the type of extensive workup often decried might have involved a chest x-ray, sigmoidoscopy, intravenous pyelogram, barium enema, and upper GI. In a woman, a pelvic examination and a mammogram would have been added. This workup might have taken place over 1-2 weeks, would frequently have been performed in the hospital, and would have had a low diagnostic yield of little clinical relevance with a high rate of false positivity. In addition, there was the discomfort, expense, and inconvenience of a prolonged workup to patients who, overall, had lifespans of generally just a few months with limited therapeutic options [27-28]. Presently, however, imaging studies are faster, more accurate, and more available, so that a CT scan of the chest, abdomen, and pelvis can be completed in just a few minutes. In searching for an upper or lower GI primary, a colonoscopy and upper endoscopy can be performed on the same day with a single sedation for patients who have, for example, liver metastases, ascites, or other infra-diaphragmatic presentations, even in the absence of other GI symptoms or signs. And while some would still note that these workups add unnecessary expense, in comparison with the cost of a therapeutic regimen, the cost of these studies, done expeditiously on an outpatient basis, is relatively modest. Thus, given the improvements in pathologic analysis discussed above, in radiologic imaging (including PET

6 Mintzer, Warhol, Martin et al. 335 imaging), and in endoscopic approaches, we can now identify the primary site more frequently than in the past. Indeed, our own Pennsylvania Hospital Tumor Registry results reveal a trend indicating that the percentage of unknown primary cancers has declined over the past decades to only 2%, with a similar percentage from the Hospital of the University of Pennsylvania Cancer Center registry. Furthermore, not only are we now able to find the primary more frequently, but it is also now more relevant therapeutically to know the primary. In the past, if chemotherapy was to be considered, an empiric regimen was chosen. However, with the availability of many newer and more relatively specific and (at least somewhat) more effective chemotherapeutic agents and regimens, it has become increasingly important to define the primary site. For example, in regard to GI adenocarcinomas, there has been a more targeted therapeutic approach as newer agents have become available. Until the past decade, 5-fluorouracil (5-FU)-based therapy was the mainstay for essentially all these tumors, be they colonic, pancreatic, or gastroesophageal in origin. However, at the present time, each of these entities might be treated with a more individualized approach (e.g., gemcitabine for pancreatic, 5-FU/leucovorin with irinotecan or oxaliplatin for colon, and perhaps epirubicin, cisplatin, and 5-FU or a taxane for gastroesophageal primaries). These changes alter the diagnostic and therapeutic nihilism of the past in searching for the unknown primary (Table 3). One approach to cancer of unknown primary is to divide it first into two groups: carcinomas of unknown primary (adeno-, squamous, poorly differentiated, and neuroendocrine) and poorly differentiated cancer of unknown primary (those that cannot be proven to be carcinomas). Adenocarcinoma of unknown primary remains the one most commonly encountered by medical oncologists. As discussed below, squamous carcinoma of unknown primary (usually presenting in cervical lymph nodes) and poorly differentiated cancer of unknown primary have almost (but not completely) disappeared. One may also encounter melanomas of unknown primary [32]. Worth emphasizing are some specific unknown primary scenarios to which we have changed our approach and with which long-term survival is sometimes achievable (Table 4). Unknown primary squamous cell carcinoma of the cervical lymph nodes, while less common than in the past, is still seen with some frequency [33, 34]. Given better imaging with CT and MRI scans and with fiberoptic endoscopy (including panendoscopy that encompasses head and neck endoscopy, esophagoscopy, and bronchoscopy) with blind biopsies of sites such as the tongue base, tonsil, and nasopharynx, the primary site can be located in many cases. Metastatic disease presenting in level II nodes is commonly found to be tonsillar in origin, and ipsilateral tonsillectomies have been reported to yield the primary site in a significant portion of these cases [35, 36]. Further, molecular genetic studies have shown identical genotyping in areas that appear normal endoscopically but harbor the clonal origins of some of these occult lesions [37]. Even when the primary remains unknown, curative treatment is possible with radiation therapy, surgery, or a combined approach. The sequencing of these modalities, the size of the radiation field, and the role of chemotherapy are controversial and may depend on the extent of the disease and the institutional approach. Nonetheless, up to 50% of these patients may be long-term survivors [33, 34]. Squamous cell carcinoma of unknown primary may occasionally present in the inguinal nodes [38]. In those cases, careful search for an anal, cutaneous, or gynecologic primary should be undertaken. The occult breast primary is also diminishing, as mammographic resolution improves and is coupled with ultrasonography and MRI scanning. A breast cancer is usually presumed when a women presents with adenocarcinoma in the axillary nodes without an evident primary [39-44]. MRI has been particularly helpful when there is a high suspicion of a breast primary with a negative physical exam and mammogram [43, 44]. In women presenting with adenocarcinoma in axillary nodes where still no primary can be isolated, an alternative to the past approach of mastectomy has been increasingly used. This new approach involves radiation therapy to the ipsilateral breast and axilla, coupled with whatever appropriate adjuvant systemic therapy would be Table 3. Factors leading to changing approaches to and declining frequency of the unknown primary cancer Improved sensitivity and specificity of body imaging Increased specificity of pathologic diagnostics (immunologic and molecular genetic) Endoscopic workup PET scanning Chemotherapeutic treatments specifically tailored for specific tumor sites Table 4. Scenarios of unknown primary with greatest potential for long-term survival Axillary nodal adenocarcinoma Peritoneal carcinomatosis Unrecognized extragonadal germ cell tumors Squamous cell cancer involving cervical lymph nodes Poorly differentiated neuroendocrine carcinoma

7 336 Karnell Cancer Center Unknown Primary given for breast cancer based on stage, age, and hormonal status [39-44]. Women, and occasionally men, who present with ascites and diffuse peritoneal seeding may have primary peritoneal cancer [45-47]. These patients generally require laparotomy for diagnosis and may therapeutically benefit from debulking. In these cases, the ovaries have sometimes been removed previously (with documented benign histology) or, if present, are either uninvolved with cancer or have only surface (metastatic) involvement. Clinically and histologically, such peritoneal cancers behave like ovarian cancer with a potential for remission and occasional longterm survival with platinum-based chemotherapy. These cases need to be distinguished from primary peritoneal mesothelioma. Some unknown primary carcinomas may show neuroendocrine features by IHC or electron microscopy [48]. Those that are poorly differentiated may be more likely to respond to small cell lung cancer-type regimens (e.g., etoposide and platinums). The scenario of cancer of unknown primary where a lesion was recognized as cancer but not otherwise discernible as carcinoma, lymphoma, sarcoma, or melanoma is all but gone. While a few cases may still defy categorization, the use of immunoperoxidase staining for keratins, vimentin, and common leukocyte antigen, as well as the availability of molecular genetic assays for immunoglobulin and T-cell receptor rearrangements has allowed categorization of most of these entities to at least a broad group of tumors, helping to focus workup and therapy. The unrecognized midline extragonadal germ cell tumor presentation is critically important to consider, as these patients, generally young males, can be cured with platinumbased testicular cancer chemotherapy programs [49]. They typically present with bulky disease in the retroperitoneum or mediastinum. Measurement of and staining for α-fetoprotein and β-human chorionic gonadotropin in serum and tissue may be helpful. Evidence of karyotypic abnormalities involving chromosome 12 are suggestive of germ cell tumor [5]. When no primary site or particular metastatic pattern is identified, one must resort to an empiric chemotherapy regimen in patients appropriate for treatment. A number of phase II and some phase III trials have been reported [30, 49-52]. However, their interpretation and comparability is problematic since the patients in those trials, by definition, had a variety of different, albeit unknown, primary sites. Nonetheless, a number of investigators, including particularly Hainsworth and Greco [30, 48, 52, 54, 55], have reported results. More recent studies have evaluated the use of a taxane/carboplatin [53] regimen coupled with etoposide [54] or gemcitabine [55]. PATIENT FOLLOW-UP The patient described in this report was treated with paclitaxel and carboplatin for three cycles, a regimen with potential activity against a wide variety of primaries. Based on her clinical presentation with supradiaphragmatic disease, her smoking history, and the pathology, we remained suspicious of a lung primary but were never able to prove it. On follow-up, no primary within the lung ever became evident. After a minor response to chemotherapy alone, radiation was added (to encompass all known sites of disease) along with low-dose weekly chemotherapy. She had a partial response but ultimately developed progressive brain metastases poorly responsive to radiation and died 8 months after her initial diagnosis. SUMMARY With this case presentation, we have reviewed cancer of unknown primary with an emphasis on newer concepts and approaches. 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