Bilateral Lacrimal Gland Mantle Cell Lymphoma in 11-Year Follow-Up: Case Report and Review of 48 Cases With Ocular Adnexal Presentation in the Literature.

A 63-year-old woman, with 11-year history of breast cancer, showed bilateral lacrimal gland enlargement on magnetic resonance imaging. Gallium-67 scintigraphy, as the standard at that time in 2004, demonstrated abnormally high uptake only in bilateral lacrimal glands. The lacrimal glands were extirpated and the pathological diagnosis was mantle cell lymphoma (MCL). She underwent bilateral orbital radiation, based on no uptake of gallium-67 in other sites of the body. In a month, bone marrow biopsy revealed the infiltration with MCL, positive for cyclin D1. She showed hepatic lymphadenopathy and splenomegaly, and so received 2 cycles of alternating Hyper-CVAD therapy and high-dose methotrexate with cytarabine, combined with rituximab, in 2 months, leading to complete remission. She underwent autologous peripheral blood stem cell transplantation and was well until the age of 68 years when she showed a recurrent intratracheal submucosal lesion of lymphoma and underwent one course of reduced-dose CHOP combined with rituximab. Next year, the left rib resection revealed the metastasis of breast adenocarcinoma, leading to daily oral letrozole. Further 2 years later, computed tomographic scan demonstrated multiple submucosal nodular lesions in the trachea and bronchi, together with cervical and supraclavicular lymphadenopathy, and intratracheal lesion biopsy and bone marrow biopsy proved the involvement with MCL. She underwent 2 courses of bendamustine and rituximab, resulting in complete remission but died of metastatic breast cancer at the age of 74 years. Clinical features in 48 previous cases with ocular adnexal MCL in the literature were summarized in this study.

Epitope Mismatch at HLA-DRB1 Associates with Reduced Relapse Risk in Cord Blood Transplantation for Standard-Risk Hematologic Malignancy.

Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematologic malignancies. CBT tolerates HLA mismatches between donors and recipients, but the HLA mismatches that generate graft-versus-tumor (GVT) effects remain unknown. Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. A total of 492 patients with hematologic malignancies who underwent single-unit, T cell-replete CBT were included in this multicenter retrospective study. HLA epitope mismatches (EMs) were quantified using HLA matchmaker software from donor and recipient HLA-A, -B, -C, and -DRB1 allele data. Patients were dichotomized by median EM value and divided into 2 groups: patients who underwent transplantation in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). The median number of EMs in the graft-versus-host direction (GVH-EM) was 3 (range, 0 to 16) at HLA class I and 1 (range, 0 to 7) at HLA-DRB1. Higher HLA class I GVH-EM was associated with increased nonrelapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; P = .021), with no significant advantage for relapse in either stage. In contrast, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, .63; P = .020), which was attributed to lower relapse risk (adjusted HR, .46; P = .014). These associations also were observed even within HLA-DRB1 allele-mismatched transplantations in the standard stage group, indicating that EM might have an impact on relapse risk independent of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. High HLA-DRB1 GVH-EM may lead to potent GVT effects and a favorable prognosis following CBT, especially in patients who underwent transplantation at the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematologic malignancies who undergo CBT.

Diffuse large B-cell lymphoma in the course of systemic sarcoidosis: A case report and review of 30 Japanese patients with sarcoidosis-lymphoma syndrome.

We report a patient with sarcoidosis who developed diffuse large B-cell lymphoma. A 71-year-old woman with persistent cough was diagnosed pathologically with sarcoidosis by resection of the right upper lung lobe with a nodule after an unsuccessful attempt of transbronchial needle aspiration for mediastinal lymphadenopathy. She was referred for an eye examination and found to have spotty retinal degeneration on the lower fundi of both eyes, together with residual macular edema and vitreous opacity in the left eye. At 76 years, she underwent cataract surgery and vitrectomy to gain a visual acuity of 0.6 in the left eye. At 77 years, she developed a cough and fever, and showed leukopenia and thrombocytopenia. Computed tomography showed multiple small nodular lesions in both lungs, and bilateral hilar, mediastinal, and hepatic lymphadenopathy. Fluorodeoxyglucose positron emission tomography demonstrated high uptake in the liver, spleen, pancreatic head, and lymph nodes. Bone marrow biopsy was intact, but liver biopsy revealed anomalous large lymphoid cells in the sinusoids which were positive for CD20 and showed a high Ki-67 index, leading to the diagnosis of diffuse large B-cell lymphoma. Chemotherapy with 8 courses of THP-COP (cyclophosphamide, pirarubicin, vincristine, and prednisolone) with rituximab, followed by intrathecal injection of methotrexate, cytarabine, and dexamethasone, resulted in complete remission. She maintained complete remission for 10 years until 88 years old at present. The literature review found 30 patients, including this case, who developed lymphoma in the course of sarcoidosis. A novel pathological diagnosis is required in the setting of acute symptomatic changes and novel lesions on imaging in patients with sarcoidosis.

FAM83G-based Peptide Induces Apoptosis on Cultured Liver Cancer Cell.

BACKGROUND: Previously, AF-956, which contains S356 of FAM83G and an N-terminal antenna peptide for entry into colon cancer cells, is markedly antiproliferative compared to a control peptide (AF-859), which lacks the N-terminal antenna peptide, by inducing apoptosis via the inhibition of HSP27 phosphorylation at residues S15 and S82. OBJECTIVE: Because FAM83G-derived peptides are promising lead compounds for colon cancer treatment, we reanalyzed the effect of AG-066, which contains S356 of FAM83G and an N-terminal antenna peptide for entry into the liver cancer cells. METHODS: HepG2 liver cancer cells were incubated with either AF-859 or AG-066 at a concentration of 54 µM at 37 °C for 24, 48, and 72 h. The effects of AF-859 and AG-066 on the cultured HepG2 cells were estimated using an inverted light microscope. Furthermore, the DNA ladder method and the dead cell assay were performed by applying Live/Dead Cell Staining Kit II. Erk phosphorylation was estimated by western blotting. RESULTS: Treatment with AG-066 markedly reduced HepG2 viable cell counts compared to the AF- 859-treated HepG2 cells, as evident from the significantly increased number of dead cells in the culture medium. Additionally, AG-066 treatment increased cellular DNA laddering. We found no difference in Erk phosphorylation status between the AG-066- and AF-859-treated groups. CONCLUSION: This study illustrated that the peptide with a structure based on FAM83G functions as a spontaneous apoptosis inducer for liver cancer cells. Hence, it is a promising lead compound for the treatment of liver cancer.

Diffuse Large B-Cell Lymphoma 18 Years After Bilateral Lacrimal Gland IgG4-Related Disease: Case Report and Literature Review.

IgG4-related disease is a recently established clinical entity. The disease might serve as the background for later development of systemic lymphoma. This study aims to confirm the diagnosis of IgG4-related disease by re-staining lacrimal gland lesions diagnosed previously with low-grade lymphoma in a patient who developed systemic diffuse large B-cell lymphoma (DLBCL) 18 years later. A 53-year-old man developed bilateral lacrimal gland swelling and right submandibular gland swelling and was diagnosed by excision as low-grade lymphoma. In follow-up, positron emission tomography showed high uptake in the median hyoid 11 years later but no malignancy was detected by laryngeal submucosal biopsy. He was well with no treatment until 18 years later when he had palatal swelling and was diagnosed with DLBCL by oral floor biopsy. He had systemic lymphadenopathy, infiltration in paranasal sinuses, hypopharynx, small intestine, kidney, and prostate. He underwent 8 courses of R-CHOP and 3 courses of high-dose methotrexate and achieved complete remission with no relapse for 1 year thereafter. Re-immunostaining of paraffin blocks of bilateral lacrimal gland lesions showed IgG and IgG4-positive lymphocytes and plasma cells among lymphoid follicles separated by fibrous bundles, with 10 or more IgG4-positive cells in high-power field. The IgG4/IgG-positive cell ratio was 100% and the number of κ chain-positive cells and λ chain-positive cells was the same. The bilateral lacrimal lesions were thus re-diagnosed as IgG4-related disease. In conclusion, systemic DLBCL occurred approximately 20 years after lacrimal gland IgG4-related disease. Literature review revealed 12 patients with IgG4-related disease, including the present patient, who later developed lymphoma in the other organs.

TBC1D8B, a GTPase-activating protein, is a novel apoptosis inducer.

Overexpressed TBC1D8B, a GTPase-activating protein, significantly reduced cultured HCT116 human colon cancer cell number. We tested N-terminal TBC1D8B, which is identical to wild type TBC1D8B from amino acid positions 1 to 427 and possesses a modified sequence from position 428 to 435 (ECGGLFLL) because of the introduction of a premature stop codon at position 436 to narrow down the minimum requirement element. The N-terminal TBC1D8B contains two GRAM domains but not the TBC domain essential for Rab-GTPase activity. The N-terminal TBC1D8B overexpression significantly reduced the cultured HCT116 cell number. When we tested C-terminal TBC1D8B, containing the portion of TBC1D8B absent in the N-terminal TBC1D8B, the cell number reduction was not observed. The N-terminal TBC1D8B overexpression significantly increased the coronin 1B expression and reduced the phosphorylation of serine 51 in eIF2α, respective markers of apoptosis and cell death/survival. Also, caspase 3 and poly ADP-ribose polymerase increased cleavage in suspended cells overexpressing the N-terminal TBC1D8B. Taken together, it is not the TBC domain for Rab-GTPase activity, but amino acids 1 to 435, including the two GRAM domains, that is enough for TBC1D8B to cause spontaneous apoptosis. TBC1D8B could be a potential anticancer therapeutic molecule.

Evaluation of bleeding control course for health-care providers in Japan.

AIM: The Bleeding Control Basic (BCon) course was developed by the American College of Surgeons to teach laypeople and health-care providers (HCPs) how to stop life-threatening bleeding. The first BCon course in Japan was held for HCPs in July 2018. Our study aimed to evaluate the utility of the course, the satisfaction and confidence level of the HCPs that participated, and their experience with using vascular tourniquets. METHOD: The BCon participants were asked to complete a survey after the BCon courses from December 2018 to December 2019. These participants included different types of HCPs (physicians, nurses, and emergency medical technicians). After the course, the participants were asked to evaluate: (i) the perceived utility of the course, (ii) their satisfaction with the course, (iii) their confidence in the techniques that they learned in the course, (iv) their experience of using tourniquets in eight specific areas using a 10-point Likert scale. RESULTS: A total of 163 HCPs, including 108 physicians, 27 nurses, and 28 emergency medical technicians completed the BCon course. The respondents rated the course highly, showing an average value of approximately 9 for each item for perceived utility, satisfaction, confidence, and experience in using tourniquets. In particular, nurses rated the overall activity more highly than physicians (P < 0.05). CONCLUSION: The BCon course and tourniquets were well-received by all types of HCPs in Japan.

FAM83G Is a Novel Inducer of Apoptosis.

The family with sequence similarity 83 (FAM83) protein family G (FAM83G) possesses a predicted consensus phosphorylation motif for serine/threonine-protein kinase D1/protein kinase C mu (PKD1/PKCµ) at serine residue 356 (S356). In this study, overexpressed wild-type FAM83G coimmunoprecipitated with PKD1/PKCµ in Chinese hamster ovary (CHO) cells inhibited heat shock protein 27 (HSP27) phosphorylation at S82 and reduced the living cell number. The expression of a FAM83G phosphorylation-resistant mutant (S356A-FAM83G) had no effect on the living cell number or the induction of spontaneous apoptosis. By contrast, the introduction of a synthetic peptide encompassing FAM83G S356 into HCT116 and HepG2 cells decreased HSP27 S15 and S82 phosphorylation and induced spontaneous apoptosis. On the other hand, the introduction of FAM83G phosphorylation-resistant mutant synthesized peptides (S356A-AF-956 and S356A-AG-066) did not reduce the living cell number or induce spontaneous apoptosis. The endogenous expression of HSP27 and FAM83G was apparently greater in HCT116 and HepG2 cells compared with in CHO cells. In various types of lung cancer cell lines, the FAM83G messenger RNA (mRNA) level in non-small lung cancer cells was at a similar level to that in non-cancerous cells. However, the FAM83G mRNA level in the small cell lung cancer cell lines was variable, and the HSP27 mRNA level in FAM83G mRNA-rich types was greater than that in FAM83G mRNA-normal range types. Taken together, these data demonstrate that FAM83G S356 phosphorylation modulates HSP27 phosphorylation and apoptosis regulation and that HSP27 is a counterpart of FAM83G.

S-1 and CPT-11 Plus Ramucirumab (IRIS+Rmab) as Second-Line Chemotherapy for Patients with Oxaliplatin-Refractory Metastatic Colorectal Cancer (mCRC): A Multicenter Phase II Study in Japan (N-DOCC-F-C-1701).

This multicenter phase II N-DOCC-F-C-1701 trial is being planned in order to investigate the efficacy and safety of CPT-11+S-1 +Ramucirumab (IRIS+Rmab), which is anticipated to have a stronger anti-tumor effect than IRIS+Bmab in patients with metastatic colorectal cancer (mCRC) previously treated with oxaliplatin (L-OHP) containing regimen, in consideration of the result of RAISE, FIRIS and some phase II trials of IRIS+Bevacicizumab (Bmab). The number of patients is set at 38 for the statistical analysis, assuming an expected median PFS of 5.0 months (threshold: 3.0 months). The primary endpoint of the study is the progression free survival (PFS), and the secondary endpoints are the overall response rate (ORR), overall survival (OS), adverse events (AE), quality of life (QOL) and review of nausea and vomiting. This trial is registered in the UMIN Clinical Trials Registry as UMIN000028170. We intend to start conducting the trial in September 1, 2017. If this trial meets the endpoint, IRIS+Rmab might be supported as a new optional standard regimen for mCRC.

Curative potential of fludarabine, melphalan, and non-myeloablative dosage of busulfan in elderly patients with myeloid malignancy.

Although the combination of fludarabine and high-dose melphalan (FLU/MEL) has been widely used in allogeneic stem cell transplantation, high-dose MEL causes life-threatening adverse events, especially in elderly patients. To reduce the toxicity of MEL without losing its antileukemic effect, we formulated a regimen comprising FLU (125 mg/m2), MEL (100 mg/m2), and a non-myeloablative busulfan dosage [4 mg/kg orally (oral) or 3.2 mg/kg intravenously (iv); FLU/MEL/BU]. We retrospectively analyzed 32 patients with myeloid malignancies who received FLU/MEL/BU at our institute. Median age was 59 years and the median observation period after allo-SCT was 8.2 years. The disease status of most of the patients (97%) at transplantation was controlled. The rate of neutrophil engraftment was 93.3%. The 5-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate (RR) were 68.5%, 62.1%, 22.0%, and 15.9%, respectively, in all patients. Notably, the outcome of FLU/MEL/iv BU was excellent, with the 5-year OS and DFS being 75.6% and 70.8%, respectively, accompanied by a reduced 5-year NRM and RR of 19.3% and 9.8%, respectively. In conclusion, FLU/MEL/BU, particularly FLU/MEL/iv BU, has curative potential for controlled myeloid malignancies.

Combination chemotherapy with gemcitabine and nab-paclitaxel for a metastatic pancreatic ductal adenocarcinoma patient undergoing hemodialysis.

In cancer patients, impairment of kidney function is not uncommon. Recently, the efficacy of the combination of gemcitabine and nab-paclitaxel for pancreatic ductal adenocarcinoma (PDAC) patients has been reported, however, there is no recommendation for dose and administration to patients undergoing hemodialysis (HD). A 66-year-old man began receiving HD for chronic renal failure 4 years previously. He suffered from diarrhea, back pain, and loss of appetite, and his weight gradually decreased. Abdominal dynamic computed tomography showed a 45-mm hypodense mass in the pancreatic body and a 30-mm hypodense mass in the liver. The patient was diagnosed with metastatic PDAC. He started combination chemotherapy of gemcitabine and nab-paclitaxel without dose modification. He developed pneumonia and neutropenia in the first and second courses, so we modified to a 60% dose of gemcitabine and nab-paclitaxel on day 1 every 2 weeks. After dose modification, he continued combination chemotherapy for over 7 months without severe adverse events or tumor progression. Combination chemotherapy using gemcitabine and nab-paclitaxel was effective in a PDAC patient undergoing HD. While it is possible to originally administer these drugs with no dose modification, early dose modification was needed for our patient because of severe adverse events.

Prospective observational study on the first 51 cases of peripheral blood stem cell transplantation from unrelated donors in Japan.

The Japan Marrow Donor Program (JMDP) has facilitated unrelated peripheral blood stem cell transplantation (URPBSCT) since 2010. We conducted a prospective multicenter observational study to evaluate the feasibility of such transplantation. Between 2011 and 2014, 51 patients underwent URPBSCT from 8/8 allele-matched donors for hematological malignancies. The median age of the patients was 50 years; 21 had high-risk disease. Myeloablative conditioning regimens were used in 31 patients, and tacrolimus based graft-versus-host disease (GVHD) prophylaxis was used for all patients. The cumulative rate of engraftment was 96%. With a median follow-up period of 610 days for survivors, 100-day and 1-year overall survival rates were 86 and 59%, respectively. The cumulative incidence of non-relapse mortality and relapse at 1 year were 14 and 35%, respectively. The incidence of grade II to IV acute GVHD at 100 days and extensive type of chronic GVHD at 1 year were 25 and 32%, respectively. The probability of overall survival was comparable with that of bone marrow transplantation from HLA matched-unrelated donors in Japan, although the incidence of chronic GVHD was higher. Further follow-up with more patients is clearly warranted to establish the optimal use of URPBSCT together with the approaches of minimizing chronic GVHD.

Bilateral inguinal hernia after axillary-femoral artery bypass effectively treated with laparoscopic repair: A case report.

We report herein our experience with bilateral inguinal hernia surgery for a patient who had previously undergone a Y-shaped vascular graft for an abdominal aortic aneurysm and then right axillary-bilateral femoral artery bypass surgery. Preoperative physical examination and imaging revealed a subcutaneous vascular graft passing from the right axilla through the right flank region and branching at the lower abdomen to reach the femoral areas on both sides. As repair surgery by inguinal incision was considered difficult, we performed laparoscopic surgery. Bilateral direct hernia was observed on intraperitoneal observation. Essentially no intraperitoneal organ adhesion to the abdominal wall was present, and the previous surgery was also confirmed not to have reached the inguinal preperitoneal space. Transabdominal preperitoneal repair was therefore performed, yielding favorable results.

Hairy Cell Leukemia with Systemic Lymphadenopathy: Detection of BRAF Mutations in Both Lymph Node and Peripheral Blood Specimens.

A 47-year-old woman with pancytopenia, excessive systemic lymphadenopathy and splenomegaly was referred to our hospital. The peripheral blood (PB) smear findings indicated neutropenia with lymphoid cells exhibiting hairy projections, while the histological findings of the cervical lymph node (LN) suggested hairy cell leukemia (HCL). In addition, the BRAF V600E mutation was detected, and the immunoglobulin gene rearrangement patterns were identical in both the cervical LN and PB specimens. Based on these findings, we diagnosed the patient with systemic lymphadenopathy due to HCL. This is the first report of a BRAF mutation detected in both the PB and LN at the onset of HCL.

Risk factors for and prognosis of hemorrhagic cystitis after allogeneic stem cell transplantation: retrospective analysis in a single institution.

Hemorrhagic cystitis (HC) is a major complication after allogeneic stem cell transplantation (allo-SCT) and can be life threatening. To analyze risk factors and prognosis, we retrospectively reviewed 249 cases receiving allo-SCT in our institution. Median age was 47 years (13-72 years). Disease status at SCT was progressive in 73 cases. Conditioning was myeloablative (MAC) in 146 cases. Acute graft-versus-host disease (aGVHD) grade II-IV treated with prednisolone occurred in 82 cases, and cytomegalovirus (CMV) was reactivated in 91 cases. HC was reported in 47 cases at a median of 35 days (7-469 days) after SCT, and 34 (72.3%) cases recovered after a median of 19.5 days (2-252 days). In univariate analysis, the identified risk factors for HC included age over 45 years, progressive disease status, MAC, aGVHD treated with prednisolone, and CMV reactivation. In multivariate analysis, older age, MAC, and CMV remained independent predictors (hazard ratios: 2.35, 3.50, and 2.87). In patients with severe HC, percentage recovery was lower (3 in 13 cases; 23.1%) and the median duration was longer (54 days) than in those with moderate HC (31 in 36 cases; 86.1%, 17 days, P < 0.01). Treatment-related mortality was also higher (59.1%, P = 0.03) and overall survival was poorer (16.7%, P < 0.01) at 1 year after SCT. Prospective studies should be started considering prophylactic antiviral administration in high-risk patients such as those identified in this study.

[A case of metastatic lung cancer from colon cancer resected successfully after preoperative chemotherapy].

We describe a case of metastatic lung cancer from colon cancer resected successfully after preoperative chemotherapy. A 68-year-old male patient underwent low anterior resection for colon cancer in October 2004 (Stage III a), transcatheteric hepatic arterial embolization (TAE) for liver metastasis (S5) in October 2005, and partial hepatectomy (S5) in February 2006. Forty-seven months after surgery, lung metastases were detected. He was treated with bevacizumab plus FOLFOX/FOLFIRI, but the lung metastases progressed. Panitumumab plus FOLFIRI was performed and a partial response was obtained. Partial pulmonary resection was performed done in June 2011. It is necessary to add many cases to decide the value of prognostic factor, surgical indication and effectiveness of preoperative chemotherapy for lung metastasis of colorectal cancer.

[Four cases of locally advanced colorectal cancer resected successfully after preoperative chemotherapy].

We describe four cases of locally advanced colorectal cancer resected successfully after preoperative chemotherapy conducted between April of 2007 and April of 2009. The average age of the patients was 66.3 years (range, 40-77 years). Because of tumor invasion into the surrounding organs, preoperative chemotherapy with FOLFOX4 was performed. The average number of courses of chemotherapy was 5.2 (range, 4-7). After chemotherapy, we were able to perform radical operations for all four cases. Histopathological examination of the tumor revealed Grade 3 in one case. There were no postoperative complications and no recurrences in any of the cases. We performed curative surgery after chemotherapy, and good results were obtained. Preoperative chemotherapy may be effective for avoiding excessive intervention surgeries such as total pelvic exenteration, preserving bladder and rectal functions, and for maintening QOL.

cIAP1 Localizes to the nuclear compartment and modulates the cell cycle.

We explored the location and function of the human cIAP1 protein, a member of the inhibitor of apoptosis protein (IAP) family. Unlike family member X-linked IAP (XIAP), which was predominantly cytoplasmic, the cIAP1 protein localized almost exclusively to nuclei in cells, as determined by immunofluorescence microscopy and subcellular fractionation methods. Interestingly, apoptotic stimuli induced nuclear export of cIAP1, which was blocked by a chemical caspase inhibitor. In dividing cells, cIAP1 was released into the cytosol early in mitosis, then reaccumulated in nuclei in late anaphase and in telophase, with the exception of a pool of cIAP1 that associated with the midbody. Survivin, another IAP family member, and cIAP1 were both localized on midbody microtubules at telophase, and also interacted with each other during mitosis. Cells stably overexpressing cIAP1 accumulated in G(2)-M phase and grew slower than control-transfected cells. These cIAP1-overexpressing cells also exhibited cytokinesis defects over 10 times more often than control cells and displayed a mitotic checkpoint abnormality with production of polyploid cells when exposed to microtubule-targeting drugs nocodazole and paclitaxel (Taxol). Our findings demonstrate a role for overexpressed cIAP1 in genetic instability, possibly by interfering with mitotic functions of Survivin. These findings may have important implications for cancers in which cIAP1 overexpression occurs.

An IAP-IAP complex inhibits apoptosis.

Regulators of apoptosis are thought to work in concert, but the molecular interactions of this process are not understood. Here, we show that in response to cell death stimulation, survivin, a member of the inhibitor of apoptosis (IAP) gene family, associates with another IAP protein, XIAP, via conserved baculovirus IAP repeats. Formation of a survivin-XIAP complex promotes increased XIAP stability against ubiquitination/proteasomal destruction and synergistic inhibition of apoptosis, which is abolished in XIAP(-/-) cells. Therefore, orchestration of an IAP-IAP complex regulates apoptosis.