Colloid Carcinoma Arising in an Intestinal-Type Intraductal Papillary Mucinous Neoplasm with High-Grade Dysplasia Appearing as Signet-Ring Cells of the Pancreas by Serial Pancreatic Juice Aspiration Cytology: A Case Report.

We report a case of colloid carcinoma (CC) arising from an intestinal-type intraductal papillary mucinous neoplasm with high-grade dysplasia (IPMNHGD) of the pancreas, diagnosed with serial pancreatic juice aspiration cytological examination (SPACE). A rapidly growing intraductal papillary mucinous neoplasm (IPMN) in a 71-year-old Japanese man accelerated his hospitalization in our institute. Clinically, a large, ruptured pancreatic cyst was suspected. Cytologically, several mucin-positive signet-ring cells were scattered in the inflammatory, necrotic, or mucinous background. Signet-ring cells in cell block specimens were immunoreactive for MUC2, MUC5AC, maspin, S100P, and claudin-18. The final cytologic diagnosis was CC arising in an intestinal-type IPMNHGD with intraperitoneal penetration. The patient died two months after an explorative laparotomy. The cytologic diagnosis was achieved through SPACE, and the presence of signet-ring cells was characteristic. Anti-claudin-18.2-specific monoclonal antibody therapy will likely be used to treat patients with IPMNHGD in the future. This case highlights the diagnostic utility of SPACE, with particular emphasis on the characteristic presence of signet-ring cells. Furthermore, it anticipates the potential use of anti-claudin-18.2- specific monoclonal antibody therapy in the management of IPMNHGD patients.

Multiple bronchiolar adenomas/ciliated muconodular papillary tumors of the bilateral lung with tumor budding and potential malignant transformation into squamous cell carcinoma: a case report and literature review.

Background: Bronchiolar adenoma (BA)/ciliated muconodular papillary tumor (CMPT) is a rare lung tumor characterized by ciliated, mucous and basal cells. Recently, some cases of driver mutations or malignant transformations have been reported. However, the nature of BA/CMPT remains controversial. Here, we report a case of bilateral pulmonary multiple BAs with tumor budding and squamous metaplasia. Case Description: A 55-year-old man presented with multiple small nodules in the lower lobes of the bilateral lungs on physical examination 7 years prior. During the past 3 years of regular follow-up, some nodules had slightly enlarged. Because the nodules were mostly solid, the patient underwent video-assisted thoracoscopic segmentectomy of the left lower lung. A postoperative pathological diagnosis of BA was made. In all lesions, the fusion and mutation of major driver genes were not detected by next-generation sequencing (NGS). No recurrence or metastasis was observed after 37 months of follow-up. Notably, all five resected lesions were BA/CMPT, and one lesion was accompanied by squamous metaplasia and tumor budding. Conclusions: Our report found that BA/CMPT with squamous metaplasia and tumor budding has the potential to transform into lung squamous cell carcinoma, expanding its connection with malignant transformation. Smoking may be one of the risk factors. We also found that BA/CMPT can be multiple lesions rather than a solitary lesion.

Synchronous Jejunal Sarcomatoid Carcinoma and Incidentally Associated Localized Peritoneal Malignant Mesothelioma.

Sarcomatoid carcinoma (SCA) of the small bowel is a rare aggressive variant of small intestinal cancer accompanying a poor prognosis. The tumor primarily affects middle-aged and elderly patients. We report herein a 67-year-old Japanese male who manifested anemia. He had a history of asbestos exposure 30 years earlier. An abdominal computed tomography (CT) scan showed a 6.5-cm aneurysmal, dilated mass of the small intestine. Capsule endoscopy revealed a large circumferential hemorrhagic ulcerative lesion in the jejunum. Biopsy indicated sarcomatoid carcinoma, and partial resection of the small bowel and adjacent transverse colon and omentum was performed. In addition to the T3N0M0 jejunal giant sarcomatoid carcinoma (SCA), a 3-mm small localized peritoneal (omental) malignant mesothelioma (LMM) was also incidentally included. Synchronous presentation of small intestinal and mesothelial malignancies is extremely rare, and the avoidance of incorrect clinical staging is critically important. Surgical resection is still considered the best first-line therapy, because of a poor response to chemotherapy and radiotherapy. Dual-color fluorescent in situ hybridization (FISH) for p16/CDKN2A and chromosome 9 indicated homologous deletion of p16/CDKN2A in SCA and a normal pattern in LMM. Methylthioadenosine phosphorylase (MTAP) was negative in SCA but positive in LMM. Both tumors consistently expressed BRCA1-associated protein 1 (BAP1). Tumor necrosis factor receptor-associated factor 7 (TRAF7) was suppressed, and neural cell adhesion molecule L1 precursor (NCAML1/L1CAM) was agitated in both tumors. Diffuse and strong expression of programmed death-ligand 1 (PD-L1) and the association of tumor-infiltrating lymphocytes in SCA may indicate a potential for PD-L1-targeted immunotherapy for treating this type of aggressive cancer. PD-L1 was focally expressed in LMM. The postoperative course was uneventful for two years.

Epstein-Barr virus-positive mucocutaneous ulcer, plasmablastic type, associated with nodal CD4+ angioimmunoblastic T-cell lymphoma and generalised pruritus: a self-limiting lymphoproliferative disorder resembling cutaneous plasmablastic lymphoma.

A woman in her 80s reported of generalised pruritus, which was treated with phototherapy and steroid administration. Two months after onset, lymph node biopsy revealed CD4+ angioimmunoblastic T-cell lymphoma with systemic superficial nodal involvement. Intractable prurigo was judged as T-cell lymphoma related. After effective chemotherapy (7 months later), skin nodules appeared multifocally, including on the lip, thumb and lower leg. The biopsied infiltrative lesion on the right lower leg microscopically revealed subcutaneous growth of atypical plasmablasts with nearly 100% Ki-67 labelling and Epstein-Barr virus (EBV)-encoded small nuclear RNA positivity. Plasmablastic lymphoma (CD45/CD19/CD38/CD138/MUM1+, CD20/CD79a/PAX5-) was suspected. Immunoglobulin light-chain restriction and nuclear expression of c-myc protein were undetectable, and the ulcers were spontaneously epithelialised by the cessation of steroid administration. After 10 months, non-progressive prurigos persisted on the extremities, but without regrowth of nodal T-cell lymphoma and cutaneous lymphoproliferative lesion. Reactive nature of the EBV-induced mucocutaneous plasmablastic growth (EBV-positive mucocutaneous ulcer, plasmablastic type) is discussed.

Adult Nodal Burkitt Lymphoma Forming Nodular Architectures.

In this report, we discuss a case of nodal Burkitt lymphoma seen in a 60-year-old Japanese male patient. Microscopic features of the biopsied 30 mm-sized cervical lymph node revealed nodular architectures with starry sky appearance surrounded by small mantle zone B-lymphocytes. Immunohistochemical and molecular studies demonstrated typical features of sporadic Burkitt lymphoma: the atypical cells were positive for CD20, CD79a, CD10, CD23, HLA-DR, bcl-6, PAX5, c-myc, and cytoplasmic IgM, but negative for CD3, CD5, CD15, CD30, CD34, TdT, bcl-2, and MUM1. The mantle zone B-cells were clearly positive for bcl-2 and IgD. In situhybridization (ISH) analysis for immunoglobulin light chains showed kappa-type monoclonality. A few nuclei were labeled for Epstein-Barr virus-encoded small nuclear RNA (EBER). Ki-67 labeling index was nearly 100%. Within the nodule, CD21, CD23, and CD35-positive follicular dendritic cells were scattered with a small number of CD3/CD5-positive small T-lymphocytes, indicating that the nodular architecture represented follicular colonization of Burkitt lymphoma cells. Karyotypic analysis revealed t(8;14)(q24;q32), and IGH-MYC fluorescence in situ hybridization (FISH) demonstrated IGH-MYC fusion signals. The presentation of follicular colonization was quite unique in Burkitt lymphoma in the present case. Differential diagnosis is also discussed.

Pancreatic Intraductal Papillary Mucinous Neoplasm with Hyaline Globules (Thanatosomes): Report of Two Cases.

Hyaline globules (HGs; thanatosomes) represent a morphologic entity representing a metabolic imbalance common to all cell types. HGs, intracytoplasmic eosinophilic globular accumulations of proteinaceous material of varying sizes, have been observed in varied tumors and benign tissues. Different explanations have been proposed for their formation, according to the tumor type and anatomic location. An earlier study suggested that HGs were closely related to apoptosis. There are some reports describing HGs in pancreatic neoplasms, such as intraductal oncocytic papillary neoplasm, solid-pseudopapillary neoplasm, oncocytic endocrine neoplasm, and invasive ductal adenocarcinoma; however, this is the first report describing HGs in pancreatic intraductal papillary mucinous neoplasm (IPMN). An ultrastructural study was performed to visualize HGs in two pancreatic IPMNs of gastric type (one non-invasive malignancy and another adenoma). Light microscopically, intracytoplasmic HGs were clustered multifocally. HGs were periodic acid-Schiff-positive and diastase-resistant, and fuchsinophilic with Masson's trichrome stain. The diameter ranged from 4.7 to 20.6 µm (mean: 13.3, median: 14.1). They were mainly seen at the supranuclear position and occasionally with subnuclear location. Ultrastructurally, HGs were round in shape and homogenously electron-dense without mitochondria or chromatin-like condensation. The nuclei of HGs-containing mucous columnar cells appeared intact without evidence of apoptosis. It is worth emphasizing that HGs in the pancreatic IPMN of gastric type belong not to apoptotic bodies but to proteinaceous secretory materials.

A Rare Collision Tumor: Adenocarcinoma in the Ampulla of Vater and Neuroendocrine Tumor in the Lower Part of the Common Bile Duct.

In the biliary tree, only three cases of neuroendocrine tumor (NET) synchronous with adenocarcinoma have been reported so far. We experienced a case of NET, grade 2 (G2), of the common bile duct associated with adenocarcinoma of the ampulla of Vater (AoV). A Japanese man at his 60's visited a local doctor, and obstructive jaundice was pointed out. Under the clinical diagnosis of carcinoma of the AoV, 20 x 20 mm, T3aN0M0 stage IIB, pylorus-preserving pancreaticoduodenectomy was performed. Dynamic computed tomography in an artery-dominant phase and microscopic examination revealed that the mass consisted of two different components; hypovascular, 2.5 cm-sized, exophytic adenocarcinoma in the AoV and hypervascular, 1.5 cm-sized, polypoid NET (G2) in the lower part of the common bile duct. The NET diffusely expressed neuroendocrine markers, including somatostatin receptor-2 (SSTR2), and adenocarcinoma cells arising from tubular adenoma focally expressed the neuroendocrine markers. Both malignancies were positive for caudal-type homeobox-2 (CDX2). It is presumed that NET occurred from intestinal-type adenoma/adenocarcinoma.

Gastric perforation caused by secondary systemic amyloidosis.

Amyloid A amyloidosis secondary to chronic inflammation involves systemic organs and tissues, including the gastrointestinal tract. In the present case, massive amyloid deposit caused gastric perforation. IgM co-deposition in the glomeruli was another finding of note.

Undifferentiated Pleomorphic Sarcoma With Hyaline Globules (Thanatosomes).

Hyaline globules (HGs) or thanatosomes belong to a well-defined microscopic phenomenon common to any cell type, representing eosinophilic and round-shaped intracytoplasmic inclusions as a result of altered cellular metabolism. We experienced a case of undifferentiated pleomorphic sarcoma (UPS) of the left thigh, immunoreactive diffusely for CD99 and p16INK4a and focally for alpha-smooth muscle actin. HGs were multifocally clustered in the cytoplasm of the tumor cells. An ultrastructural study using a formalin-fixed, paraffin-embedded block was performed to visualize HGs in the UPS cells. Light microscopically, multifocally clustered HGs were PAS-positive with diastase-resistance and fuchsinophilic in Masson's trichrome staining. HGs were immunoreactive for cleaved caspase-3, but negative for ubiquitin. Ultrastructurally, apoptotic tumor cells contained clusters of small-sized electron-dense globules. Granular material was often deposited in the globule matrix. The formation of the HGs is supposedly related to an apoptotic process of the tumor cells. Though a nonspecific and minor microscopic finding, HGs in soft tissue sarcomas may represent a useful histologic marker of enhanced cell turnover and/or ischemic injury. This is the third report describing HGs in UPS.

Late relapse of IgM nephropathy-associated nephrotic syndrome after repeated administration of immune checkpoint inhibitor against pulmonary adenocarcinoma.

ICPIs were effective for primary and metastatic foci of lung adenocarcinoma, but their repeated use provoked a late relapse of IgM nephropathy and lethal lesions in pancreas and lung. ICPIs should be used carefully in cases of immune-related disease.

Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.

A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).

Acute Coronary Syndrome in Acute Myeloid Leukemia with Maturation Accompanying Megakaryocytic Differentiation.

An autopsy case (85-year-old Japanese male) of myeloperoxidase- (MPO-) positive acute myeloid leukemia with maturation (M1) accompanying megakaryocytic differentiation is presented. The patient manifested acute coronary syndrome. Even after emergent percutaneous coronary intervention, his performance status remained poor, so no chemotherapy against leukemia was given. The final white blood cell count reached 291,700/µL, and the platelet count was elevated to 510,000/µL. No cytogenetic studies were performed. He died at the 25th day of hospitalization. Autopsy revealed marked leukemic infiltration to the endocardium and subendocardial myocardium. Subendocardial myonecrosis was surrounded or replaced by the leukemic blasts, and neither granulation tissue reaction nor fibrosis was observed. In the cardiovascular lumen, lard-like blood clots were formed and microscopically consisted of leukemic blasts and platelets (leukemic thrombi). Infiltration of leukemic blasts was seen in the body cavities and systemic organs including the lung. The MPO-positive blasts lacked azurophilic granules and expressed the stem cell markers, CD34 and CD117 (c-kit). No features of myelofibrosis were seen in the 100% cellular marrow. In the endocardium, liver, lymph nodes, and bone marrow, megakaryocytic cells (CD42b/CD61+, MPO-) were distributed, while the small-sized blastic cells in the blood and tissues predominantly expressed MPO. The blasts lacked expression of CD42b/CD61. Megakaryocytic differentiation might be stimulated by certain tissue factors. AML accompanying megakaryocytic differentiation in certain tissues and organs should be distinguished from acute megakaryoblastic leukemia. The mechanisms provoking acute coronary syndrome in acute myeloid leukemia are discussed.

Colitis nucleomigrans: The third type of microscopic colitis (part 1).

Microscopic colitis (MC), encompassing collagenous colitis and lymphocytic colitis, is featured by chronic diarrhea, normal-looking endoscopic findings and unique microscopic appearance. After reviewing biopsied nonspecific colitis, we propose the third type of MC: colitis nucleomigrans (CN). Histopathological criteria of CN included: (i) chained nuclear migration to the middle part of the surface-lining columnar epithelium; (ii) apoptotic nuclear debris scattered below the nuclei; and (iii) mild/moderate chronic inflammation in the lamina propria. Thirty-three patients (M:F = 20:13; median age 63 years, range 17-88) fulfilled our criteria. Seven cases demonstrated MC-like clinical/endoscopic features. Mucosal reddening with or without erosion/aphtha was endoscopically observed in the remaining 26 cases with inflammatory bowel disease (IBD)-like features: occult/gross hematochezia seen in 19, abdominal pain in two and mucin secretion in two. Cleaved caspase-3-immunoreactive apoptotic debris appeared more frequently in IBD-like CN than in MC-like CN, while CD8-positive intraepithelial lymphocytes comparably appeared in both. Proton pump inhibitors (PPIs) were administered in five (71%) cases with MC-like features, and in three diarrhea improved after drug cessation. In IBD-like CN cases, eight (31%) received PPIs. Four patients received chemotherapy against malignancies. Four patients associated immune-related disorders. Microscopic appearance of CN also appeared in a remission state of ulcerative colitis (12/20 lesions).

Colitis nucleomigrans: The third type of microscopic colitis (part 2). An ultrastructural study.

In the preceding article (part 1), we proposed the third type of microscopic colitis: colitis nucleomigrans (CN). Microscopically, the nuclei of surface-lining columnar cells were migrated in chain to the middle part of the cells, and apoptotic nuclear debris was scattered in the cytoplasm beneath the nuclei. For ultrastructural analysis, buffered formalin-fixed biopsy tissue of CN (n = 2) was dug out of paraffin blocks. After deparaffinization, tissue blocks were prepared with conventional sequences. Ultrathin sections were stained with uranyl acetate and lead citrate. Fine morphological preservation was satisfactory even after paraffin embedding. Apoptotic nuclear debris was localized within the cytoplasm beneath the migrated nuclei of the surface-lining columnar cells. Abnormality of cytoskeletal filaments (actin, cytokeratin and tubulin) was scarcely recognized in the epithelial cytoplasm. Macrophages located in the uppermost part of the lamina propria phagocytized electron-dense globular materials. Intraepithelial lymphocytes with scattered dense bodies were observed among the columnar cells. We suppose that altered apoptotic processes in the colorectal surface-lining epithelial cells may be involved in the pathogenesis of CN. Mechanisms of nuclear migration to the unusual position or impairment of nuclear anchoring to the basal situation in the surface-lining epithelial cells remain unsettled, because cytoskeletal components showed little ultrastructural abnormality.

Paraneoplastic Pemphigus Involving the Respiratory and Gastrointestinal Mucosae.

Paraneoplastic pemphigus (PNP), an autoimmune mucocutaneous disorder involving the oral and bronchial mucosae, is a rare complication of hematologic malignancy. Serologically, serum autoantibodies against varied desmosome-related proteins are of notice. PNP is often lethal due to bronchiolitis obliterans and opportunistic infection. A 70-year-old Japanese male complained of dry cough, stomatitis, and sore throat. The lips and oral mucosa were severely eroded, and skin eruptions were seen on the chest and abdomen. The biopsy features were consistent with PNP, and the deposition of IgG and IgM was shown on the plasma membrane of the involved keratinocytes. Serological studies demonstrated autoantibodies to desmoglein-3, desmocollins-2 and -3, bullous pemphigoid antigen-1, envoplakin and periplakin. Systemic evaluation disclosed mantle cell lymphoma, stage 4B. After chemotherapy, partial remission was reached. PNP was treated with methylprednisolone and intravenous immunoglobulins, and the oral lesion only temporarily responded. He died of respiratory failure two months after onset. Autopsy revealed residual indolent lymphoma and systemic opportunistic infections. Aspergillus colonized the eroded bronchial/bronchiolar mucosa, associated with extensive vascular invasion. Coinfection of cytomegalovirus (CMV) and Pneumocystis jirovecii caused interstitial pneumonia. The oropharyngeal, respiratory, esophageal, and gastrointestinal mucosae were diffusely infected by CMV. Bronchiolitis obliterans was observed in the peripheral lung. PNP-related acantholysis-like lesions were microscopically identified in the bronchial and gastrointestinal mucosa. IgG deposition and cleaved caspase-3-immunoreactive apoptotic cell death were proven in the involved mucosal columnar cells. Pathogenesis of the mucosal involvement is discussed.

Distal-type bronchiolar adenoma of the lung expressing p16INK4a - morphologic, immunohistochemical, ultrastructural and genomic analysis - report of a case and review of the literature.

Bronchiolar adenoma (BA) of the lung is a rare benign neoplasm. Because of a chest abnormal shadow indicated by health checkup, a 77-year-old female nonsmoker underwent computed tomography, revealing an 8 mm ground glass nodule in the peripheral field of the right lower lobe. Wedge resection of the nodule was performed, with a frozen diagnosis of primary lung adenocarcinoma. The localized, 8 × 4 × 3 mm-sized, jelly-like mass microscopically revealed a lepidic-growing lesion composed of ciliated columnar cells, mucous cells and basal cells surrounded by mucin pool. Neither nuclear atypia nor mitotic activity was noted. Immunohistochemically, the ciliated, mucous and basal cells were positive for TTF-1 and p16INK4a . Mucous cells were positive for napsin A and focally expressed MUC5AC. MUC6 was negative. Basal cells were positive for CK5/6, p40, p63 and podoplanin. Human papillomavirus genome was undetectable by in situ hybridization. Ultrastructurally, the bronchiolar epithelial tubules consisted of two layers, the inner nonciliated microvillous cells and the outer basal-like cells, and some of the inner cells were filled with mucin granules in cytoplasm. Molecular analysis of the tumor failed to show driver mutations. The final diagnosis was distal-type BA. The postoperative course was uneventful for 6 months.

[A Case Of cT3bN2M0 Pleomorphic Giant Cell Carcinoma of the Bladder without Recurrence after Neoadjuvant Chemotherapy and Radical Cystectomy for 4 Years].

Pleomorphic giant cell carcinoma of the bladder is a highly malignant subtype and its prognosis is very poor. Among 22 previously reported cases, 14 cases were diagnosed as muscle-invasive tumors and the 10 patients died within 1.5 years after the initial diagnosis. We herein report a long-surviving patient with cT3bN2M0 pleomorphic giant cell carcinoma of the bladder without recurrence. A 73-year-old man presented with macroscopic hematuria and cystoscopy revealed a papillary nodular tumor 45 millimeters in diameter at the right bladder wall. Bilateral external iliac lymph node metastases were found on computed tomography (CT) and magnetic resonance imaging (MRI). The histopathological diagnosis of the transurethral resection specimen was pleomorphic giant cell urothelial carcinoma, high-grade, G3, pT2 or higher. The pleomorphic giant cells were composed of large epithelioid cells with single or multiple bizarre nuclei. The patient underwent 2 cycles of neoadjuvant chemotherapy using gemcitabine and cisplatin. Follow-up CT and MRI revealed disappearance of iliac lymph node matastases. Laparoscopic radical cystectomy and lymphadenectomy were performed. The histopathological diagnosis was pleomorphic giant cell urothelial carcinoma, ypT3aN0M0, RM0. Giant cells were found in 70% of the tumor. No recurrence has been found for 4 years after surgery. If neoadjuvant chemotherapy is effective, long-term survival without recurrence may be possible after radical cystectomy even in cases of muscle-invasive or N2 pleomorphic giant cell carcinoma of the bladder.

[Laparoscopic resection of a retroperitoneal müllerian cyst: a case report].

A 51-year-old woman had a cystic mass in the retroperitoneal space, below the left kidney, which was incidentally detected at a medical check-up. The size of the mass was 6 cm in diameter, which was similar to that obtained by magnetic resonance imaging 4 years ago. We followed the case and found that the mass was slightly enlarged a year later. Because malignancy could not be ruled out, we performed a laparoscopic tumor excision. Histologically, the cyst was diagnosed as a Müllerian cyst, and there was no evidence of malignancy. Retroperitoneal Müllerian cyst is a rare tumor. Sixteen cases have been reported previously and this is the fourth case of a laparoscopic excision.

[A case of resected pulmonary mucormycosis that was suspected of mixed infection with Aspergillus fumigatus, diagnosed by transbronchial lung biopsy].

A 73-year-old man was admitted with high fever and right chest pain. Chest X-ray showed a rapidly growing mass shadow in the right lower lung field. The patient had been in remission for malignant lymphoma and had developed interstitial pneumonia and diabetes mellitus following 1 year of corticosteroid therapy. His illness was diagnosed as invasive aspergillosis because of a high level of beta-D-glucan and cultured Aspergillus fumigatus in the sputum. He was treated with a combination of micafungin and itraconazole. However, because these agents did not improve his clinical condition, transbronchial lung biopsy was performed. Histologically, Mucor hyphae were detected in these specimens. Micafungin and itraconazole were stopped and infusion of liposomal amphotericin B was initiated. Because his condition worsened, a right lower lobectomy was performed. Rhizopus Oryzae was detected in the lung tissue. We report a case of pulmonary mucormycosis in which mixed infection with A. fumigatus was suspected. Pulmonary mucormycosis is a life-threatening infection in which it is rare that an antemortem diagnosis is established and organisms are isolated. We believe diagnostic tests should be performed aggressively, even when pulmonary aspergillosis is suspected.

Ankyrin repeat domain 28 (ANKRD28), a novel binding partner of DOCK180, promotes cell migration by regulating focal adhesion formation.

DOCK180 is a guanine exchange factor of Rac1 originally identified as a protein bound to an SH3 domain of the Crk adaptor protein. DOCK180 induces tyrosine phosphorylation of p130(Cas), and recruits the Crk-p130(Cas) complex to focal adhesions. To understand the role of DOCK180 in cell adhesion and migration, we searched for DOCK180-binding proteins with a nano-LC/MS/MS system, and identified ANKRD28, a protein that contains twenty-six ankyrin domain repeats. Knockdown of ANKRD28 by RNA interference reduced the velocity of migration of HeLa cells, suggesting that this protein plays a physiologic role in the DOCK180-Rac1 signaling pathway. Furthermore, knockdown of ANKRD28 was found to alter the distribution of focal adhesion proteins such as Crk, paxillin, and p130(Cas). On the other hand, expression of ANKRD28, p130(Cas), Crk, and DOCK180 induced hyper-phosphorylation of p130(Cas), and impaired detachment of the cell membrane during migration. Consequently, cells expressing ANKRD28 exhibited multiple long cellular processes. ANKRD28 associated with DOCK180 in an SH3-dependent manner and competed with ELMO, another protein bound to the SH3 domain of DOCK180. In striking contrast to ANKRD28, overexpression of ELMO induced extensive lamellipodial protrusion around the entire circumference. These data suggest that ANKRD28 specifies the localization and the activity of the DOCK180-Rac1 pathway.