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Original Articles: Clinical Transplantation

Posttransplant Lymphoproliferative Disorder in Pancreas Transplantation: A Single-Center Experience

Paraskevas, Steven1; Coad, James E.2; Gruessner, Angelika1; Kandaswamy, Raja1; Humar, Abhinav1; Sutherland, David E.R.1; Gruessner, Rainer W.G.1,3

Author Information
doi: 10.1097/01.tp.0000168366.07896.d7
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Abstract

Posttransplant lymphoproliferative disorder (PTLD) is a spectrum of diseases of the lymphoid cell lineage commonly associated with primary infection by Epstein-Barr virus (EBV) in the context of posttransplant immunosuppression. The incidence in transplant recipients ranges from 0.8% to 20%, and this variation, as with diagnosis and treatment, relies on the method of classification (1–4). After primary EBV infection, the other common risk factors for the development of PTLD are the use of antilymphocyte antibody (ALA) preparations and concurrent cytomegalovirus (CMV) disease (5). To date, no one study of this disease has focused on the pancreas transplant recipient, although some cases have been mentioned in large series of patients with various types of solid organ transplants (6–16). Any particular difference in the behavior or incidence of PTLD in this group of patients has been therefore unrecognized.

As recipient survival following organ transplantation improves, management of complications such as PTLD has become more important. Successful treatment of this condition is also important in improving the risk-to-benefit ratio for life-enhancing or life-extending transplants, such as the pancreas. The identification of individuals at high risk for this problem is essential to proper immunosuppressive management. The purpose of this study was to identify the incidence of PTLD in pancreas transplant recipients, to describe their clinical course, and to compare their outcomes to recipients of other abdominal solid organ transplants with PTLD.

METHODS

Patients

From January 1, 1988 through December 31, 2002, 1,357 pancreas transplants were performed at the University of Minnesota. Of these, 299 were solitary pancreas transplants (PTA), 488 were in patients with a previous kidney transplant (PAK), 569 were simultaneous pancreas-kidney transplants (SPK), and 1 was a simultaneous pancreas-liver. Over the same period, 2,715 solitary kidney, 526 solitary liver, 21 simultaneous liver-kidney, 5 simultaneous liver-intestine, and 8 solitary intestine transplants were performed. From the group of pancreas recipients, we have diagnosed 18 patients with PTLD. Their range from polymorphic disease to malignant B- and T-cell lymphomas, but do not include diagnoses plasmacytic hyperplasia. This group was compared with recipients of liver and/or small bowel transplants and 33 recipients of kidney transplants who, during the same time period, developed PTLD.

Immunosuppression

Between 1988 and 1991, induction immunosuppression for kidney and pancreas recipients consisted of Minnesota antilymphocyte globulin. Several antilymphocyte agents were used between 1992 and 1998; rabbit antithymocyte globulin (rATG) (Thymoglobulin) (Genzyme, Cambridge, MA) was used exclusively after 1998. Maintenance therapy for pancreas recipients involved cyclosporine and azathioprine before 1995 (era 1) and tacrolimus and mycophenolate mofetil after 1995 (era 2). Corticosteroids were used in all patients. Acute rejection episodes were treated with a 5 to 7 day course of ALA in moderate-severe cases, and with a steroid pulse in mild cases. For patients with multiple organ transplants, the total lifetime ALA dose was calculated up to the time of diagnosis.

Antiviral Therapy

Antiviral prophylaxis was with at least 12 weeks of acyclovir from January 1988 through December 1996, and with ganciclovir from January 1997 to the present.

Posttransplant Lymphoproliferative Disorder Data

The medical record was examined for cases of PTLD of either polymorphic or monomorphic histology. Cases of plasmacytic hyperplasia were excluded from this analysis. A database was created with pertinent patient and tumor characteristics including latency, cell type, donor/recipient CMV status, transplant dates, immunosuppression including ALA dose, CD20 positivity, clonality, extranodal involvement, treatment modality, and outcome.

Laboratory Analyses

All biopsy and autopsy tissues involved by posttransplant lymphoma were reviewed and classified by morphology. The monomorphic posttransplant lymphomas were classified according to the revised European-American lymphoma (REAL) classification (17).

EBV early mRNA (EBER) in situ hybridization was performed on deproteinized formalin-fixed paraffin-embedded tissue sections according to the manufacturer's protocol (BioGenex, San Ramon, CA). The EBER-negative cases were confirmed by the polymerase chain reaction (PCR) method.

PCR testing was performed on DNA extracted from fresh tissue, using oligonucleotide primers that amplify a 401 base pair product, corresponding to a region in the BamH1 W fragment of the EBV genome. Appropriate controls were included in all analyses. PCR products were separated by polyacrylamide gel electrophoresis and visualized using ethidium bromide.

Patients were considered to have had active CMV infection within 6 weeks prior to their diagnosis of lymphoma, if they had any of the following: positive seroconversion, shell-vial assay, viral culture, and/or CMV cytopathic effect in tissue biopsies.

CMV in situ hybridization was performed on deproteinized, formalin-fixed, paraffin-embedded tissue sections according to the manufacturer's protocol (Enzo Diagnostics, Farmingdale, NY). The CMV probe was prepared by nick translation of cloned fragments of the CMV Towne strain. This probe has been shown to hybridize with CMV DNA from clinical isolates from all regions of the U.S. and to not hybridize with the DNA from other herpes simplex viruses.

Statistical Analysis

The Kaplan-Meier cumulative incidence of PTLD was calculated for each transplant type and by era. Survival curves were also generated for patient and disease subgroups. All survival curves were compared statistically using the log-rank test on SAS software. ALA dose and organ involvement were calculated from the medical record and compared using the two-tailed Student's t test.

RESULTS

Patients ranged in age at the time of their first transplant from 27 to 48 years with a mean of 41 ± 2 years. There was no significant difference in age at transplantation between pancreas, kidney, and liver recipients. Patient and disease characteristics for the series of 18 cases are summarized in Table 1.

T1-12
TABLE 1:
Posttransplant lymphoproliferative disorder in pancreas recipients at the University of Minnesota from 1988–2002: Disease and patient characteristics

The cumulative incidence of PTLD over 10 years posttransplant was examined for each transplant group, using the time of pancreas transplant as the reference point for PAK recipients. There was no significant difference between SPK, PAK, and PTA recipients, with 5-year rates of 2.5%, 1.2% and 1.0%, respectively (Fig. 1A) (P = 0.23). The same analysis was performed comparing immunosuppressive eras. There was a noticeably higher cumulative incidence in the more recent era, with 5-year rates of 2.1% vs. 0.9%, but this difference was not statistically significant (Fig. 1B) (P = 0.15).

F1-12
FIGURE 1.:
(A) Kaplan-Meier curve of cumulative incidence of posttransplant lymphoproliferative disorder (PTLD) with time, stratified by pancreas transplant type. No significant difference was seen in the rates of PTLD in SPK (▴), PAK (♦), and PTA (▪) recipients. The reference point for PAK recipients was the time of pancreas transplant. (B) Kaplan-Meier curve of cumulative incidence of PTLD with time, stratified by immunosuppressive era. A noticeable, though not statistically significant, difference was seen between era 1 (cyclosporine A/azathioprine, 1988-1994) (♦) and era 2 (tacrolimus/mycophenolate mofetil, 1995-2002) (▪) (P = 0.15).

Comparing PTLD survival by transplant type, pancreas recipients had a significantly shorter overall survival relative to the two other groups (Fig. 2A) (P = 0.001). The 50% cumulative survival was 0.16 years in pancreas recipients, in contrast to 1.7 years for kidney recipients. With follow-up periods of up to 9 years, 57% of liver or small-bowel recipients are still living. Survival for patients with B-cell lesions was also significantly lower in recipients of pancreas transplants compared with recipients of kidney or liver (Fig. 2B) (P < 0.005). For T-cell lesions, pancreas recipients had a significantly higher survival compared with kidney recipients, although the number of patients with this type of lesion was small (Fig. 2C) (P = 0.011). No lesions of this type were seen among liver or small-bowel recipients. In the category of EBER+ B-cell lesions, the most common form of PTLD, pancreas recipients had a significantly poorer survival compared with recipients of other organs (Fig. 2D) (P = 0.025). Among pancreas recipients, no difference was seen between B- and T-cell groups (data not shown), between those with EBER-negative vs. those with EBER-positive lesions (data not shown), or between immunosuppressive eras (Table 2).

F2-12
FIGURE 2.:
(A) Kaplan-Meier survival curves for all cases of clonal posttransplant lymphoproliferative disorder (PTLD). Stratification by organ transplant type demonstrates a significantly shorter survival in pancreas or pancreas-kidney recipients (•) vs. kidney alone (✦) and liver or small bowel recipients (▴). (B) Kaplan-Meier survival curves for all cases of clonal B-cell lineage PTLD. Stratification by organ transplant type demonstrates a significantly shorter survival in pancreas or pancreas-kidney recipients (•) vs. kidney alone (▪) and liver or small bowel recipients (▴). (C) Kaplan-Meier survival curve for all cases of clonal T-cell lineage PTLD. Stratification by organ transplant type demonstrates a significantly longer survival in pancreas or pancreas-kidney recipients (✦) vs. kidney alone (▪) recipients. (D) Kaplan-Meier survival curves for all cases of clonal B-cell lineage, EBER-positive PTLD. Stratification by organ transplant type demonstrates a significantly shorter survival in pancreas or pancreas-kidney grafts (•) vs. kidney, liver, and small bowel recipients (▪) using the Wilcoxon test.
T2-12
TABLE 2:
PTLD and patient characteristics by immunosuppressive era

Examining the B-lineage lymphomas, the mean time to disease diagnosis in pancreas/kidney recipients was 1.5 ± 0.5 years, which compared unfavorably to kidney recipients (5.2 ± 1.2 years) and liver recipients (3.8±1.6 years), a difference for which there was a trend toward significance (Fig. 3) (P = 0.07). The recipients with T-cell lesions exhibited a wide range of latency periods. For pancreas or kidney recipients, this was 6.7 ± 2.8 years, significantly shorter than the 16.6 ± 3.2 year mean latency for kidney recipients (Fig. 3) (P = 0.04).

F3-12
FIGURE 3.:
Disease latency stratified by organ transplant type and cell type. Pancreas recipients with B-cell lesions had a shorter time to presentation; this difference approached significance vs. kidney and liver recipients. Pancreas recipients with T-cell lesions had a shorter time to presentation vs. kidney recipients. #P = 0.07. *P = 0.04.

To evaluate the effect of latency period on prognosis, pancreas recipients were stratified by length of latency period. Two analyses were conducted, using 1 year and 3 years as the defining limit of early onset. Both analyses showed a significant difference in survival, with the early-onset lesions in each case associated with a significantly decreased survival time (Figs. 4A and B). When compared with kidney recipients, pancreas recipients with early lesions had a significantly poorer survival. This was true whether early onset was defined as being within 1 year or 3 years posttransplant (Figs. 4C and D). In the case of late-onset lesions, there was no significant difference between pancreas and kidney recipients (data not shown).

F4-12
FIGURE 4.:
Kaplan-Meier survival curves for all cases of clonal posttransplant lymphoproliferative disorder in pancreas recipients. Stratification by disease latency demonstrates a significantly shorter survival for early-onset disease (•), whether defined as occurrence <1 year posttransplant (A) or <3 years posttransplant (B) vs. late-onset disease (▪). Kaplan-Meier survival curves for all cases of clonal posttransplant lymphoproliferative disorder with onset <1 year posttransplant (C) and with onset <3 years posttransplant (D). Stratification by organ transplant type demonstrates a significantly shorter survival in the recipients of pancreas or pancreas-kidney recipients (•) vs. kidney, liver, and small bowel recipients (▪).

The two eras were compared by patient, treatment, and tumor characteristics (Table 2). There was no significant difference with respect to patient age, disease latency, or EBER positivity. Of note, there was a larger proportion of T-cell lesions in era 1 (33% vs. 22%). The use of ALA was examined in each of the 18 cases in pancreas recipients. In era 1, the patients who developed PTLD were exposed to a significantly higher number of doses of ALA (25 ± 5 vs. 10 ± 0.8)(P < 0.05) including induction and treatment of rejection.

Overall, five recipients received treatment for acute rejection, prior to the diagnosis of PTLD. Of these, two recipients had two episodes and one had five episodes. All but one episode of rejection was treated with 5 to 7 doses of ALA. OKT3 was used primarily before 1998 and Thymoglobulin was used since. One other patient was treated for graft-versus-host disease, with seven doses of Thymoglobulin.

Widespread involvement was common in pancreas recipients, with most lesions involving extranodal sites at the time of presentation. The mean number of organs involved at diagnosis (3.7 ± 2.0) was significantly greater than the organ involvement in liver or small-bowel recipients (2.0 ± 1.5) and kidney recipients (1.7 ± 1.2)(Fig. 5A)(P = 0.007). In the pancreas recipients, 50% of those with B-cell lesions had evidence of bone marrow involvement, whereas this was seen in only 6% of the affected kidney recipients and none of the affected liver recipients (Fig. 5B) (P = 0.053). Gastrointestinal involvement was seen in four recipients, with liver involvement appearing in three more. This clinical entity was associated with a diminished survival and a more fulminant clinical course, whether or not gastrointestinal morbidity was observed. Central nervous system involvement, seen in three recipients, was not associated with a higher mortality. Survival in this group of recipients exceeded 12 months. Allograft involvement, whether of the pancreas (n=2) or a kidney (n=5), was rarely seen at the time of presentation (Table 1).

F5-12
FIGURE 5.:
Multiorgan involvement in clonal posttransplant lymphoproliferative disorder cases. (A) Pancreas recipients with posttransplant lymphoproliferative disorder presented with a higher mean number of organs involved than kidney or liver or small bowel recipients (P = 0.007). (B) A higher percentage of pancreas recipients presented with bone marrow involvement than kidney or liver or small bowel recipients, a trend which approached significance (P = 0.053). In situ hybridization on tissue biopsies was performed for Epstein-Barr virus early mRNA (C) and cytomegalovirus DNA (D), demonstrating the absence of cytomegalovirus in the transformed cell populations, even in cases with recent cytomegalovirus infection preceding presentation.

Most recipients presented with constitutional symptoms or symptoms of localized disease (gastrointestinal and central nervous system involvement). One presented with pancreatic graft dysfunction and was found on computed tomography to have a diffusely enlarged gland. All recipients had reduction of immunosuppression as the primary intervention but clinical rejection was uncommon, even after prolonged immunosuppressive withdrawal. One underwent graft removal, but died subsequently of the underlying disease. Two long-term survivors lost their grafts after withdrawal of immunosuppression; these events were comparatively early, at 1 and 3 months postdiagnosis, respectively. Treatment modalities used are listed inTable 1.

Infection with CMV within 6 weeks prior to the diagnosis of PTLD of B-cell lineage was seen in 60% of recipients with EBV-positive lesions, and no recipients with EBV-negative lesions (P = 0.04). It was also more common in recipients of pancreas recipient vs. kidney and liver recipients (75% vs. 53% and 25% respectively). Although recipients with clinical evidence of CMV infection prior to their PTLD appeared to have a longer latency period and shorter survival, these differences did not reach statistical significance (data not shown). On pathologic examination, no evidence of CMV infection was seen in the lesions themselves, when analyzed by CMV in situ hybridization (Figs. 5C and D).

DISCUSSION

There are few reports focusing on PTLD after pancreas transplantation, in contrast to the published series on patients receiving liver, kidney, or thoracic organ grafts. The majority of reported cases are mentioned in larger multiorgan series that rarely include more than one or two pancreas recipients (6–16). Keay et al. describe four cases of early-onset PTLD, each presenting within 62 days after pancreas transplantation. The use of OKT3 for induction was associated with the occurrence of the disease, whereas that of rATG was not. Additionally, the absence of antiviral prophylaxis was significantly associated, although seroconversion for CMV was not. All four recipients had a favorable course and remained disease-free at least 1.5 years (9).

The analysis of this series of patients from a single institution shows important trends in the presentation, progression, and prognosis of the disease in pancreas transplant recipients as compared with recipients of other organ types. In our analysis, we have excluded plasmacytic hyperplasia, focusing only on mono- and polymorphic PTLD and malignant lymphoma. As these entities represent a continuum of disease, false elevation of incidence or longer survival times may result from the inclusion of more benign lesions. Clearly mandated is a strict, standardized approach to diagnosis and reporting of these cases, so that meaningful interpretation of treatment protocols can be made. Unusually, our pancreas recipient group exhibited a relatively high proportion of T-cell lesions. Although reportedly rare in other graft types, the incidence of T-cell PTLD in our series is 33%. In two recipients, EBV+ T-cell PTLD was documented, a rare condition (only 16 cases have been reported in the literature).

The rate of development of PTLD with time was not affected by the type of transplant and was comparable to rates reported in other analyses (18). Most important, we saw an organ-specific difference in survival, which has not been reported previously. In cases with B-lineage disease, pancreas recipients had significantly shorter survival times than others. This trend was reversed in the case of T-cell lesions, where pancreas recipients had a longer survival than kidney recipients, although the small numbers make these findings difficult to interpret. It is interesting to note that although pancreas recipients tended to present with more advanced disease, survival was similarly poor in patients with relatively few extranodal sites at the time of diagnosis. The lethality of the disease was, in these patients, reflected in the resistance to treatment as well as in the rapid progression to multisystem organ involvement and death. Whether or not the background of long-standing diabetes makes these individuals more susceptible to complications of surgery or chemotherapy is unclear, although such complications were not a common cause of death. It is also interesting to note that the least aggressive disease was seen in liver transplant recipients, a group subjected to lower levels of immunosuppression. The multiple inductions and retransplants faced by diabetics with end-stage renal disease, who often receive kidneys and pancreata sequentially, result in a greater cumulative exposure to ALA, a stronger baseline immunosuppression. This may predispose them, not necessarily to a higher incidence of PTLD, but to more aggressive disease.

In general, PTLD in pancreas recipients in this series was characterized by a shorter latency period than that seen in other transplant recipients, though in the series of B-cell lesions, these differences only approached statistical significance. The effect was more pronounced and significant in the series of T-cell lesions, although the number of cases allows for limited interpretation. The effect of disease latency, however, was quite marked. Early lesions, whether defined at 1 year or 3 years, were much more lethal than late ones in pancreas recipients. When pancreas recipients were compared with other organ recipients, the survival was significantly worse if lesions appeared within the first year and within the first 3 years. Lesions appearing after 3 years did not lead to an organ-specific difference in survival. Other published series have described a similar trend in mortality with early-onset PTLD (19). When the two immunosuppressive eras were compared, disease latency in general has become even shorter with time, although it is important to note that characteristically, T-cell lesions have longer latency periods and the mean latency in era 2 may be shorter because some T-cell lesions have not yet appeared.

The reasons for this phenomenon may again include a more profound degree of immunosuppression in pancreas recipients, particularly in the first few months after transplantation. It is also not clear if diabetes plays a role in the increased susceptibility of these recipients. Defective T-cell and antiviral immunity has been seen both as a consequence of the type 1 diabetic state (20,21), and, of course, as a cause (22,23). EBV infection was specifically and anecdotally related to the onset of type 1 diabetes (24); molecular mimicry between the EBV protein BOLF1 and the HLA-DQW8 β-chain had been previously suggested (25). Poor glycemic control in diabetic patients has also been associated with reduced CD4+ and CD8+ T-cell populations (26). Although these data remain limited, a greater susceptibility of diabetics to EBV infection cannot be completely excluded.

PTLD incidence and survival have not changed significantly over time in this series, despite exposure to significantly lower doses of ALA (Table 2). Still, a noticeably higher incidence was observed in the more recent era, marked by the use of tacrolimus and mycophenolate mofetil in baseline immunosuppression (Fig. 1B). No comparison was possible with recipients receiving no antibody induction because standard protocols have always included induction at this institution. It is difficult to compare ALA preparations on a dose equivalence basis, as differences in potency and side effect profiles invariably exist. Bustami et al. associated the use of rATG with the highest increase in relative risk for developing PTLD after kidney transplantation, compared with other ALA preparations (18). In recipients not receiving induction, similar rates were achieved, albeit 1 to 2 years later. Furthermore, for recipients not receiving induction therapy, baseline immunosuppression with tacrolimus significantly increased the risk of developing PTLD (18). In this series, only six recipients received additional ALA treatments for acute rejection or GVHD. Overall, these observations and the published data suggest a shift to more aggressive disease as baseline immunosuppression, rather than induction therapy, has become more potent. Similar conclusions have been made in studies of kidney recipients (27).

In our series of pancreas recipients, there appeared to be an association with recent CMV infection, despite the standard use of antiviral prophylaxis. CMV infection also seemed more common in pancreas recipients (75%) than in recipients of kidney (53%) and liver (25%) allografts. The association between CMV infection and PTLD has been recognized for some time, and relates to the degree of suppression of natural antiviral T-cell activity (5,28,29). Some evidence also indicates that antiviral therapies for CMV may be protective against EBV as well (30), but whether or not this approach prevents PTLD is unknown. That CMV itself may promote neoplastic transformation has been proposed per in vitro evidence (31,32). Clinical studies have further suggested a link: EBV reactivation has been observed in immunocompetent and immunocompromised individuals after CMV infection (33,34). Aalto et al. suggested that the observed increase in EBV viral capsid antigen (VCA) IgG levels and avidity were most likely due to a direct effect of CMV infection, rather than antibody cross-reactivity or polyclonal B-cell stimulation (34). The mechanisms by which CMV may alter EBV-specific immunity are still being investigated. Because of similar clinical findings, however, we (35) and others (36) have linked CMV infection to occurrence of EBV+ PTLD as a cause rather than a simple marker of depth of immunosuppression. Across transplant type, at our institution, recipients with preceding CMV infection appeared to have a longer latency period, a finding compatible with the theory of CMV as a precipitating event. The difference, however, did not reach statistical significance. The absence of detectable CMV in tissue samples showing EBER expression on in situ hybridization suggests that such an association would involve indirect effects of CMV on EBV-mediated B-cell transformation (Figs. 4C and D).

A variety of treatment options were used, as shown inTable 1. No association could be drawn between the modality and patient outcomes. We relied on early oncologic consultation and consideration of chemotherapy and α-CD20 monoclonal antibody, combined with the immediate reduction of immunosuppression to low-dose steroids alone. Radiation was considered for central nervous system involvement and surgical intervention was largely reserved for gastrointestinal complications or localized disease. Acute rejection was not a universal event even after prolonged reduction of immunosuppression, but it is interesting to note that in two of five long-term survivors, graft loss occurred within three months was reduced immunosuppression. This suggests the importance of a rapid return to immune competence. Graft pancreatectomy was performed infrequently in this series, and therefore, no recommendation can be made for its routine use in all cases. Because the pancreas graft is not life-sustaining, however, this should be considered an option. Longer follow-up and comparison with other published experience will be necessary to draw any conclusions about the advantages of particular agents and approaches (13,14,37,38).

We are well aware of the limitations of this study. First, this is an observational study over 14 years of pancreas transplantation at our institution, including both cyclosporine A and tacrolimus-based immunosuppressive regimens. It involves a series of over 1,500 pancreas transplants, with 18 cases of PTLD. To the best of our knowledge, however, this represents the largest single-institution experience with PTLD after pancreas transplantation, and one of the largest such series in abdominal solid organ transplantation. Although multicenter registry data may provide more statistically robust analyses based on larger numbers, studies such as this are important because of consistency of treatment, close follow-up, and detailed pathologic evaluations.

The bulk of the pancreas transplant experience is recent and information reflecting long-term outcomes and complications is only now being compiled by most centers. Although the incidence of PTLD in pancreas recipients at our institution is comparable to that of recipients of other abdominal solid organ allografts, its clinical course is markedly more aggressive and survival is decreased. Pancreas recipients appear to have earlier-onset PTLD, as well as a higher proportion of T-cell lesions. These characteristics may be related to the innate susceptibility of the diabetic transplant recipient, who also often faces multiple transplants and courses of induction. The association with CMV infection as a possible causative event needs to be further investigated, as this may influence antiviral prophylaxis protocols. A high index of suspicion for this rare, yet devastating, problem is essential; proper identification of the patient at risk for PTLD clearly begins at the time of patient selection and transplantation. Increased efforts at monitoring and preventive therapy are currently the only tools to effectively decrease its impact. We would recommend standard testing of all deceased donors, not only for CMV but for EBV as well, to identify higher risk donor-recipient combinations. This is now common practice in our own region.

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Keywords:

Pancreas; Lymphoma; Cytomegalovirus; Outcomes

© 2005 Lippincott Williams & Wilkins, Inc.