High alpha-1 antitrypsin clearance predicts severity of gut graft-versus-host disease (GVHD) in children.

The clinical evaluation and management of gut GVHD is a significant challenge in pediatric HSCT. It is often difficult to obtain pathological evidence to confirm diagnosis and/or to determine response to treatment. The severity of the disease itself may not be related to just the classic symptom of diarrhea. The objectives of this study were to prospectively evaluate patients with suspected gut GVHD for PLE as measured by AATC in stools at two different times for each patient and to compare the severity of the PLE with the severity of clinical acute gut GVHD. Thirteen patients were suspected of gut GVHD by clinical criteria (diarrhea > 10 mL/kg/24 h); one patient was excluded for being unable to complete the stool collection. Therefore, 12 patients, 10 boys and two girls, were studied. Median stool volume was 27.5 mL/kg/day (range 10.1-109.0).The median age at BMT was 11.1 yr (range 3.9-17.0 yr). All patients had negative stool electron microscopy for viruses and cultures for C. difficile on their first collection. Nine patients (75%) had two 24-h stool collections performed at a median of eight days apart (range 7-14 days). At the time of the first collection, six patients had ≥ stage 2 acute gut GVHD, and at second collection, four patients had ≥ stage 2 gut GVHD and four collections were of non-diarrheal stool (hence treatment response). Median AATC from all 21 collections was 19.0 mL/day (range 3.0-561.0), and levels >22 mL/day indicate the diagnosis of PLE. The four children initially suspected of GVHD but who had a negative biopsy completed a total of five collections with a median AATC of 5.0 mL/day (range 3.0-16.0) vs. a median of 33.5 for the remainder of the collections (range 3-561). Stage of gut GVHD correlated with elevated AATC and with stool volume. AATC > 22 mL/day showed a sensitivity of 70% and specificity of 82% for significant gut GVHD (≥ stage 2). Seven stool collections were taken at ≥ stage 3 gut GVHD; six of those seven patients were positive for PLE. Larger stool volumes were more predictive, and five collections with stool volumes >30 mL/kg/day were positive for PLE. We conclude that a significant positive correlation exists between the severity of PLE and the stage of gut GVHD (p < 0.04), particularly obvious in patients with stages 2-4 GVHD (p = 0.03). Despite the small number of patients recruited, this study emphasizes the need to consider PLE as a useful aspect of the clinical picture. We suggest that in order to see a response to therapy and therefore a decrease in AATC, clinicians should wait at least 2 wk from the initiation of therapy before repeating AATC test. In light of the significant morbidity and mortality associated with ≥ stage 2 gut GVHD, and as an important therapeutic decision for these patients, one may consider evaluating AATC if a biopsy is not an option.

Early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia.

To study the effect of early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation (HSCT) on outcome in pediatric ALL, we reviewed 136 consecutive pediatric patients with ALL who received allogeneic HSCT between 1994 and 2005 at the Hospital for Sick Children, Toronto, Canada. Patients with an absolute lymphocyte count (ALC) <0.3 x 10(9) per liter at day 21 (n=104) had more than five times risk of relapse compared to those with ALC >0.3 x 10(9) per liter (n=32) (hazard ratio (HR) 5.3; P=0.002) and had inferior 3-year event-free survival, (EFS), 0.42 (95% confidence interval (CI) 0.32, 0.51) compared to 0.66 (95% CI 0.48, 0.82; P=0.02). Similarly, patients with an ALC <0.3 x 10(9) per liter (n=48) at day 30 were more than twice as likely to relapse compared to those with an ALC >0.3 x 10(9) per liter (n=88) (HR 2.2; P=0.01) and had an inferior 3-year EFS, 0.30 (95% CI 0.18, 0.45) compared to 0.57 (95% CI 0.46, 0.68; P=0.0001). Interestingly, increasing ALC at days 21 and 30 was not associated with increased incidence of acute or chronic GVHD or transplant-related mortality (TRM). Early lymphocyte recovery post-HSCT is associated with a significant GVL without increase in GVHD.

A comparison of the outcomes of children with acute myelogenous leukemia in either first or second complete remission (CR1 vs CR2) following allogeneic hematopoietic stem cell transplantation at a single transplant center.

We reviewed 70 consecutive children with AML who received hematopoietic stem cell transplantation (HSCT) in our institution between 1994 and 2005. Forty-seven children were transplanted in CR1 and 23 were transplanted in CR2. BU/CY was the most common pretransplant conditioning regimen for CR1 patients and a TBI-based conditioning regimen was the most common regimen for CR2 patients. Most patients transplanted in CR1 (81%) received related donor HSCT, whereas most of the CR2 patients (74%) received unrelated donor HSCT. Expectedly, there was a significant increase in acute GVHD incidence in CR2 patients (40 vs 25% for grades I-II and 30 vs 10% for grades III-IV; P=0.02) and a significant increase in transplant-related mortality (38 vs 11%; P=0.01). Although the difference between 3-year EFS for CR1 and CR2 was not statistically significant, there was a significantly superior 3-year overall survival for CR1 patients (74 vs 51%; P=0.05). Children with relapsed AML who achieve and maintain remission until HSCT, have a reasonable survival, but the outcome of children receiving HSCT in CR1 remains superior.

Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations.

To determine graft-versus-leukemia (GVL) effect after hematopoietic stem cell transplantation (HSCT), we studied the outcome of consecutive children with acute lymphoblastic leukemia (ALL) who received fully matched marrow allografts comparing relapse rate post HSCT between matched sibling donor (MSD) and matched unrelated donor (MUD) recipients. Furthermore, we estimated event-free survival (EFS) on the basis of the occurrence of acute graft-versus-host disease (aGVHD). Between 1998 and 2006 we performed 37 fully MSD and 36 fully MUD HSCTs. All patients received identical conditioning regimens with cyclophosphamide/total body irradiation and dual GVHD prophylaxis with cyclosporine (CSA) and methotrexate (MTX). Three-year cumulative incidence of relapse for the MSD and MUD groups were 55.6+/-12.3 and 22.0+/-8.1%, respectively (P=0.03). Three-year EFS according to aGVHD was 32.7+/-12.2% for no aGVHD, 61.2+/-10.0% for grade I-II aGVHD and 66.7+/-11.1% for grade III-IV aGVHD. Three-year EFS and overall survival (OS) were 40.5+/-11.6, 49.1+/-9.5% for the MSD group, and 60.5+/-8.7, 62.3+/-8.4% for the MUD group. In children with ALL receiving dual GVHD prophylaxis, relapse rate is significantly higher among recipients of MSD compared to MUD transplantation, which may in part be attributed to a better GVL effect with the unrelated graft.

Unsuccessful treatment attempt: cord blood stem cell transplantation in a patient with Niemann-Pick disease type A.

Niemann-Pick disease type A (NP-A; OMIM 257200) is an autosomal recessive lysosomal storage disorder caused by deficiency of acid sphingomyelinase and resulting in accumulation of sphingomyelin, unesterified cholesterol, and other complex lipids in many tissues. It is characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course culminating in death by 3 years of age. There is no known effective treatment. We report the case of a prenatally diagnosed girl who underwent cord blood stem cell transplantation (CBSCT) at 3 months of age. She was neurologically intact at the time of CBSCT. Hepatosplenomegaly, was detected at 6 weeks of age; the splenomegaly resolved following CBSCT. Recovery was complicated by graft-versus-host disease. She subsequently developed and continues to show marked global developmental delay, generalized hypotonia, and signs of neurological regression, despite continued engraftment. Bilateral cherry red spots were detected at 10 months of age, 7 months post-CBSCT. Although she is doing better than her affected brother, she shows little overall benefit from CBSCT.

The burden of chemotherapy-induced nausea and vomiting in children receiving hematopoietic stem cell transplantation conditioning: a prospective study.

This prospective study describes chemotherapy-induced nausea and vomiting (CINV) in children (4-18 years) receiving their first hematopoietic stem cell transplant. Emetic episodes, nausea severity (assessed using a validated, self-report nausea severity assessment tool) and antiemetic administration were documented from the start of conditioning until 24 h after the last conditioning agent was administered (acute) and for a further 7 days (delayed). Relationships between CINV control and parenteral nutrition (PN) use and acute gut GvHD (aGvHD) were explored. Fifty-nine children (4.6-17.4 years) were evaluable. Complete chemotherapy-induced vomiting (CIV; acute: 24%; delayed 22%) and chemotherapy-induced nausea (CIN; acute 7%; delayed 12%) control rates were low. Few children experienced complete CINV control (no vomiting/retching and no nausea) during the acute (5%) or delayed phases (12%). Children experiencing complete acute or delayed CIN control or complete delayed CIV control were more likely to have received: a lower proportion of their total energy requirement as PN at the end of the delayed phase (P<0.036) and PN for a shorter time (P<0.044). Low patient numbers did not permit evaluation of the association between gut aGvHD and CINV control. Effective and safe interventions aimed at improving CINV control in children are required.

Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens.

To compare the outcome of hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) conditioned with two different regimens: (1) single dose of VP16 (60 mg/kg over 4 h) and total body irradiation (TBI; 1200 cGy, in six fractions) or (2) Cyclophosphamide 50 mg/kg over 1 h daily for 4 days followed by the same dose of TBI. One hundred and seven children with ALL received fully matched HSCT from 1990 to 2003 in the Hospital for Sick Children, Toronto. All received cyclosporin A and a short course of methotrexate for graft-versus-host disease (GVHD) prophylaxis. The VP16 group, there were 36 matched related donor transplants (MRD) and 26 matched unrelated donor transplants (MUD), and in the cyclophosphamide group there were 23 MRD and 22 MUD transplants. Neutrophil engraftment occurred at a median of 18 and 17 days for the VP16/TBI and the CY/TBI groups, respectively. The 3 year event-free survival and overall survival were 47 +/- 7 and 55 +/- 7% for those receiving VP16/TBI, and 51 +/- 8 and 53 +/- 8% for the CY/TBI group. There were no significant differences in the prevalence of acute or chronic GVHD and transplant-related mortality between the two groups. Both VP16/FTBI and CY/FTBI regimen are equally effective regimens.

Subsequent malignant neoplasms in pediatric cancer patients treated with and without hematopoietic SCT.

Pediatric cancer patients are at increased risk of subsequent malignant neoplasms (SMNs). However, little is known about the contribution of hematopoietic SCT (HSCT) to the development of SMNs. The objective of this study was to compare the incidence of SMNs in a population cohort of childhood cancer survivors treated with and without HSCT. A cohort of 7986 children (age 0-14 years) diagnosed with cancer in the province of Ontario, Canada between 1985 and 2009 was identified in POGONIS (Pediatric Oncology Group of Ontario Networked Information System), a population-based active cancer registry, and linked to a clinical HSCT database. Among this cohort, 796 patients had an HSCT as part of their primary treatment. Of the 375 allogeneic HSCT patients, 14 (3.7%) developed a SMN at a median follow-up of 12.3 years (range: 2.0-22.9 years). Of the 421 autologous HSCT patients, 8 (1.9%) developed a SMN at a median of 4.5 years (range: 1.3-14.3 years). Of the 7190 patients who did not receive an HSCT, 160 (2.2%) developed a SMN at a median follow-up of 6.8 years (range: 0.0-24.9 years). The 15-year cumulative incidence of SMN was 3.1% among the allogeneic HSCT group, 2.5% among the autologous group and 2.3% in the non-HSCT group. The cumulative incidence curves for the allogeneic HSCT and non-transplant groups only diverged after ~15 years from primary diagnosis. Our findings further corroborate the observation that children who undergo allogeneic HSCT are at a significantly increased risk of developing SMN compared with pediatric cancer survivors treated without HSCT.

Major ABO incompatible BMT in children: determining what residual volume of donor red cells can safely be infused following red cell depletion.

Major ABO incompatible BM transplantation carries a risk of acute haemolysis. Red cell depletion reduces this risk but not all incompatible RBC (iRBCs) are removed and in children the residual volume can be significant relative to body weight. We sought to determine the volume of iRBCs that can be safely given to children. All patients receiving fresh BM from a donor with a major ABO blood group mismatch between January 2000 and July 2013 at the Hospital for Sick Children, Toronto, were included. Seventy-eight patients were identified. The median volume of iRBCs transfused was 1.6 mL/kg (range 0.1-10.6 mL/kg). Thirty-five patients had minor haemolytic events and five patients had clinically significant adverse events. Two patients, who received 3.66 and 3.9 mL iRBCs/kg, developed renal impairment and in one case hypoxia and hyperbilirubinaemia. One patient had mild hypotension that resolved with i.v. fluid. Two patients developed hypotension secondary to sepsis and unrelated to BM infusion. Although signs of haemolysis occur, with appropriate hydration and monitoring of renal function, clinically significant adverse events related to the infusion of ABO incompatible BM are rare, and, in this study, were only seen in patients receiving >3 mL/kg of iRBCs per kg.

Life-threatening pulmonary hemorrhages post bone marrow transplantation in Hurler syndrome. Report of three cases and review of the literature.

Hurler syndrome (MPS-IH) is an autosomal recessive mucopolysaccharide storage disorder caused by deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. This results in accumulation of heparan sulfate and dermatan sulfate substances. Untreated children develop progressive developmental deterioration and multisystem morbidity with a median survival of 5 years. Allogeneic bone marrow transplantation (BMT) is the only long-lasting treatment that ameliorates or halts the aggressive course of the disease. Pulmonary hemorrhage (PH) is an unusual complication of BMT and has not been previously reported in MPS-IH post-BMT. We report three children with MPS-IH with life-threatening PH around the time of engraftment. All needed intensive-care support and one child developed recurrent PH that required prolonged ventilation.

Acute gut GVHD in children: does skin involvement matter?

Gut GVHD (G-GVHD) is frequently the most severe and difficult to treat compared with skin GVHD. It is unknown if skin involvement with G-GVHD has prognostic significance. To compare the prognosis of acute isolated G-GVHD vs acute gut and skin GVHD (GS-GVHD) in children following allo-SCT. Allo-SCT recipients from Jan 2000-Dec 2009 were included and patients who underwent endoscopy and gut biopsy for G-GVHD were identified. Four hundred and fifty children (0-18 years) underwent allo-SCT during the study period. Seventy-nine (17.5%) patients underwent endoscopy and biopsy. At least stage II was required for skin involvement. Forty nine patients had G-GVHD and 30 had combined, GS-GVHD. The majority of patients received CsA and MTX for GVHD prophylaxis. Sixty-seven percent of patients with GS-GVHD had grade III-IV while only 31% had grade III-IV in the G-GVHD group. Median follow-up was 6.3 years (range 3.6-11.9 years). Relapse rate was similar in both the groups. However, children with G-GVHD had a significantly higher risk of dying from GVHD related complications (37% vs 16%) resulting in superior survival for those with skin involvement (79% vs 49% P=0.02). Extension of G-GVHD to the skin may suggest a better outcome.

Chest health surveillance utility in the early detection of bronchiolitis obliterans syndrome in children after allo-SCT.

To prospectively assess whether periodic chest health surveillance is beneficial for the early detection of bronchiolitis obliterans syndrome (BOS) in children after allo-SCT. Children up to 18 years of age receiving allo-SCT from September 2009 to September 2011 were included. Surveillance consisted of the following: a 7-item respiratory system questionnaire of cough, wheeze and shortness of breath; focused physical examination; and pulmonary function test (PFT) conducted before SCT and at 1, 3, 6, 9, 12, 18 and 24 months after SCT. Thirty-nine patients were enrolled. Five children developed BOS at a median time of 192 days (range 94-282). Positive response comparisons between the BOS group vs the non-BOS group were NS for history questionnaire (P=0.2), heart rate (P=0.3), respiratory rate (P=0.3) and oxygen saturation monitoring (P=0.8). Differences between the two groups for chest auscultation and PFT were statistically significant (P=0.03 and P=0.01, respectively). However, chest auscultation in the BOS group was only positive after BOS diagnosis. PFT reduction was evident in the asymptomatic phase (BOS group 33%; non-BOS group 4.5%, P=0.01). Changes in PFT, but not history/physical examination, allow the early detection of BOS in children after SCT. Our study is limited by the small sample size.

Late mortality after hematopoietic SCT for a childhood malignancy.

Hematopoietic SCT (HSCT) has been used as a curative therapy for pediatric malignancies. Survivors of HSCT are at risk for disease recurrence, late morbidity and mortality. We assessed late mortality (≥2 years post-HSCT) in a population-based cohort of children who underwent HSCT for a malignancy. Mortality outcomes were determined by linking a clinical transplant database with the Canadian province of Ontario's pediatric cancer mortality files. Seven hundred and fifty-four children underwent HSCT (371 allogeneic, 383 autologous). Of the 479 (63.5%) who were alive ≥2 years post HSCT, 98 (20.5%) suffered a late death. Late mortality in the allogeneic HSCT group was 14.9% (median follow-up 10.0 years; range: 2.0-25.6 years), mainly due to relapse of the primary malignancy (64.7%). Chronic GVHD and second malignancies were not major causes of late mortality. A total of 25.5% suffered a late death following autologous HSCT (median follow-up 6.7 years; range: 2.0-22.2 years). Recurrence of the primary malignancy accounted for 87.5% of these deaths. Recurrence of the primary malignancy is the predominant cause of late mortality after HSCT. In contrast to studies of adult patients, non-relapse mortality is less common in children, and death due to chronic GVHD and secondary malignancies is uncommon.

Outcome of children who experience disease relapse following allogeneic hematopoietic SCT for hematologic malignancies.

Relapse after allogeneic hematopoietic SCT (HSCT) carries a poor prognosis and is a common cause of death. Outcomes of children who relapse post HSCT are not well known. In this retrospective multicenter study we included 532 patients who underwent allogeneic HSCT and examined the outcomes of 160 patients (30%) who relapsed. Treatment options after relapse included (i) palliative therapy with non-curative intent (n=43), (ii) salvage chemotherapy (without a second HSCT, n=55) or (iii) salvage chemotherapy followed by a second HSCT (n=62). Sixty two patients underwent a second HSCT. The 1-year disease-free survival (DFS) for those given palliative therapy, chemotherapy alone and who underwent a second transplant was <1%, 9% and 50% (P=<0.0001), respectively. The DFS at 1 and 2 year was 50% and 35%, respectively, among the patients who received a second transplant versus 9% and 2% in those who did not (P=<0.0001). In multivariable analysis longer time to relapse (P=0.04) and undergoing a second HSCT (P<0.001) were associated with improved outcome. Withdrawal of immunosuppressive therapy, followed by curative intent chemotherapy should be offered to all patients who relapse after an allogeneic HSCT. A second HSCT should be considered, especially in patients who respond to salvage chemotherapy.

Cord stem-cell transplantation in Ontario: do we need a public bank?

It has been 21 years since the first successful use of umbilical cord blood as a source of donor cells for hematopoietic stem cell transplantation (HSCT). Over those years, cord blood transplantation (CBT) has shown marked success as an effective modality in the treatment of children and adults with hematologic malignancies, marrow failure, immunodeficiency, hemoglobinopathy, and inherited metabolic diseases. Furthermore, transplantation without full human leukocyte antigen (HLA) matching is possible and, despite a lower incidence of graft-versus-host disease, graft-versus-leukemia effect is preserved. More than 20,000 cbts have been performed worldwide. Ontario is the most populated province in Canada, and its cbt numbers have increased dramatically in recent years, but most of the umbilical cord blood units are purchased from unrelated international registries. There is no public cord bank in Ontario, but there is a private cord banking option, and notably, Ontario has the largest number of live births in Canada [approximately 40% of all Canadian live births per year occur in Ontario (Statistics Canada, 2007)]. In this brief review, the pros and cons of private and public cord banking and the feasibility of starting an Ontario public cord bank are discussed.

Hematopoietic stem-cell transplantation following solid-organ transplantation in children.

Reports of hematopoietic stem-cell transplantation (HSCT) following solid-organ transplantation have been described in adults mainly as case reports. These reports demonstrate feasibility but likely do not reflect true outcomes due to a positive reporting bias. We report herein the outcomes of all our pediatric recipients of allogeneic HSCT following previous solid-organ transplantation between 2000 and 2009. Four children were identified. Two patients underwent heart transplantation followed by cord-blood allogeneic HSCT for T-cell lymphoma/post transplant lymphoproliferative disease (PTLD) and two patients underwent liver transplantation followed by living-donor allogeneic HSCT for severe aplastic anemia (SAA). The mean time between transplants was 4.2 years (range 1.5-6 years). All patients engrafted; however, all patients died from 37 days to 1 year after HSCT. Causes of death included infections (n=2), multi-organ failure (n=1) and solid-organ graft rejection (n=1). Though three patients survived beyond day+100, multiple complications were observed including EBV re-activation followed by EBV-positive PTLD (n=1) and five episodes of severe infections. The patients transplanted for lymphoma did not have evidence of recurrence at last follow-up. Although feasibilty has been shown with this cohort, we conclude that allogeneic HSCT in immunosuppressed patients following solid-organ transplantation remains a very high risk procedure that results in severe morbidity and mortality in children.

Dismal response to high-dose methylprednisolone after failure to respond to standard dose in patients with acute GVHD.

Corticosteroids such as methylprednisolone (MP) remain the primary therapy for acute GVHD (aGVHD). Patients who are refractory to standard treatment (MP 2 mg/kg/day) may be treated with high-dose MP. This study evaluated the response to high-dose MP in children with aGVHD refractory to standard dose MP. Children who underwent hematopoietic SCT (HSCT) at our hospital between 1 June 2002 and 31 July 2006 and were treated with high-dose MP upon developing steroid-refractory aGVHD were included. Response to aGVHD therapy, adverse effects attributed to MP and overall outcomes were documented. Ten children received high-dose MP (≥ 20mg/kg/day) on 3-5 consecutive days followed by a tapering dose for steroid-refractory aGVHD, at a median of 12 days after starting standard treatment. Nine patients had ≥ grade III aGVHD. Only one patient with grade III aGVHD had a complete response. Two patients had a partial response but flared when MP was tapered. Complications included hypertension (100%), hyperglycemia requiring insulin therapy (33%) and four documented severe infections. Five children (50%) died (median follow-up: 5.9 years). Salvage therapy other than high-dose MP should be considered in children who fail to respond to MP 2 mg/kg/day.

Early lymphocyte recovery after allogeneic hematopoietic SCT is associated with significant GVL effect in pediatric ALL but not acute myelogenous leukemia-Update study.

We earlier published data on 136 children who received hematopoietic SCT (HSCT) for ALL, and showed that early lymphocyte recovery is a powerful indicator for survival by GVL effect without increase in GVHD. To answer the question whether this is true for AML, we extended our cohort to 207 consecutive children with acute leukemia by adding 71 children with AML who received 75 HSCT's between 1994 and 2005. For the AML cohort, all patients at time of HSCT were in complete morphological remission (CR) except for one patient in CR1, who had 8% blasts in the BM before HSCT. All patients received myeloablative regimens. Stem cell sources were: matched sibling donor in 40 patients, mismatched related donor in eight patients, matched unrelated donor in 25 children and two children received cord progenitor stem cells. ALL results were published with significant P-values. In AML, absolute lymphocyte count <0.3 x 10(9)/l or >0.3 x 10(9)/l on days 21 and 30 were not predictive of relapse with a hazard ratio at day 21=0.88; P=0.8, and hazard ratio at day 30=0.5; P=0.2.

Pediatric standard-risk AML with fully matched sibling donors: to transplant in first CR or not?

Allogeneic hematopoietic SCT (HSCT) for children with standard-risk AML in first CR (CR1) is controversial. We reviewed 32 consecutive children with standard-risk AML who received matched sibling donor HSCT in CR1 from 1995 to 2004. With a median follow-up of 76 months (range: 36-114), 3 year EFS was 0.74 (95% confidence interval (CI): 0.57-0.88) and the overall survival was 0.81 (95% CI: 0.66-0.93). Only one patient died as a result of TRM. Larger studies, such as the MRC-UK 10 and 12, reported 60-62% EFS. Outcome of children with standard-risk AML transplanted from a matched sibling donor in CR1 is very encouraging with minimal toxicity.