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Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML. The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance.

Spliceosome mutations (SRSF2, SF3B1, U2AF1, ZRSR2), are encountered in ∼50% of secondary acute myeloid leukemia cases (sAML) and define a molecular subgroup with outcomes similar to sAML in de novo AML patients treated with intensive chemotherapy. Outcomes in patients with spliceosome mutations treated with hypomethylating agents in combination with venetoclax (HMA+VEN) remains unknown. The primary objective was to compare outcomes in patients with spliceosome mutations vs wild-type patients treated with HMA+VEN. Secondary objectives included analysis of the mutational landscape of the spliceosome cohort and assessing the impact of co-occurring mutations. We performed a retrospective cohort analysis of patients treated with HMA+VEN–based regimens at The University of Texas MD Anderson Cancer Center. A total of 119 patients (spliceosome mutated n = 39 [SRSF2, n = 24; SF3B1, n = 8; U2AF1, n = 7]; wild-type, n = 80) were included. Similar responses were observed between spliceosome and wild-type cohorts for composite complete response (CRc; 79% vs 75%, P = .65), and measurable residual disease–negative CRc (48% vs 60%, P = .34). Median overall survival for spliceosome vs wild-type patients was 35 vs 14 months (P = .58), and was not reached; 35 months and 8 months for patients with SRSF2, SF3B1, and U2AF1 mutations, respectively. IDH2 mutations were enriched in patients with SRSF2 mutations and associated with favorable outcomes (1- and 2-year overall survival [OS] of 100% and 88%). RAS mutations were enriched in patients with U2AF1 mutations and associated with inferior outcomes (median OS, 8 months). Comparable outcomes were observed between patients with vs without spliceosome mutations treated with HMA+VEN regimens, with specific co-mutation pairs demonstrating favorable outcomes.

Clonal haematopoiesis (CH) in patients with acute myeloid leukaemia (AML) may persist beyond attaining complete remission. From a consecutive cohort of 67 patients with nucleophosmin 1-mutated (NPM1mut ) AML, we identified 50 who achieved NPM1mut clearance and had parallel multicolour flow cytometry (MFC) and next generation sequencing (NGS). In total, 13 (26%) cleared all mutations, 37 (74%) had persistent CH frequently involving DNA methyltransferase 3α (DNMT3A,70%), tet methylcytosine dioxygenase 2 (TET2, 27%), isocitrate dehydrogenase 2 (IDH2, 19%) and IDH1 (11%). A small number (

Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine., Understanding the evolutionary trajectory of cancer samples may enable understanding resistance to treatment. Here, the authors used single cell sequencing of a cohort of acute myeloid leukemia tumours and identify features of linear and branching evolution in tumours.

Patients with immunodeficiency or immunosuppression are at risk of developing a lymphoproliferative disorder (LPD). Methotrexate (MTX) is an iatrogenic cause of LPD, which in up to 50% cases occurs in extranodal sites. The occurrence of MTX-related LPD with osteonecrosis of the jaw (ONJ) has rarely been reported. Moreover, there are no clear diagnostic criteria and treatment strategies for management of these lesions. In the present cases, discontinuing MTX and debridement of the necrotic bone were effective. This report describes 3 cases of MTX-related LPD in patients with longstanding rheumatoid arthritis (RA) who presented with ONJ. The first patient was a 74-year-old man with RA who had received treatment with MTX for 7 years before presenting with ONJ and submental lymphadenopathy. The second patient was a 79-year-old woman who had been treated for 21 years with MTX and who presented with ONJ. The third patient was a 67-year-old man who had been treated with MTX for more than 15 years. In all 3 cases, biopsy, histology, and immunohistochemistry using a panel of lymphoid markers (Epstein-Barr virus [EBV], CD79a, CD20, PAX-5, CD3, and CD30) resulted in the diagnosis of EBV-driven T-cell, B-cell, and Hodgkin-like LPD. All 3 patients recovered after cessation of MTX and surgical debridement. Biopsy examination, diagnostic immunohistochemistry using lymphoid immune markers, and imaging studies using computed tomography, magnetic resonance imaging, and positron-emission tomographic computed tomography were useful for the correct diagnosis of this condition.

Here we report a case of localized AL amyloidosis of the tongue that caused discomfort and tissue mass in the mid-dorsal surface of the tongue. A 70-year-old woman became aware of discomfort and tissue mass in the mid-dorsal surface of the tongue. Biopsy of the lesion was performed in 2010, and pathological examination suggested amyloidosis. A gradual increase in size of the tongue lesion was seen during clinical follow-up. Second biopsy of the tongue lesion was performed in October 2013, and the pathological diagnosis was amyloidosis. The patient was referred to our hospital for definitive diagnosis. Extensive examination excluded systemic involvement, and localized primary amyloidosis was diagnosed. The lesion was surgically resected and no clinical progression to systemic amyloidosis or local recurrence has been observed during 2 years of follow-up. In English literature, 25% of patients with systemic amyloidosis show macroglossia related to tongue amyloidosis, and there was no consensus for management of localized tongue amyloidosis. Some reports indicated there was no case of localized amyloidosis progressing to the systemic form. On the other hand, there were some reports that amyloidosis of mucosal sites in the head and neck was associated with underlying malignancy. Careful regular follow-up for this disease is thus necessary. Because therapeutic principles are different between localized tongue amyloidosis and oral amyloidosis related to systemic form, oral surgeons must investigate systemic involvement in cases like this.

Cherubism is a rare genetic disorder and the majority of patients with cherubism are children. The aim of this study was to determine if analysis of mutations in the SH3BP2 gene using collected blood could distinguish cherubism from other similar diseases and might therefore replace the current extensive and invasive methods of diagnosis of cherubism with a minimally invasive method. Exon 9 of the SH3BP2 gene of a child with cherubism and of the child's parents was sequenced using PCR of the genomic DNA of collected leucocytes. The patient's lesions were analyzed radiographically. Biopsied lesions of the patient were histopathologically analyzed. The genomic DNA analysis indicated that the exon 9 sequence of the child and that of its mother, but not its father, was mutated. The combined radiographic and histopathological analyses suggested cherubism. In conclusion, sequencing of mutations in exon 9 of the SH3BP2 gene can diagnose cherubism and may therefore replace the combined extensive and more invasive methods previously required for such diagnosis.

Oral mucositis (OM) is a painful complication of radiation therapy (RT) for head and neck cancer. OM can compromise nutrition, require opioid analgesics and hospitalization for pain control, and lead to interruption of treatment. Severe oral mucositis appears inevitable in superselective intra-arterial chemotherapy concurrent with radiotherapy (SSIACRT), requiring management of OM for the patient. The objective of this study was to assess the utility of professional oral health care (POHC) for the management of OM in patients undergoing SSIACRT. Thirty-three patients were enrolled in this study. The first 17 patients underwent SSIACRT before we created an oral management team, and thus did not receive POHC. The remaining 16 patients received POHC. Fever duration, duration of oral feeding difficulty, opioid usage, duration of opioid administration, duration of hospitalization, and number of hospital days from the end of irradiation to discharge were compared between these two groups. Median total dose of morphine during SSIACRT, median number of hospital days from end of irradiation to discharge, and duration of hospitalization all differed significantly between groups (P

We report the case of a 3-month-old female infant who presented with a cystic swelling in the left side of the oral floor (i.e., a congenital ranula). Observation was initially carried out because of the patient's poor general condition. A puncture was performed twice because the ranula enlarged gradually and caused difficulty with sucking during follow-up. Despite being punctured, the ranula recurred again and resulted in difficulty with sucking. Therefore, we performed marsupialization of the ranula under general anesthesia. There was no sign of recurrence for 4 years after marsupialization.

A penetrating injury by a foreign body is comparatively common in the oral and maxillofacial region. On the other hand, injury to the temporomandibular joint (TMJ) by a foreign object is very rare. The TMJ is an anatomically narrow space surrounded by hard bony processes. An unusual case of trauma with severe trismus caused by a foreign body that impaled the TMJ is reported. A 55-year-old man presented with a 5 × 1-cm laceration to the right cheek caused by a flying object propelled during the use of a lawn mower. The edge of the foreign body had a metallic wire, which became imbedded in the wound. His jaw opening was severely limited. Computed tomography revealed that the foreign body was 3 mm in diameter and was impaled on the articular capsule. The object was successfully removed, and the wound and interior of the TMJ were irrigated. Rehabilitation of mouth opening was started on postoperative day 3. On day 9, mouth opening had improved to 35 mm, and he was discharged. After 1 year, mouth opening was 45 mm with no sign of any TMJ disorders.

Background. Distant metastasis is considerably more frequent in superselective intra-arterial chemoradiotherapy than other radical treatments for advanced oral cancers. However, there is no evidence supporting such claim. The purpose of this study was to report our experience in superselective intra-arterial chemoradiotherapy and conventional surgical management with particular focus on distant metastasis. Methods. One hundred seventy-two patients with oral squamous cell carcinoma in stages III and IV were included in this study. Retrospective analysis for DM rates and background between surgical management and superselective intra-arterial chemoradiotherapy was performed. Results. Distant metastasis developed clinically was detected in 24 out of 141 patients (17.0%) treated surgically and in 6 out of 31 patients (19.4%) treated with superselective intra-arterial chemoradiotherapy. There was no significant difference in the rate of distant metastasis between the 2 groups. Comparison of patients in both groups with and without distant metastasis revealed no differences in age, T classification, N classification, and treatment effect. Neck recurrence was the only significant risk factor for distant metastasis. Conclusion. No significant difference was found in the rate of distant metastasis between patients treated with surgical treatment and superselective intra-arterial chemoradiotherapy, and additional effort is needed to reduce the risk of distant metastasis.