Malignant Infiltration Research Articles

Abstract 1829: Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma

Abstract BACKGROUND: Glioblastoma (GBM) is a highly infiltrative and aggressive malignancy with few treatment options; all patients develop recurrence after initial therapy. Due to the dismal outcome of these patients, identification of GBM-specific targets for therapeutic development is urgently needed. PRMT5 is a protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine residues within histones marks, resulting in chromatin restructuring, which in turn promotes oncogenic processes. PRMT5 inhibition has shown efficacy against multiple malignancies; MTAP loss has been associated with increased sensitivity to PRMT5 inhibitors. Here, we examined the effects of pharmacological abrogation of PRMT5 function using highly specific, brain penetrant, orally bioavailable inhibitors and assessed the role of MTAP and p53 expression on sensitivity to these agents. MATERIALS AND METHODS: Using pharmacological inhibition of PRMT5 using with the highly specific inhibitors PRT808 and PRT811, we examined their effects on apoptosis, cell proliferation, cell cycle distribution, and methylation markers in patient-derived glioma stem-like cells (GSC) with epigenetic and genetic signaling. Additional studies to identify transcriptomic (RNA-seq), and proteomic (RPPA) landscape related to PRMT5 in gliomas are ongoing. RESULTS: PRT808 and PRT811 induced potent reduction of symmetrical dimethylation (SDMA) protein marks in all GSC tested. However, treatment of GSC214 (mutant p53), GSC262 (mutant p53), GSC811 (truncated p53), and GSC11 (wild type p53) showed that wild type and truncated p53-expressing lines (GSC811 and GSC11) were more sensitive than GSC cell lines expressing mutant p53 (GSC214 and GSC262). There was no correlation between MTAP status and sensitivity to PRMT5 inhibition. In addition, PRMT5 inhibition resulted in reduced proliferation and alteration of several cell survival pathways; induction of apoptosis in GSC cell lines at late time points around 8-9 days after single dose treatment even though SDMA reduction occurred as early as 3 days. CONCLUSIONS: Our results demonstrate pharmacological PRMT5 inhibition induced SDMA reduction and late apoptosis in genetically and epigenetically heterogeneous patient-derived GSC lines and that mutant p53 lines are less sensitive to PRMT5 inhibition. Additional studies related to splicing defects upon PRMT5 inhibition are ongoing and will be presented at the meeting. Citation Format: Tsung-Lin (Gavin) Tsai. Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1829.

104 Acute mononeuritis multiplex in a patient with plasma cell leukaemia

A 74 year old male with a history of plasma cell leukaemia, treated with VMP (bortezomib, melphalan, prednisolone) presented with a 2 week history of lumbar back pain and weakness of the hands and ankles.Clinical examination confirmed asymmetric weakness in the hands and ankles. Sensory examination was initially normal, reflexes preserved and plantars mute. Other than the known IgG paraproteinaemia and longstanding hyponatraemia, bloods, including a vasculitis screen, were unremarkable. MRI brain and spine were non-contributary. CSF examination revealed paired bands consistent with the presence of an IgG paraprotein, but was otherwise bland. Nerve conduction studies showed a severe sensorimotor axonal neuropathy.The patient was treated with plasma exchange followed by IV methylprednisolone but continued to progress developing more proximal weakness and sensory loss to the knees and elbows, with loss of deep tendon reflexes within 2 weeks. Sural nerve biopsy showed axonal degeneration but no vasculitis or malignant infiltration. The patient became increasingly fatigued and cachectic and the decision was made jointly with the haematologists to palliate.Plasma cell leukaemia is a rare and aggressive subtype of multiple myeloma with a poor prognosis which has been associated with malignant nerve infiltration. Bortezomib may also cause a peripheral neuropathy.o.poole@nhs.net

Acute Tubulointerstitial Nephritis due to Malignant Cells Infiltration in a Patient with Chronic Myelomonocytic Leukaemia

慢性骨髄単球性白血病（chronic myelomonocytic leukaemia：CMML）は経過中にさまざまな機序で腎障害を来たす1，2）．単球の性質上，臓器への浸潤例も少なくはないが3，4），腫瘍細胞が腎臓へ直接浸潤したことによる腎障害は極めて稀である5～7）．今回，CMMLの60歳台女性が経過中に急性腎不全を呈し，腎生検にて腫瘍細胞の直接浸潤を病理学的に証明できたため報告する．

Verrucous Squamous Cell Cancer of the Esophagus: A Case Report

Verrucous Cancer of the esophagus is basically a type of squamous cell carcinoma and is associated with a chronic inflammatory process in the lower esophagus usually secondary to gastro-esophageal reflux disease (GERD). Mostly it is a local disease process but sometimes it can invade distant structures also. We report a case is a 62-year-old female patient who presented with marked weight loss, anorexia, and difficulty to take solid food. On Upper GI endoscopy there was a warty appearing irregular mass at the mid to distal esophagus. Superficial multiple biopsies were taken but turned negative for malignancy and re-endoscopy after a few days with deep multiple biopsies revealed the diagnosis of verrucous carcinoma on histopathology. The patient was having multiple co-morbid conditions like hypertension, diabetes mellitus, and early nephropathy along with infiltration of malignancy in surrounding structures on CT scan chest. Therefore a decision was taken to place an esophageal stent by upper GI endoscopy followed by chemotherapy and radiotherapy by the oncology department. Patient symptoms were much relieved after 4 months of chemotherapy and radiotherapy and the patient is still on regular follow-up in medical OPD. Chronic inflammation due to gastritis and esophagitis is the main risk factor for verrucous carcinoma of the esophagus. Although surgery is the treatment of the choice for the local and early disease but as in our case disease was already spread palliative stenting followed by chemo-radiation is the best possible option that can be offered.

Hematological Malignancies and the Kidney.

The incidence of hematologic malignancies is on the rise worldwide. Kidney disease is ubiquitous in patients with hematologic malignancies, encompassing a wide spectrum of disorders involving each kidney compartment, including the vasculature, tubules, interstitium, and glomerulus, and there is significant overlap of kidney involvement with each hematologic malignancy. Vascular disorders include both microvascular and macrovascular damage, via thrombotic microangiopathy, hyperleukocytosis, hyperviscosity, and cryoglobulinemia. The tubulointerstitial compartment may be affected by prerenal azotemia and acute tubular injury, but malignant infiltration, tumor lysis syndrome, extramedullary hematopoiesis, cast nephropathy, granulomatous interstitial nephritis, and lysozymuria should be considered in certain populations. Obstructive uropathy may occur due to nephrolithiasis or retroperitoneal fibrosis. Glomerular disorders, including membranoproliferative, membranous, minimal change, and focal segmental glomerulosclerosis, can rarely occur. By understanding how each compartment may be affected, care can best be optimized for these patients. In this review, we summarize the widely varied etiologies of kidney diseases stratified by kidney compartment and hematologic malignancy, focusing on demographics, pathology, pathophysiology, mechanism, and outcomes. We conclude with common electrolyte abnormalities associated with hematologic malignancies.

Malignant Melanoma Disguised as Biliary Obstruction

In melanoma, symptomatic involvement of the small bowel is exceedingly rare. When melanoma spreads to the gastrointestinal tract, the prognosis worsens significantly. We present the case of a 70-year-old woman with secondary malignant melanoma of the gastrointestinal tract. Our patient, who had been treated for a stage I melanoma 4 years prior, presented with symptoms of frequent constipation, heartburn, and nausea. A biopsy of the masses on her back and axilla showed malignant melanoma. Computed tomography showed marked dilation of the common bile duct. Endoscopic retrograde cholangiopancreatography was unsuccessful owing to malignant infiltration of the ampulla. Biliary drainage via percutaneous port placement and immunotherapy were initiated.

Neoplastic nerve lesions.

Though metastasis and malignant infiltration of the peripheral nervous system is relatively rare, physicians should have a familiarity with their presentations to allow for prompt diagnosis and initiation of treatment. This article will review the clinical presentations, diagnostic evaluation, and treatment of neoplastic involvement of the cranial nerves, nerve roots, peripheral nerves, and muscle. Due to the proximity of the neural structure traversing the skull base, metastasis to this region results in distinctive syndromes, most often associated with breast, lung, and prostate cancer. Metastatic involvement of the nerve roots is uncommon, apart from leptomeningeal carcinomatosis and bony metastasis with resultant nerve root damage, and is characterized by significant pain, weakness, and numbness of an extremity. Neoplasms may metastasize or infiltrate the brachial and lumbosacral plexuses resulting in progressive and painful sensory and motor deficits. Differentiating neoplastic involvement from radiation-induced injury is of paramount importance as it dictates treatment and prognosis. Neurolymphomatosis, due to malignant lymphocytic infiltration of the cranial nerves, nerve roots, plexuses, and peripheral nerves, deserves special attention given its myriad presentations, often mimicking acquired demyelinating neuropathies.

Disseminated histoplasmosis mimicking hematologic malignancy in a patient with human immunodeficiency virus.

A 25-year-old recent immigrant from El Salvador with a known human immunodeficiency virus (HIV) infection was transferred to the University of Maryland Greenebaum Comprehensive Cancer Center with altered mental status, fever, epistaxis, gingival hemorrhage, melena, and rash. He was cachectic and acutely ill, with axillary and inguinal adenopathy and a palpable spleen tip. Hemoglobin was 66 g/L, white blood cell (WBC) count 6.6 × 109/L with 38% segmented neutrophils, 10% bands, 11% metamyelocytes, 13% myelocytes, 6% blasts and 200 nucleated red blood cells per 100 WBC, and platelet count 64 × 109/L. Creatinine was 472 μmol/L, lactate dehydrogenase 15,983 iu/L, and uric acid 702 μmol/L. HIV viral load was 82,040 copies/ml and absolute CD4 count was 16 cells/dl. Computerized tomography of the chest and abdomen showed extensive upper mediastinal and axillary adenopathy, bilateral pleural effusions, scattered retroperitoneal, mesenteric and inguinal adenopathy, splenomegaly, and ascites. The presumed diagnosis was a hematologic malignancy. However, the peripheral blood smear demonstrated not only leukoerythroblastic changes, including nucleated red blood cells (A) and myelocytes (B) but also intracytoplasmic yeast organisms in myelocytes (B) and neutrophils (C), and bone marrow aspirate (D) and biopsy (E, F) showed prominent histiocytosis with innumerable intracellular ovoid yeast forms. The patient was diagnosed with disseminated histoplasmosis involving blood, bone marrow, skin and cerebrospinal fluid, as well as mycobacterium avium complex and klebsiella septicemia, complicating uncontrolled HIV infection. He responded to antibiotics, including a 6-week course of liposomal amphotericin B. Uncontrolled HIV infection is rare in the setting of currently available highly active antiretroviral therapy, but does occur, and can be complicated by disseminated opportunistic infections, as well as by high-grade lymphomas and other malignancies. Leukoerythroblastosis, defined by the presence of nucleated red blood cells and immature myeloid cells in the circulating blood, can be caused by malignant bone marrow infiltration, but also by disseminated infection. Our patient's bone marrow failure, leukoerythroblastosis, and extensive lymphadenopathy were caused by disseminated histoplasmosis, rather than by a hematologic malignancy. NIH-NCI, Grant/award no: P30 CA134274. The authors declare that they have no conflict of interest.

Dual role of ARPC1B in regulating the network between tumor-associated macrophages and tumor cells in glioblastoma

ABSTRACT The tumor microenvironment (TME) plays a critical role in promoting the growth and metastasis of glioblastoma (GBM). Tumor-associated macrophages (TAMs), the most abundant myeloid cells infiltrating in TME, produce proinflammatory cytokines, regulate glioma cell pools, and lead to GBM progression. Understanding the mechanism of GBM-TAMs regulation can help to find new targeted therapeutic strategies against GBM. Based on the CGGA and TCGA GBM cohorts, ARPC1B was defined as the key macrophage-associated gene with prognostic value. Higher ARPC1B expression was associated with progressive malignancy, poor outcomes and TAM infiltration. We demonstrated that macrophage-expressed ARPC1B promoted the migration, invasion, and epithelial–mesenchymal transition of glioma cells. Glioma-intrinsic ARPC1B also maintained the malignant phenotype and promoted macrophage recruitment. Positive feedback signaling between macrophages and glioma cells via ARPC1B was determined to be under control of the IFNγ-IRF2-ARPC1B axis. This study highlights the important role of ARPC1B in GBM malignancy progression and the regulation network between GBM and TAMs, suggesting ARPC1B as a novel biomarker with potential therapeutic implications.

A case of pathological femoral diaphyseal fracture with malignant lymphoma infiltration

A case of pathological femoral diaphyseal fracture with malignant lymphoma infiltration

OPTIMIZATION OF PLASMA CELL ENRICHMENT FOR CNV DETECTION BY SNP ARRAY AND MLPA

Multiple myeloma is characterized by the uncontrolled proliferation of an atypical plasma cell clone. The main factor preventing the characterization of plasma cells is their low rate in the analyzed samples. Through this study we tried to highlight the necessity of enrichment of MM samples to be analyzed by MLPA and SNParray. Samples from 5 patients diagnosed with MM were investigated and 2 of them were enriched by magnetic sorting with anti-CD138 antibodies and analyzed by SNParray and MLPA. Unsorted samples showed a lower incidence of abnormalities. By analyzing the data, we concluded that even a 30% malignant cell infiltration in the MM sample is not enough and the magnetic sorting is a mandatory for the enrichment of target cells from the sample. &nbsp

Crown-Cut Endobronchial Ultrasound Guided Transbronchial Aspiration Needle: First Real-World Experiences.

Advancements in personalized medicine have increased the demand for quantity and preservation of tissue architecture of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples. These demands may be addressed by the SonoTip TopGain® needle, which has a 3-point crown-cut design that contrasts with the standard single bevel design of the ViziShot 2®. The objective was to compare the SonoTip TopGain® and ViziShot 2® needles by considering biopsy sample characteristics, diagnostic accuracy, and patient safety. The primary endpoint of the study was the number of high-power fields (HPFs) in the center of the formalin-fixed paraffin-embedded cell block per sample. The lymph node with the highest probability for malignant infiltration based on size and sonographic appearance was chosen as the target lymph node for 20 patients. The same lymph node in each patient was sampled using both the ViziShot 2® and SonoTip TopGain® needles. The samples were measured, sliced, and analyzed by a pathologist. Sixteen patients were biopsied with both needles. Four patients could not be biopsied with the SonoTip TopGain® needle since it could not penetrate cartilage or be repositioned to bypass cartilage. HPFs and sample dimensions were significantly greater in the patients where sampling with the SonoTip TopGain® needle was possible (p = 0.007 and p = 0.005, respectively). Diagnostic accuracy and safety profiles were comparable. Significantly more material can be sampled using the SonoTip TopGain® needle when cartilage penetration can be avoided. This improves the yield for molecular workup in the era of personalized medicine.

Small but Challenging Conjunctival Melanoma: New Insights, Paradigms and Future Perspectives.

Simple SummaryConjunctival melanoma (CM) is a small but highly aggressive and infiltrative periocular malignancy. Despite wide surgical excision followed by adjuvant therapy, about one third and one quarter of patients will experience local recurrence and metastatic spread, respectively. The management of locally advanced (≥T2) tumours may require mutilating surgeries such as orbital exenteration to achieve local control. The last decade has been marked by the emergence of eye-sparing strategies based on wide surgical excision followed by adjuvant proton beam therapy. More recently, new genetic and immunological insights have incriminated several signalling pathways (MAPK, PI3K-AKT) and immune cells, making CM a “targetable” malignancy. Anti-BRAF and anti-MEK targeted therapies and immunotherapies have revolutionized the current management of CM through the use of new eye-sparing strategies and treatment of metastases.Although its incidence has increased over the last decades, conjunctival melanoma (CM) remains a rare but challenging periocular malignancy. While there is currently no recognized standard of care, “no-touch” surgical excision followed by adjuvant treatments is usually recommended. Despite its small size, managing CM is challenging for clinicians. The first challenge is the high risk of tumour local recurrence that occurs in about one third of the patients. The management of locally advanced CM (≥T2) or multiple recurrences may require mutilating surgeries such as orbital exenteration (OE). The second challenge is the metastatic spread of CM that occurs in about one quarter of patients, regardless of whether complete surgical excision is performed or not. This highlights the infiltrative and highly aggressive behaviour of CM. Recently, attention has been directed towards the use of eye-sparing strategies to avoid OE. Initially, wide conservative surgeries followed by customized brachytherapy or radiotherapy have appeared as viable strategies. Nowadays, new biological insights into CM have revealed similarities with cutaneous melanoma. These new findings have allowed clinicians to reconsider the management of locally advanced CM with “medical” eye-sparing treatment as well as the management of metastatic spread. The aim of this review was to summarize the current and future perspectives of treatment for CM based on recent biological findings.

Prediction of Malignant Cell Infiltration Patterns with Texture Features of Biopsy-Correlated Positron Emission Tomography of Osteolytic Lesions in Multiple Myeloma

Prediction of Malignant Cell Infiltration Patterns with Texture Features of Biopsy-Correlated Positron Emission Tomography of Osteolytic Lesions in Multiple Myeloma

Identification of patients at high risk of secondary extramedullary multiple myeloma development.

SummaryMultiple myeloma (MM) is characterized by malignant plasma cell infiltration of the bone marrow. In extramedullary multiple myeloma (EMD), a subclone of these cells migrates out of the bone marrow. Out of 4 985 MM patients diagnosed between 2005 and 2017 in the Czech Republic, we analyzed 234 secondary EMD patients to clarify risk factors of secondary EMD development. We found younger age [<65 years; odds ratio (OR) 4·38, 95% confidence interval (CI): 2·46–7·80, P < 0·0001], high lactate dehydrogenase (LDH) levels (>5 μkat/l; OR 2·07, 95% CI: 1·51–2·84, P < 0·0001), extensive osteolytic activity (OR 2·21, 95% CI: 1·54–3·15, P < 0·001), and immunoglobulin A (IgA; OR 1·53, 95% CI: 1·11–2·11, P = 0·009) or the non‐secretory type of MM (OR 2·83; 95% CI: 1·32–6·04, P = 0·007) at the time of MM diagnosis to be the main risk factors for secondary EMD development. Newly diagnosed MM (NDMM) patients with subsequent EMD had inferior median progression‐free (PFS) and overall (OS) survival when compared to NDMM patients without future EMD [mPFS: 13·8 months (95% CI: 11·4–16·3) vs 18·8 months (95% CI: 17·7–19·9), P = 0·006; mOS: 26·7 months (95% CI: 18·1–35·4) vs 58·7 months (95% CI: 54·8–62·6), P < 0·001]. We found that NDMM patients with specific risk factors associated with secondary EMD development have a more aggressive disease course before secondary EMD develops.

CXCR4 is a Novel Biomarker Correlated With Malignant Transformation and Immune Infiltrates in Gastric Precancerous Lesions.

Background: As early gastric cancer (EGC) has a far better prognosis than advanced gastric cancer (GC), early diagnosis and treatment are essential. However, understanding the mechanism of the process from gastric precancerous lesion (GPL) becoming EGC has made little advances. Besides, biomarkers that can monitor the progression of GPL-to-GC are still much insufficient. Methods: Key gene modules associated with GPL progression to EGC were identified by integrating two GPL-related data sets, GSE55696 and GSE130823, using the WGCNA method. Combining with the TCGA-STAD cohort, hub genes were identified. Immunofluorescence was conducted to validate the expression. To explore the implication of hub genes in GPL malignant transformation, a correlation test was conducted to identify their co-expression genes, co-expression cytokines, and co-expression immune cells. Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to shrink CXCR4-related predictors and construct a prognostic model. Functional enrichment was applied for exploring the potential mechanism. Results: The green module in GSE55696 and the yellow module in GSE130823 were regarded as key gene modules associated with GPL progression to EGC, and 219 intersection genes from them were mainly enriched in critical immune biological processes. Combining with the TCGA-STAD cohort, CXCR4 was identified as a novel biomarker correlated with the malignant transformation of GPL, the positive rate of which was increased with GPL progression according to immunofluorescence. CXCR4 co-expression genes were found mainly involved in regulation of actin. CXCR4 co-expression cytokines were enriched in regulation of chemotaxis, cell chemotaxis, mononuclear cell migration, leukocyte chemotaxis, etc. As for co-expression immune cells, the expression level of CXCR4 was positively correlated with the abundance of macrophages but negatively correlated with that of effector memory T cells and NKT cells during GPL malignant transformation. In addition, the CXCR4-related prognostic model was able to predict the prognosis of GC and serve as an independent predictor for overall survival (OS). Conclusions: CXCR4 was a novel biomarker correlated with malignant transformation of GPL and played a vital role in the control of tumor immunity. CXCR4 is possible to serve as a therapeutic target for malignant transformation of GPL.

Review of diffusion-weighted imaging and dynamic contrast-enhanced MRI for multiple myeloma and its precursors (monoclonal gammopathy of undetermined significance and smouldering myeloma).

The last decades, increasing research has been conducted on dynamic contrast-enhanced and diffusion-weighted MRI techniques in multiple myeloma and its precursors. Apart from anatomical sequences which are prone to interpretation errors due to anatomical variants, other pathologies and subjective evaluation of signal intensities, dynamic contrast-enhanced and diffusion-weighted MRI provide additional information on microenvironmental changes in bone marrow and are helpful in the diagnosis, staging and follow-up of plasma cell dyscrasias. Diffusion-weighted imaging provides information on diffusion (restriction) of water molecules in bone marrow and in malignant infiltration. Qualitative evaluation by visually assessing images with different diffusion sensitising gradients and quantitative evaluation of the apparent diffusion coefficient are studied extensively. Dynamic contrast-enhanced imaging provides information on bone marrow vascularisation, perfusion, capillary resistance, vascular permeability and interstitial space, which are systematically altered in different disease stages and can be evaluated in a qualitative and a (semi-)quantitative manner. Both diffusion restriction and abnormal dynamic contrast-enhanced MRI parameters are early biomarkers of malignancy or disease progression in focal lesions or in regions with diffuse abnormal signal intensities. The added value for both techniques lies in better detection and/or characterisation of abnormal bone marrow otherwise missed or misdiagnosed on anatomical MRI sequences. Increased detection rates of focal lesions or diffuse bone marrow infiltration upstage patients to higher disease stages, provide earlier access to therapy and slower disease progression and allow closer monitoring of high-risk patients. Despite promising results, variations in imaging protocols, scanner types and post-processing methods are large, thus hampering universal applicability and reproducibility of quantitative imaging parameters. The myeloma response assessment and diagnosis system and the international myeloma working group provide a systematic multicentre approach on imaging and propose which parameters to use in multiple myeloma and its precursors in an attempt to overcome the pitfalls of dynamic contrast-enhanced and diffusion-weighted imaging.Single sentence summary statementDiffusion-weighted imaging and dynamic contrast-enhanced MRI provide important additional information to standard anatomical MRI techniques for diagnosis, staging and follow-up of patients with plasma cell dyscrasias, although some precautions should be taken on standardisation of imaging protocols to improve reproducibility and application in multiple centres.

Evolution of the management of retrorectal masses: A retrospective cohort study.

Retrorectal masses are abnormalities located anatomically in the retrorectal space. A significant proportion are asymptomatic with no malignant potential while others cause symptoms due to mechanical pressure or malignant infiltration. We reviewed and categorised the retrorectal masses encountered over a 30-year time period in a specialist colorectal hospital and describe our management algorithm for consideration by other multidisciplinary teams (MDT). This was a retrospective analysis of consecutive patients referred between 1984-2019. A detailed review of clinical presentation, imaging features, postoperative histology and impact on morbidity and anorectal function is reported. A total of 143 patients with median age of 46years and female preponderance (74%) were reviewed. The commonest presenting symptom was pain (46%) and all malignant cases had symptoms (n=17). Over the last decade, more asymptomatic patients have presented with a retrorectal mass (33%, p=0.04) and more patients are opting for surveillance rather than resection (33%, p=0.013). Increasing age and lesion size were associated with malignancy (p<0.05). Radiological features associated with malignancy included: solid/heterogeneous component, lobulated borders or locally invasive. Following surgery, complications included chronic pain (40%), poor wound healing (23%) and bowel dysfunction (10%). The management of retrorectal masses remains complex. There are features, both clinical and radiological, that can help determine the best management strategy. Management should be in a high-volume tertiary centre and preferably through a complex rectal cancer MDT. Long-term sequelae such as chronic pain must be highlighted to patients. We advocate the establishment of an international registry to further record and characterise these rare, potentially troublesome lesions.

A rare electrocardiographic evolution and near complete normalization in response to chemoimmunotherapy in a patient with lung cancer and malignant myocardial infiltration: a follow-up case report

A rare electrocardiographic evolution and near complete normalization in response to chemoimmunotherapy in a patient with lung cancer and malignant myocardial infiltration: a follow-up case report

Landscape of Bone Marrow Metastasis in Human Neuroblastoma Unraveled by Transcriptomics and Deep Multiplex Imaging.

Simple SummaryBone marrow metastasis frequently occurs in patients with solid cancers and most often leads to poor outcome. Yet, the composition of bone marrow metastases, including tumor and surrounding cells, has so far not been characterized. Herein, we aimed to investigate the diversity of tumor and surrounding cells, i.e., the microenvironment, in bone marrow metastases, using the childhood tumor neuroblastoma as a model. To this end, we screened genome-wide datasets to define a panel of cell-specific markers for multiplex microscopy of metastatic bone marrow samples, and developed DeepFLEX, a computational pipeline for subsequent image analysis. Thereby, we identified 35,000 single cells covering metastasized tumor cells, and various types of developing immune and bone marrow cells. In parallel, we analyzed the transcriptome, i.e., all genes that are expressed as mRNA, of 38 patients with and without bone marrow metastasis. We found vast tumor cell diversity and identified a marker protein, FAIM2, which can help to identify a broader range of tumor cell variants. In addition we showed that tumor cell metastasis in the bone marrow is associated with an immune response resembling inflammation, and the presence of cells that can repress an immune attack against cancer cells. Our study suggests that metastatic tumor cells are shaping the bone marrow microenvironment and builds the basis to further investigate its clinical relevance.While the bone marrow attracts tumor cells in many solid cancers leading to poor outcome in affected patients, comprehensive analyses of bone marrow metastases have not been performed on a single-cell level. We here set out to capture tumor heterogeneity and unravel microenvironmental changes in neuroblastoma, a solid cancer with bone marrow involvement. To this end, we employed a multi-omics data mining approach to define a multiplex imaging panel and developed DeepFLEX, a pipeline for subsequent multiplex image analysis, whereby we constructed a single-cell atlas of over 35,000 disseminated tumor cells (DTCs) and cells of their microenvironment in the metastatic bone marrow niche. Further, we independently profiled the transcriptome of a cohort of 38 patients with and without bone marrow metastasis. Our results revealed vast diversity among DTCs and suggest that FAIM2 can act as a complementary marker to capture DTC heterogeneity. Importantly, we demonstrate that malignant bone marrow infiltration is associated with an inflammatory response and at the same time the presence of immuno-suppressive cell types, most prominently an immature neutrophil/granulocytic myeloid-derived suppressor-like cell type. The presented findings indicate that metastatic tumor cells shape the bone marrow microenvironment, warranting deeper investigations of spatio-temporal dynamics at the single-cell level and their clinical relevance.