Proliferation Of Neoplastic Cells Research Articles

Systemic Lymphadenopathic Mastocytosis with Eosinophilia.

Systemic mastocytosis is a neoplastic proliferation of mast cells that most frequently involves cutaneous sites. Mastocytosis involves various extracutaneous sites, but the lymph node is rare. We present an interesting image of systemic mastocytosis in the lymph node with marked eosinophilia. It is a rare subtype of systemic mastocytosis requiring high suspicion levels for the correct diagnosis.

Fangchinoline Inhibited Proliferation of Neoplastic B-lymphoid Cells and Alleviated Sjögren's Syndrome-like Responses in NOD/Ltj Mice via the Akt/mTOR Pathway.

Fangchinoline is a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore that is conventionally used as an analgesic, antirheumatic, and antihypertensive drug in China. However, the application of Fanchinoline in Sjögren syndrome (SS) remains unreported. This study aimed to identify the potential role of Fangchinoline in the treatment of SS via altering Akt/mTOR signaling. First, we examined levels of p-Akt and p-mTOR in infiltrating lymphocytes of labial glands from SS patients by immunohistochemistry. Then, the effects of Fangchinoline on Raji cells and Daudi cells were investigated using the CCK-8 assay, propidium iodide (PI)/RNase, and Annexin V/PI staining. Western blotting was used to identify the levels of Akt, p-Akt(ser473), mTOR, and p-mTOR. For in vivo analyses, NOD/Ltj and wild-type ICR mice were treated with a Fangchinoline solution, an LY294002 solution (an inhibitor of the PI3K/Akt/mTOR pathway), or their solvent for 28 days. Then, salivary flow assays and hematoxylin and eosin staining of submandibular glands were performed to determine the severity of SS-like responses in the mice. Immunohistochemical staining of labial glands from SS patients showed that activation of p-Akt and p-mTOR in infiltrating lymphocytes might be correlated with SS development. In vitro, Fangchinoline and LY294002 inhibited proliferation, induced cell cycle arrest, and promoted apoptosis in Raji and Daudi cells by altering Akt/mTOR signaling. In vivo, Fangchinoline and LY294002 significantly improved the salivary secretion by NOD/Ltj mice and reduced the number of lymphocytic foci in the submandibular glands. These results indicated that Fangchinoline could effectively inhibit the proliferation of neoplastic B-lymphoid cells and reduce SS-like responses in NOD/Ltj mice. Our study highlights the potential value of the clinical application of Fangchinoline for SS treatment.

Abstract B018: Physical tumor microenvironment biomarkers to predict DCIS progression, upstaging, and early metastasis

Abstract Ductal carcinoma in situ (DCIS) is defined as a neoplastic proliferation of epithelial cells confined to the mammary ductal-lobular system. Although metastasis can occur at the very early stages of DCIS, the majority of metastatic breast cancers are believed to arise through a years-long process of somatic evolution within the physical constraints of milk ducts, characterized by the accumulation of heritable genetic and epigenetic changes. While these genetic alterations during breast carcinogenesis have been extensively studied without any outcome that can be used as a clinical biomarker, less attention has been paid to the microenvironmental conditions that select for these genotypes. We have demonstrated that evolving pre-cancerous hyperplastic breast cells are selected under physical tumor microenvironment conditions such as hypoxia, acidosis, and starvation. We have also shown that these harsh conditions select cells with more aggressive phenotypes. We have developed several markers for the adapted cells under these harsh conditions such as LAMP2b for acidosis or CA9 for hypoxia. We, therefore, hypothesize that the expression of physical microenvironment adaptation proteins (PMA) can differentiate indolent from aggressive DCIS and that this can be used for decision support. DCIS can be detected by screening mammography followed by a percutaneous Biopsy for pathologic confirmation, which may be followed by surgery +/- adjuvant therapy. Citation Format: Mehdi Damaghi, Zainab Raza, Rana Adil Farman, JiDong Bai, Joel Saltz, Bethany L. Niell. Physical tumor microenvironment biomarkers to predict DCIS progression, upstaging, and early metastasis [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B018.

Abstract IA002: DCIS: Pathological heterogeneity and prognosis definition

Abstract Ductal carcinoma in situ represents 15 to 20% of all breast carcinomas and is a non-obligate precursor of invasive carcinomas. Clinically DCIS presents most frequently as microcalcifications detected on screening mammography. DCIS is a proliferation of neoplastic cells confined to the ductulo-lobular tree. Its morphology can recapitulate the diversity of that of invasive carcinomas. DCIS lesions are classified according to the nuclear grade (low, intermediate, high), the presence of necrosis and microinvasion. In resection specimens, the extent of the disease and the quality of the margins are key element for patients management as well as the association of DCIS to the microcalcifications. The reproducibility of the DCIS grading system is relatively poor and promising help emerges from deep learning approaches. The four molecular classes of invasive carcinomas exist but with different proportion in DCIS. Triple negative represent 5-8% of DCIS. Conversely, HER2 overexpression is more frequently observed in particular in high grade DCIS (up to 60% of the cases). The analysis of Estrogens and progesterone receptors is not systematic in clinical practice unless an endocrine therapy may be decided after the patient has completed the loco-regional treatment. At initial diagnosis, it remains very challenging to predict the clinical outcome of the lesion. However, after complete surgical excision followed by whole breast irradiation therapy, the prognosis is excellent with a mortality of 3.7%. The rate of relapse is 7% at 5 years and 16% at 10 years of follow-up. Concerns about overdiagnosis and overtreatment exist worldwide. Retrospective studies identified older age, mammographic detection, small size, non-high grade histology and negative margins at excision associated with favorable outcome. Unfortunately, de-escalation clinical prospective trials based on these criteria, failed to identify the patients presenting DCIS of good prognosis. Biological parameters have been retrospectively associated with a poor prognosis (HER2 amplification, proliferation, RB loss, COX2 expression…). The molecular signature Oncotype DCIS®, has been validated retrospectively in a subgroup of patients from the ECOG E5194, and determined DCIS associated with different risk of relapse. Its prospective validation is on-going in a non randomized trial (DUCHESS). Three on-going trials based in part on clinical criteria, one adding estrogen receptors expression, the other comedonecrosis, propose after a diagnostic biopsy, a simple surveillance. Another trial, leaded by UNITRAD/UNICANCER (France), Romance is a prospective randomized study of omission of whole-breast radiotherapy following breast-conserving surgery in patients with very low risk luminal A ductal carcinoma in situ and enrolment is on. Research efforts is moving into the integration the ecosystem of DCIS (myoepithelial cells, stroma, immune cells and carcinomatous cells) to identify more accurately the DCIS associated with a higher aggressiveness that would allow secure de-escalation clinical trials. Citation Format: Anne Vincent-Salomon. DCIS: Pathological heterogeneity and prognosis definition [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA002.

PATH-11. THE LONGITUDINAL EVOLUTIONARY TRAJECTORY OF OLIGODENDROGLIOMA IS DRIVEN BY TREATMENT-ASSOCIATED GENETIC ALTERATIONS

Abstract Oligodendroglioma is a subtype of diffuse glioma defined by a mutation in the isocitrate dehydrogenase (IDH) genes and a co-deletion of chromosome arms 1p and 19q. These tumors primarily occur in adult patients in their third and fourth decade of life and are universally fatal due to an inevitable recurrence that follows a treatment regimen of surgical resection and an optional combination of alkylating chemotherapy and/or radiation therapy. While initially slow growing, recurrent tumors exhibit increasingly aggressive phenotypes that become progressively more difficult to treat with conventional therapy. Currently, the molecular mechanisms and cellular phenotypes that drive this recurrence remain unknown. To understand these factors, we assembled a cohort of matched initial and recurrent oligodendroglioma samples from over 100 patients and performed whole-genome sequencing and whole-exome sequencing on each of them. To link these molecular profiles to cell state changes, we additionally performed bulk and single-nucleus RNA-sequencing on a subset of these tumor pairs. In nearly 40% of alkylating chemotherapy-treated patients, recurrent tumors presented with hypermutation that corresponded with an increase in neoplastic cell proliferation. Additionally, while individual somatic alterations specific to recurrence were relatively rare, we observed a subset of tumors that acquired deletions in the cell cycle regulator CDKN2A following treatment with radiotherapy. Acquisition of either of these features associated with shorter patient survival and higher grade at recurrence, implicating cell cycle dysregulation as a mechanism of treatment resistance and increased tumor severity. Together, these results indicate that oligodendrogliomas evolve in a treatment-specific manner following chemo- and radiation therapy and highlight key pathways that can be targeted to delay the onset of recurrence.

Intravascular large B-cell lymphoma (IVLBCL): Subtle Presentation and Challenging Diagnosis

Abstract Introduction/Objective Intravascular large B-cell lymphoma (IVLBCL) is a rare, clinically aggressive lymphoma defined by the proliferation of atypical lymphoma cells in the lumen of all sized blood vessels, particularly capillaries. The reasons for this unusual neoplastic cell proliferation are still only partially understood. IVLBCL is considered stage IV lymphoma and manifests with a variety of nonspecific signs and symptoms. Patients with IVLBCL usually do not present with lymphadenopathy. The tumor cells invade the blood vessels of multiple organs such as the central nervous system, skin, lungs, kidneys, and bone marrow. Common presenting symptoms are based on the organ affected and include mental status changes and fever of unknown origin. Although immunochemotherapy has significantly improved the often-poor prognosis of this kind of lymphoma, a large percentage of patients relapse. Methods/Case Report We present a 63-year-old man who had been diagnosed with diffuse large B cell lymphoma in the bone marrow in March 2021 and was in remission state after completing six cycles of chemotherapy. There was no abnormal FDG uptake on a post-chemotherapy PET/CT scan. Patient presented to the ER two months later with fever and dyspnea. The entire workup was completed and showed pancytopenia and elevated ESR. While chest CT scan did not show lymphadenopathy or lesions, PET/CT scans revealed a widespread increase in FDG uptake in both the lungs and spleen. Lung biopsy revealed large atypical cells within alveolar septae and vessels. Immunohistochemical stains demonstrated that these cells were positive for CD20 and PAX-5 and had high proliferation rate based on Ki67. Results (if a Case Study enter NA) NA Conclusion IVLBCL has a low incidence rate with non-specific clinical presentation. The diagnosis can be easily missed in both clinical, radiological and the corresponding histopathological findings . Radiological finding and CT scan are not sensitive enough and may miss the lesion. Even though the PET/CT scan is more sensitive, the definitive diagnosis of IVLBCL relies mainly on histopathology and immunohistochemistry, at which point awareness of this entity by the Pathologist is most necessary.

Protein-Functionalized Microgel for Multiple Myeloma Cells' 3D Culture.

Multiple myeloma is a hematologic neoplasm caused by an uncontrolled clonal proliferation of neoplastic plasma cells (nPCs) in the bone marrow. The development and survival of this disease is tightly related to the bone marrow environment. Proliferation and viability of nPCs depend on their interaction with the stromal cells and the extracellular matrix components, which also influences the appearance of drug resistance. Recapitulating these interactions in an in vitro culture requires 3D environments that incorporate the biomolecules of interest. In this work, we studied the proliferation and viability of three multiple myeloma cell lines in a microgel consisting of biostable microspheres with fibronectin (FN) on their surfaces. We also showed that the interaction of the RPMI8226 cell line with FN induced cell arrest in the G0/G1 cell cycle phase. RPMI8226 cells developed a significant resistance to dexamethasone, which was reduced when they were treated with dexamethasone and bortezomib in combination.

Ptp61F integrates Hippo, TOR, and actomyosin pathways to control three-dimensional organ size.

Precise organ size control is fundamental for all metazoans, but how organ size is controlled in a three-dimensional (3D) way remains largely unexplored at the molecular level. Here, we screen and identify Drosophila Ptp61F as a pivotal regulator of organ size that integrates the Hippo pathway, TOR pathway, and actomyosin machinery. Pathologically, Ptp61F loss synergizes with RasV12 to induce tumorigenesis. Physiologically, Ptp61F depletion increases body size and drives neoplastic intestinal tumor formation and stem cell proliferation. Ptp61F also regulates cell contractility and myosin activation and controls 3D cell shape by reducing cell height and horizontal cell size. Mechanistically, Ptp61F forms a complex with Expanded (Ex) and increases endosomal localization of Ex and Yki. Furthermore, we demonstrate that PTPN2, the conserved human ortholog of Ptp61F, can functionally substitute for Ptp61F in Drosophila. Our work defines Ptp61F as an essential determinant that controls 3D organ size under both physiological and pathological conditions.

Long-Term Outcomes in Patients with Plasma Cell Myeloma Following High-Dose Chemotherapy with Autologous Stem Cell Transplantation

Plasma cell myeloma (PCM) is a hematopoietic malignancy characterized by the neoplastic proliferation of clonal plasma cells in the bone marrow. High-dose chemotherapy (HDCTx) followed by autologous stem cell transplantation (ASCT) is considered the standard of care treatment for eligible patients. Although the introduction of new therapeutic agents has further contributed to improved survival outcomes, the disease remains incurable, with most patients eventually experiencing relapse or disease progression. Circulating tumor cells at the time of stem cell collection that are reinfused with the autograft may be one of the factors influencing the clinical outcomes. The objective of this study was to evaluate the association of patient- and treatment-related parameters with progression-free survival (PFS) and overall survival (OS) in PCM patients who underwent ASCT. The survival data of 204 patients diagnosed with PCM who received ASCT between 2010 and 2014 at the University Hospital Zurich were collected and analyzed. Most patients received proteasome inhibitor- or immunomodulatory drug-based induction therapy followed by high-dose melphalan conditioning before ASCT. The median PFS was 33.3 months and the median OS was 65.1 months. In patients with follow-up data of at least 5 years (n=174), the estimated 5-year OS rate was 68.4%. The median number of reinfused CD34^+^ cells was 3.77x10^6^ per kg body weight per reinfusion. In patients who received single ASCT (n=144), no significant difference was observed based on the mean number of reinfused CD34^+^ cells (three tiers: <2.65x10^6^ vs 2.66−4.49x10^6^ vs >4.49x10^6^ CD34+ cells per kg body weight per reinfusion) in terms of OS (p=0.103) and PFS (p=0.704). There was also no significant difference in OS (p=0.786) and PFS (p=0.425) correlated with remission status on the day of ASCT. In conclusion, this study suggests that the anticipated influences of graft composition no longer play a major role in the era of modern second- and subsequent lines of therapies. HDC and ASCT remain the mainstay of therapy for eligible patients and further investigations into variables influencing the outcome of PCM patients are warranted.

RT-qPCR Expression Profiles of Selected Oncogenic and Oncosuppressor miRNAs in Formalin-Fixed, Paraffin-Embedded Canine Mammary Tumors.

MicroRNAs (miRNAs) can act as oncogenes or oncosuppressor genes, and their involvement in nearly all cancer-associated processes makes these small molecules promising diagnostic and prognostic biomarkers in cancer, as well as specific targets for cancer therapy. This study aimed to investigate the expression of 7 miRNAs (miR-18a, miR-18b, miR-22, miR-124, miR-145, miR-21, miR-146b) in formalin-fixed, paraffin-embedded canine mammary tumors (CMTs) by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Twenty-six mammary samples were selected, including 22 CMTs (7 benign; 15 malignant) and 4 control samples (3 normal mammary gland and 1 case of lobular hyperplasia). Oncogenic miR-18a, miR-18b and miR-21 were significantly upregulated in malignant tumors compared with control tissues (p &lt; 0.05). Conversely, oncosuppressor miR-146b was significantly downregulated in benign and malignant mammary tumors compared with control samples (p &lt; 0.05) while, no group-related differences in the expression levels of miR-22, miR-124 and miR-145 were found (p &gt; 0.05). Upregulated miRNAs found here, may regulate genes involved in receptor-mediated carcinogenesis and proteoglycan remodeling in cancer; while miRNA with reduced expression can regulate genes involved in Toll-like receptor and MAPK signaling pathways. According to the results obtained in the current study, the oncogenic and oncosuppressor miRNAs analyzed here are dysregulated in CMTs and the dysregulation of miRNA targets may lead to specific altered cellular processes and key pathways involved in carcinogenesis. Of note, since oncogenic miRNAs predicted to regulate neoplastic cell proliferation and hormonal activities, they may play an active role in neoplastic transformation and/or progression, having mechanistic and prognostic relevance in CMTs.

The inflammasomes: crosstalk between innate immunity and hematology.

The inflammasome is a cytosolic multi-protein complex responsible for the proteolytic maturation of pro-inflammatory cytokines IL-1ß and IL-18 and of gasdermin-D, which mediates membrane pore formation and the cytokines release, or eventually a lytic cell death known as pyroptosis. Inflammation has long been accepted as a key component of hematologic conditions, either oncological or benign diseases. This study aims to review the current knowledge about the contribution of inflammasome in hematologic diseases. We attempted to depict the participation of specific inflammasome receptors, and the possible cell-specific consequence of complex activation, as well as the use of anti-inflammasome therapies. We performed a keyword-based search in public databases (Pubmed.gov, ClinicalTrials.gov.). Different blood cells variably express inflammasome components. Considering the immunosuppression associated with both the disease and the treatment of some hematologic diseases, and a microenvironment that allows neoplastic cell proliferation, inflammasomes could be a link between innate immunity and disease progression, as well as an interesting therapeutic target.

MM-547 Multiple Myeloma Response to Therapeutic Protocols: An Iraqi Center Experience

Multiple myeloma (MM) is a clonal proliferation of neoplastic plasma cells producing a monoclonal paraprotein of light and/or heavy chain present in the serum and/or urine. Achieving complete response (CR) is the initial goal of myeloma therapy. The recent therapeutic protocols increase MM CR and survival age. This study aimed to determine the efficacy of the main protocols used in Iraq. A cross-sectional study consecutively included all MM patients between July 2015 and May 2022 at one of the main hematology hospitals in Iraq, the National Hematology Centre, to assess the overall response rate (ORR) which represents ≥very good partial response (VGPR). Of the 52 enrolled patients, the mean (±SD) age was 61.5±11.0 years with a 1.5:1.0 male to female ratio and 30.8% had comorbidities. Two participants (3.8%) died before the end of the study. The presenting features include bone pain and backache (67.3%), followed by a mass and lower limb weakness (1.9% each). The radiological changes were lytic lesions (34.6%) and vertebral wedging (15.4%). The main laboratory features were anemia (69.2%, 10.0±1.5g/dL), IgG kappa paraprotein (51.9 %), and high levels of creatinine (35.3%, 1.4±1.5mg/dL) and calcium (30.8%, 9.5±1.7mg/dL). The available drugs include bortezomib (V), lenalidomide (R), thalidomide (T), cyclophosphamide (C), and dexamethasone (D) were used in triple therapeutic regimens, VRD, VTD, and VCD, with or without autologous stem cell transplantation (ASCT). The outcomes were assessed for each protocol used. Results and Main Outcomes: Among 52 patients, 50 were evaluated at a median follow-up of 60.5 months. The median survival could not be calculated, since 2 patients died due to renal failure. ORR was achieved in 75% of the patients, and partial response (PR) in 11.5%. When outcomes were stratified by treatment regimens, there were statistically significant differences in ORR; the best was observed among VRD-group (p<000.1). Subsequently, 21 (40.4%) patients received ASCT with non-significant differences in ORR from those without transplants (P>0.05). VRD achieved the best antitumor activity in MM, followed by VTD, and VCD was the least. Triple therapeutic regimens effectiveness showed non-significant differences, whether used alone or with ASCT.

S2214 A Rare Case of Secondary Extramedullary Plasmacytoma With Ileocecal Involvement

Introduction: Extramedullary plasmacytomas (EMPs) are a rare type of plasma cell dyscrasia characterized by the neoplastic proliferation of plasma cells in soft tissue.EMPs share characteristics with multiple myeloma (MM) and can present as primary tumors or secondary to other plasma cell neoplasms.Herein we present an extremely rare case of a patient with established MM who was found to have an asymptomatic ileocecal mass with biopsy findings consistent with secondary EMP. Case Description/Methods: A 62-year-old female with a past medical history of MM and Ulcerative Colitis (UC) presented to the gastroenterology clinic for evaluation of her UC before consideration of an experimental therapy trial for her refractory MM.On presentation, she denied changes in her bowel habits or blood in her stool. Lab results 2 weeks prior to presentation were significant for leukopenia at 2.9k/uL, normocytic anemia with hemoglobin at 8.5gm/dL, Calcium 8.2 mg/dl, and total protein of 5.7g/dl. Colonoscopy showed nodular, ulcerated mucosa at the hepatic flexure as well as a large polypoid non-bleeding, non-obstructing, non-circumferential mass at the ileocecal valve. Histopathology of the mass returned positive for CD138 Kappa and negative for lambda AE1/AE3, CAM 5.2, GATA3, ER, consistent with a diagnosis of plasma cell myeloma. The patient continued on salvage chemotherapy but passed shortly thereafter (Figure). Discussion: Plasma cell neoplasms (PCNs) involving extra-osseous tissues are known as extramedullary plasmacytomas (EMPs).EMPs are further classified into primary EMPs, which are localized proliferation of clonal plasma cells in the absence of a systemic plasma cell dyscrasia, and secondary EMPs, where there is already a known primary PCN present. To the best of our knowledge, secondary EMP involving the small intestine and cecum is rare and only reported in a handful of case reports.Due to the indolent course of EMPs, nonspecific gastrointestinal manifestations may go undiagnosed in a subset of patients with MM. The prognosis of secondary EMP involving the gastrointestinal tract remains unclear, however, the limited data we have indicates a poor prognosis.On the other hand, novel treatments of MM continue to improve survival rates in patients with MM. As mortality in these patients decreases, the incidence of secondary EMPs is expected to proportionately rise as well. As such, more data is needed to understand how to monitor and treat this patient population for extramedullary involvement in order to generate good outcomes.Figure 1.: Large polypoid non-bleeding, non-obstructing, non-circumferential mass at the ileocecal valve before and after biopsy.

Light-Chain Multiple Myeloma Presenting as a Bone Tumor in the Right Knee Joint – a Case Report

Myeloma is the neoplastic proliferation of plasma cells. The peak age of onset of this disease is the seventh decade, and it is rare in young patients. Myeloma usually presents as lytic lesions in axial bones and rarely present as a joint disease. Usually, the tumor cells secrete monoclonal immunoglobulins. Non-secretory myeloma is a rare clinical entity. The incidence of light-chain myeloma is 16 – 20 % among all multiple myelomas, and the more common subtype is the lambda chain type. We present a case of kappa light chain-type myeloma in a 29-year-old male with the presenting lesion in the right knee joint. The case is presented for its rarity due to the age of patient, presentation, and type of myeloma.

Mastocytosis Colitis in 54 year old woman: A rare case report

Introduction: Mastocytosis is a rare disorder occurring due to neoplastic clonal proliferation of mast cells accumulating in one or more organ systems. Systemic mastocytosis is generally diagnosed after the second decade of life, reported male-to-female ratios range from 1:1 to 1:1.5. Case description : A 54-year-old woman came complaining weakness and diarrhea for the last 2 months. Symptoms are watery stools for 2-4 times a day and nausea. Physical examination found that the body temperature was 37.60C, tachycardia, increased bowel sounds, and tenderness on stomach. An endoscopic examination was performed with results: transverse colon appears with polyps with a size of 3 mm, with a mosaic pattern of mucosa. The mucosa of the ascending colon and caecum also appears to be a mosaic pattern. Biopsy was sent for histopathological examination. Morphological features show significant increase of eosinophils &amp; mast cells, differentially diagnosed with Mastocytosis colitis, Eosinophilic colitis, systemic mastocytosis with GI involvement. Methodology : Descriptive study of the case report type, data were obtained from the patient's record. Discussion and Conclusion : To rule out the differential diagnosis, an immunohistochemical examination and clinical correlation were performed. On histopathological examination, microscopic features showed the proliferation of mast cells in the aggregate only in the colon, without any other systemic manifestations, an increase in the number of mast cells &gt;20/HPF was found in the colonic mucosa. The staining of CD117 on cells in the superficial (1/3 top) of the lamina propria suspected of being a mastocyte, supporting mastocytosis colitis.

WNT5A-RHOA Signaling Is a Driver of Tumorigenesis and Represents a Therapeutically Actionable Vulnerability in Small Cell Lung Cancer.

The p130-WNT5A-RHOA pathway drives SCLC progression and is a potential target for the development of therapeutic interventions and biomarkers to improve patient treatment.

LACTB, a Metabolic Therapeutic Target in Clinical Cancer Application

Serine beta-lactamase-like protein (LACTB) is the only mammalian mitochondrial homolog evolved from penicillin-binding proteins and β-lactamases (PBP-βLs) in bacteria. LACTB, an active-site serine protease, polymerizes into stable filaments, which are localized to the intermembrane space (IMS) of mitochondrion and involved in the submitochondrial organization, modulating mitochondrial lipid metabolism. Cancer pathogenesis and progression are relevant to the alterations in mitochondrial metabolism. Metabolic reprogramming contributes to cancer cell behavior. This article (1) evidences the clinical implications of LACTB on neoplastic cell proliferation and migration and tumor growth and metastasis as well as LACTB’s involvement in chemotherapeutic and immunotherapeutic responses; (2) sketches the structural basis for LACTB activity and function; and (3) highlights the relevant regulatory mechanisms to LACTB. The abnormal expression of LACTB has been associated with clinicopathological features of cancer tissues and outcomes of anticancer therapies. With the current pioneer researches on the tumor-suppressed function, structural basis, and regulatory mechanism of LACTB, the perspective hints at a great appeal of enzymic property, polymerization, mutation, and epigenetic and post-translational modifications in investigating LACTB’s role in cancer pathogenesis. This perspective provides novel insights for LACTB as a metabolic regulator with potential to develop targeted cancer therapies or neoadjuvant therapeutic interventions.

Correlation of pituitary histomorphometry with dopamine and dopamine D2 receptor expression in horses with pituitary pars intermedia dysfunction

Pituitary pars intermedia dysfunction (PPID) is an endocrinopathy commonly affecting old horses. It is a spontaneously occurring, progressive disease that is still poorly understood. Previous studies have observed neurodegeneration of the dopaminergic inhibition of melanotrophs, which leads to decreased dopamine (DA) in the pars intermedia (PI) and increased pro-opiomelanocortin-derived peptides circulating in plasma. However, rats knockout for the dopamine D2 receptor (D2r) similarly develop PI hypertrophy and hyperplasia. Thus, based on the current pathophysiological theory of PPID, whether the decreased DA or the D2r dysfunction leads to PPID is still unclear. To test this, a total of 28 retrospective cases of horses with PPID were collected, graded and the expression of tyrosine hydroxylase (TH) and D2r in the PI were determined. The histological and immunohistochemical results demonstrated that horses with higher tumor histological grades had reduced TH expression with increased D2r immunoreactivity colocalized in the PI (p < 0.001, p < 0.05 respectively). This correlation supports the role of DA in the pathogenesis of continuous unregulated proliferation of neoplastic cells in PI and indicates the efficiency of D2r agonists as a treatment for PPID.

The benefits of vitamin A as a complementary treatment for oncology patients: a systematic review.

Vitamin A and its derivatives positively influence the differentiation of epithelia and other tissues and prevent the proliferation of preneoplastic and neoplastic cells. Vitamin A is therefore taken into account as a potential supporting factor in cancer therapy. In November 2020, a systematic search was conducted searching five electronic databases (EMBASE, Cochrane, PsycINFO, CINAHL and Medline) to find studies looking at the effects of using vitamin A as a complementary therapy for cancer patients. From all 12,823 search results, 9 publications referring to 9 studies with 4296 patients were included in this systematic review. The patients treated with vitamin A were diagnosed with various cancers and stages. Outcome variables were overall survival of cancer, progression-free survival, occurrence of second primary tumours and recurrences, improvement of chronic radiation-induced proctopathy and side effects of vitamin A. For the most part, the studies had a limited methodological quality. In summary, it can be said that due to the methodological deficiencies of the studies, no concrete statement can be made regarding the prolongation of overall survival and progression-free survival. There is also no evidence of the benefit of vitamin A in the treatment of chronic radiation-induced proctopathy, which can be attributed to methodological deficiencies in the study, as well. In the studies that report on side effects, it becomes clear that side effects, such as mucocutaneous symptoms, temporary increase in liver enzymes and gastrointestinal side effects occur more frequently in the group with vitamin A intervention. The limited interpretability of the results due to the methodological deficiencies of the included studies does not allow a final statement on the benefits of vitamin A as a complementary treatment for cancer patients.

LANGERHANS CELL HISTIOCYTOSIS IN THE MANDIBLE OF ELDERLY PATIENT: A CASE REPORT

Langerhans cell histiocytosis (LCH) is a rare condition commonly described in children, with limited reports in adults. The local and systemic environments are described with a microscopic presentation of neoplastic Langerhans cell proliferation. We present a case of a 61-year-old woman with a swelling in the right mandibular body region. Computed tomography revealed a unilocular, ill-defined mixed lesion with a slightly expansive character. Microscopy analysis revealed diffuse infiltration of Langerhans cells with grooved nuclei combined with inflammatory infiltrate. Immunohistochemistry analysis showed positivity for S-100 and CD1a antibodies compatible with an LCH diagnosis. The patient underwent resection of the lesion and showed no signs of recurrence until a few months after. There is no current information on the patient. Though rare, LCH may affect elderly patients. Gnathic bone lesions usually respond well to conservative treatment. However, these patients must be monitored because of the possibility of dissemination of the disease.