Tumor heterogeneity and immune-evasive T follicular cell lymphoma phenotypes at single-cell resolution.

T follicular helper (TFH) cell lymphomas (TFHLs) are characterized by TFH-like properties and accompanied by substantial immune-cell infiltration into tumor tissues. Nevertheless, the comprehensive understanding of tumor-cell heterogeneity and immune profiles of TFHL remains elusive. To address this, we conducted single-cell transcriptomic analysis on 9 lymph node (LN) and 16 peripheral blood (PB) samples from TFHL patients. Tumor cells were divided into 5 distinct subclusters, with significant heterogeneity observed in the expression levels of TFH markers. Copy number variation (CNV) and trajectory analyses indicated that the accumulation of CNVs, together with gene mutations, may drive the clonal evolution of tumor cells towards TFH-like and cell proliferation phenotypes. Additionally, we identified a novel tumor-cell-specific marker, PLS3. Notably, we found a significant increase in exhausted CD8+ T cells with oligoclonal expansion in TFHL LNs and PB, along with distinctive immune evasion characteristics exhibited by infiltrating regulatory T, myeloid, B, and natural killer cells. Finally, in-silico and spatial cell-cell interaction analyses revealed complex networking between tumor and immune cells, driving the formation of an immunosuppressive microenvironment. These findings highlight the remarkable tumor-cell heterogeneity and immunoevasion in TFHL beyond previous expectations, suggesting potential roles in treatment resistance.

Doublet or Triplet Antiemetic Prophylaxis for Nausea and Vomiting Induced by Trastuzumab Deruxtecan: an Open-Label, Randomized, and Multicenter Exploratory Phase 2 Study.

Background: Trastuzumab deruxtecan is classified as an anticancer agent that poses a moderate emetic risk in the international guidelines for antiemetic therapy. The guidelines recommend emesis prophylaxis using a two-drug combination therapy comprising a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and dexamethasone (DEX). However, the high incidence of nausea and vomiting associated with trastuzumab deruxtecan is problematic. The National Comprehensive Cancer Network guideline version 1.2023 classified trastuzumab deruxtecan as having a high risk of emesis and changed its recommendation to a triplet regimen including a neurokinin-1 receptor antagonist (NK1RA). However, the emetogenic potential of trastuzumab-deruxtecan and the optimal antiemetic prophylaxis are controversial. Hence, this exploratory phase 2 study aimed to assess the efficacy and safety of treatment comprising 5-HT3RA and DEX with or without a NK1RA in preventing trastuzumab deruxtecan-induced nausea and vomiting. Methods: We conducted an open-label and randomized exploratory phase 2 study at 14 centers in Japan. Patients with breast cancer who were scheduled to receive trastuzumab deruxtecan were enrolled in this study. The patients were randomly assigned to receive granisetron and DEX (arm GD) or granisetron, DEX, and aprepitant (fosaprepitant; arm GDA). The primary endpoint was complete response (CR; no emesis or no rescue therapy) during the overall phase (120 h after the start of trastuzumab deruxtecan). Results: Between September 2020 and March 2023, 40 patients were randomly assigned to the GD (n = 19) or GDA (n = 21) arm. In the GDA arm, one patient who did not complete the use of the rescue medication listed in the diary was excluded from the efficacy analysis, which included the use of rescue medication. The CR rates during the overall phase were 36.8% and 70.0% in the GD and GDA arms, respectively (odds ratio 0.1334; 95% confidence interval [CI]: 0.0232-0.7672; P = 0.0190), with a difference of 33.2%. No grade 3 or 4 toxicity related to antiemetic therapy was observed. Conclusions: Patients receiving trastuzumab deruxtecan require triple therapy, including mandatory NK1RA administration.

Absolute Lymphocyte Count as an Independent Prognostic Factor in Metastatic Breast Cancer: A Retrospective Study.

INTRODUCTION: Recently, absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) have been reported to be prognostic and/or predictive factors in breast cancer. However, most of the investigations on the relationship between systemic inflammatory markers and prognosis have been conducted perioperatively, with few studies reporting on patients with metastatic or recurrent breast cancer (MBC). Here, we investigated the role of ALC and NLR as prognostic factors of MBC. METHODS: This was a retrospective observational study of patients with MBC treated at the University of Tsukuba Hospital between 2013 and 2020. ALC and NLR clinical data were obtained from the patients' charts. Based on the previous reports, the cutoff value of ALC was set at 1,500/µL and that of NLR, at 3. We investigated the prognostic significance of ALC and NLR. RESULTS: About 80% of the 243 included patients were hormone receptor-positive, 20% were HER2-positive, and 10% were triple negative. The patients were grouped as follows: 114 (46.9%) and 129 (53.1%) in the high and low ALC groups and 145 (59.7%) and 98 (40.3%) in the high and low NLR groups, respectively. The group with high ALC at diagnosis of MBC showed significantly better prognosis (p = 0.002), and the median overall survival (OS) was 70.9 months, as compared with 40.2 months for the low ALC group. On multivariate analysis, visceral metastasis, subtype, and ALC were independent variables for OS; the NLR status was not correlated with OS. CONCLUSIONS: Analysis of real-world data suggests that ALC at diagnosis of MBC is an independent prognostic factor.

A single-cell atlas of non-haematopoietic cells in human lymph nodes and lymphoma reveals a landscape of stromal remodelling.

The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas are reported to underlie lymphomagenesis. However, our understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here we constructed a single-cell transcriptome atlas of more than 100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, and it revealed 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was useful for comparative analyses with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs. This facilitates our understanding of stromal remodelling in lymphoma and highlights potential clinical biomarkers. Our study largely updates NHC taxonomy in human LNs and analysis of disease status, and provides a rich resource and deeper insights into LN and lymphoma biology to advance lymphoma management and therapy.

Preoperative diagnosis of a giant cell tumor of soft tissue arising from the breast by ultrasound-guided core needle biopsy.

Giant cell tumors of soft tissue (GCT-ST) arising in the breast are extremely rare. Herein, we report a case of a 45-year-old woman with a 5-cm mass in her left breast. Ultrasonography revealed a mainly well-circumscribed mass that contained a cystic lesion. Magnetic resonance imaging showed a fibrous capsule-covered mass that contained a high-intensity area, suggesting hemorrhaging. Ultrasound-guided core needle biopsy (CNB) revealed mononuclear histiocytic cells with a round shape or spindled appearance that was mixed with multinucleated giant cells. Immunohistochemical analysis revealed CD68-positive staining in the mononuclear and giant cells but negative staining for pancytokeratin. Preoperatively, the tumor was highly suspected of being GCT-ST. Histopathological results after a left mastectomy showed similar findings to CNB. The final diagnosis was GCT-ST in the breast. To the best of our knowledge, this is the first case report of a GCT-ST arising in the breast diagnosed by ultrasound-guided CNB.

Intramammary Metastasis in a Patient with a History of Renal Cell Carcinoma: A Case Report.

Intramammary metastasis of renal cell carcinoma (RCC) is extremely rare, accounting for only 1.5% of all intramammary metastases. Distinguishing intramammary metastases from benign tumors and breast cancer is clinically problematic. Some patients undergo excessive surgery after a misdiagnosis of breast cancer instead of a mammary tumor. We performed a core needle biopsy (CNB) of a breast mass that developed in a 71-year-old woman after surgeries for bilateral RCC and breast cancer, leading to a diagnosis of intramammary metastasis of RCC. In this case, the CNB and immunohistochemical examination were critical for reaching a definitive diagnosis. We conclude that, when examining patients with mammary tumors, establishing their history of malignant tumors may help diagnose intramammary metastasis and select the best treatment strategy.

Effects of sorafenib and an adenylyl cyclase activator on in vitro growth of well-differentiated thyroid cancer cells.

Well-differentiated thyroid carcinomas have driver mutations involving growth factor receptor-tyrosine kinases (RTKs) or their intracellular signaling pathway, that is, the mitogen-activated protein kinase (MAPK) pathway. Sorafenib is a multikinase inhibitor of RTKs and the MAPK pathway and has recently been used for the treatment of unresectable well-differentiated thyroid carcinoma. In normal thyroid follicular cells, stimulation of the thyroid-stimulating hormone (TSH) receptor activates the cyclic adenosine monophosphate (cAMP) pathway and promotes cell growth as well as hormonal secretion. However, an adenylyl cyclase (AC) activator, forskolin, has been reported to suppress the growth of thyroid carcinoma cells. To clarify the roles of the MAPK and cAMP pathways in proliferation of well-differentiated thyroid carcinoma cells, we compared the effects of sorafenib and forskolin in in vitro models. Sorafenib inhibited constitutive activation of the MAPK pathway, cyclin-dependent kinase 4 (CDK4), and phosphorylated retinoblastoma protein (RB) in 3 well-differentiated carcinoma cell lines, but it did not show sufficiently effective suppression of cell growth. Forskolin significantly suppressed the growth of all 3 cell lines and also activated the cAMP pathway and inhibited expression of cyclin D1. Our results suggest that activation of the cAMP pathway could be more potent than activation of the MAPK pathway in suppressing proliferation of well-differentiated thyroid cancer cells. We postulate that the AC activator suppresses growth of thyroid carcinoma cells through undetermined mechanisms.

A case of hemorrhagic cystitis caused by nab-paclitaxel.

Nab-paclitaxel (nab-PTX) is a nanoparticle albumin-bound paclitaxel and, as such, is free of solvents like ethanol and polyoxyethylene castor oil. The absence of solvents from this formulation has several practical advantages: it has a shorter infusion time, it negates the need for premedications for hypersensitivity reactions, and it can be administered to patients with alcoholic hypersensitivity. It is thought that nab-paclitaxel will be in widespread use in the near future because of its convenience and efficacy. Here, we report the case of a breast cancer patient who developed hemorrhagic cystitis potentially due to treatment with nab-paclitaxel. The patient was 69-year old lady with stage IIB left breast cancer. She was due to undergo neoadjuvant chemotherapy and started weekly treatment with nab-paclitaxel. On the second day of the first cycle of treatment, she experienced symptoms of cystitis, but was not hemorrhagic and the symptoms were managed with antibiotics. After the third cycle, the symptoms of cystitis became severe, and she was diagnosed with hemorrhagic cystitis and discontinued chemotherapy with nab-paclitaxel. This is the first case report of hemorrhagic cystitis associated with nab-paclitaxel.