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Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.

We sought to determine risk factors for iv iron infusion-related reactions (IRR), and identify strategies for iron repletion after IRR.We conducted a retrospective chart review of patients treated in the classical hematology clinic at Yale Cancer Center (n = 330 consecutive patients) from 2016 to 2021, who received iv ferumoxytol (60.3%), iron sucrose (14.8%), or iron dextran (10.9%).The iv iron IRR was noted in 58 (17.6%) patients, 62.1% of whom had previously tolerated iv iron. The severity of IRR was mild in 22, moderate in 23, and severe in 11 patients. Most (72.4%) patients who experienced IRR tolerated a subsequent iv iron infusion. On multivariable analysis, a history of non-medication allergies was associated with greater odds of IRR (odds ratio [OR] 2.12, 95% confidence interval (CI): 1.16-3.87, p = .01). No patients with type AB blood, and few with type A blood (n = 6), had IRR; compared to type A or AB together, patients with type B (OR 5.00, 95% CI: 1.56-16.06, p = .007) or type O (OR 3.71, 95% CI: 1.44-9.55, p = .007) blood had greater odds of IRR.This study highlights a possible association of blood type with iv iron IRR; prospective studies with larger patient numbers are warranted to explore this association.

Cancer is the second leading cause of death worldwide. Triple-negative breast cancer (TNBC) patients show the poorest prognosis and survival and the highest metastasis prevalence among all breast cancer subtypes. Matcha (powder of Japanese green tea) has recently been associated with multiple health benefits, and in vitro studies showed the potential effect of matcha in inhibiting cancer development and metastasis. We aimed to determine the safe, non-toxic dose of matcha in zebrafish, and to investigate the anticancer effect of matcha on the metastasis and growth of human TBNC cells using a zebrafish xenograft model. Wild-type AB zebrafish were used to conduct multiple general toxicity assessments, including developmental, neuromuscular, and cardiovascular toxicities. 50 μg/ml and 100 μg/ml were determined as safe, non-toxic concentration of matcha in zebrafish. Afterward, the zebrafish xenograft model was successfully established by injection of MDA-MB-468 and MDA-MB-231 human TNBC cells. The tumor size and metastasis of the injected cancer cells were traced through CM-Dil red fluorescent dye. Exposure to non-toxic doses of matcha, showed a trend toward reduction in tumor size of MDA-MB-231 and MDA-MB-468 in a dose-dependent manner. Our results point to a potential dose-dependent anticancer effect of matcha on TNBC tumors; however, more extended observation periods after xenotransplantation are required to confirm the long-term anticancer effect of matcha on tumor growth and metastasis.

Acute pancreatitis (AP) is one of the most common gastrointestinal-related causes of hospitalization in the USA, accounting for more than 200,000 admissions annually. Although mild and moderate cases usually improve within a week, severe AP conditions could lead to life-threatening pancreatic necrosis, multiple-organ dysfunction, and be fatal in some cases. Excessive alcohol use and gallstones are the two leading causes, nonetheless other systemic complication could also lead to AP. Hypertriglyceridemia is an important, yet uncommon, cause/risk factor of AP, especially when associated with heavy alcohol use. Additionally, the level of triglycerides (TGs) was found to be an important factor of determining the method and duration of treatment. Here we present a case of 38-year-old obese and active smoker male with hypertension and alcohol use disorder presented with a chief complaint of 2 weeks of progressive sharp epigastric pain. His medical history was significant of opioid use disorder that is maintained on methadone therapy. Computed tomography (CT) scan of the abdomen and pelvis revealed infiltration of the fat along the pancreatic tail and distal body with focus of decreased enhancement in the very distal pancreatic tail, which could represent a small infarct or phlegmon. In addition, laboratory data was significant of elevated lipase level (> 1,000 mg/dL), which together with the CT result confirmed the diagnosis of AP. Additional laboratory workup revealed extremely high level of TGs of > 2,000 mg/dL. The patient was subsequently transferred to the intensive care unit for management of hypertriglyceridemia. He was started on insulin therapy along with supportive treatment for the management of pancreatitis. Hypertriglyceridemia and pancreatitis rapidly improved over the course of hospitalization period and no additional intervention was needed. He was successfully discharged on fenofibrate.

A main feature of coronavirus disease 2019 (COVID-19) pathogenesis is the high frequency of thrombosis, predominantly pulmonary embolism (PE). Anticoagulation therapy is a crucial part of the management. Heparin use for anticoagulation could increase the risk of heparin-induced thrombocytopenia (HIT), a potentially fatal complication that presents with thrombocytopenia with or without thrombosis. We present a 69-year-old unvaccinated female patient with severe COVID-19 pneumonia. Initial laboratory investigation was significant for thrombocytopenia and low D-dimer levels. She was initially started on enoxaparin followed by unfractionated heparin. On hospital day 8, she developed left facial droop and dysarthria and was found to have non-occlusive thrombus in proximal middle cerebral artery as well as bilateral pulmonary emboli. She received intravenous thrombolysis followed by heparin infusion. On day 13 of hospitalization, platelet count dropped from 120,000/mm3 to 43,000/mm3, raising suspicion of HIT. Heparin was stopped and fondaparinux was started. After 3 days, HIT antibody testing returned positive, then a positive serotonin release assay confirmed the diagnosis. On discharge, she was transitioned to apixaban to complete 3 months of anticoagulation for provoked PE. This case represents the diagnostic challenge of HIT in COVID-19 patients. Thrombocytopenia after heparin infusion should raise clinical suspicion of HIT, which allows appropriate discontinuation of heparin products and initiation of alternative anticoagulants to limit devastating complications. To our knowledge, this is the first case report of a COVID-19 patient presenting with venous thrombosis as well as arterial thrombotic event in the context of underlying HIT.

Glioblastoma multiforme (GM) is the most common type of aggressive malignant glioma in the brain or spinal cord and represents 15% of all primary brain tumors among adults. Although ischemic strokes in the setting of an underlying glioma is a rare occurrence, its diagnosis is usually challenging due to the overlapping neurological manifestations with the underlying brain tumor. We report a case of a 58-year-old white male who presented with subacute worsening symptoms of expressive aphasia with focal neurological symptoms, including right-sided extremity motor weakness and intermittent vision spots. Magnetic resonance imaging (MRI) of brain revealed a large 9.5 cm infiltrating mass in the left frontal and temporal lobes, strongly indicative of a primary glioma. The patient underwent resection to confirm diagnosis and remove part of the tumor mass. Pathological examination revealed GM. Expressive aphasia was markedly improved following the surgery; however, on postoperative day 3, the patient developed acute onset of right-sided weakness and sensory deficit. MRI revealed acute left posterior, frontal, and parietal infarct. Unfortunately, recent brain surgery would not allow for intravenous thrombolysis, and, therefore, he was discharged with a plan for outpatient radiation treatment and oral temozolomide chemotherapy.

A middle-aged woman presented with a mechanical fall. Physical examination revealed a massive purulent ulcerated lesion spanning her entire back and axilla, which had reportedly been brewing for over a decade. Punch biopsy revealed infiltrative basal cell carcinoma. She was treated with Vismodegib, with a remarkable decrease in the size of the cancer. However, surveillance imaging after 6 months of treatment revealed new bone metastases. In the setting of progressive disease, medical therapy was switched to cemiplimab instead. Basal cell carcinoma is commonly known as a benign tumour of the skin, rarely larger than 5 cm. Here, we discuss the entity of metastatic super giant basal cell carcinoma; this case is one of the largest reported lesions. As locoregional therapy, such as surgery is sometimes not appropriate for such advanced lesions, we discuss the current forefront of therapy including oral hedgehog pathway and check point inhibitors.

Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.

Simple Summary The ATR-CHK1 axis of the DNA damage response is crucial for the survival of most colorectal cancer stem cells (CRC-SCs), but a significant fraction of primary CRC-SCs either is resistant to ATR or CHK1 inhibitors or survives the abrogation of the ATR-CHK1 cascade despite an initial response. Here, we demonstrate that the targeting of RAD51 or MRE11 improves the sensitivity of primary CRC-SCs to the CHK1/2 inhibitor prexasertib by sequentially inducing replication stress, the abrogation of cell cycle checkpoints, and the emergence of mitotic defects. This results in the induction of mitotic catastrophe and CRC-SC killing via a caspase-dependent apoptosis. Abstract Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, because they are endowed with a very robust DNA damage response (DDR). This favors the survival of DNA-damaged CSCs instead of their inhibition via apoptosis or senescence. The DDR represents a unique CSC vulnerability, but the abrogation of the DDR through the inhibition of the ATR-CHK1 axis is effective only against some subtypes of CSCs, and resistance often emerges. Here, we analyzed the impact of druggable DDR players in the response of patient-derived colorectal CSCs (CRC-SCs) to CHK1/2 inhibitor prexasertib, identifying RAD51 and MRE11 as sensitizing targets enhancing prexasertib efficacy. We showed that combined inhibition of RAD51 and CHK1 (via B02+prexasertib) or MRE11 and CHK1 (via mirin+prexasertib) kills CSCs by affecting multiple genoprotective processes. In more detail, these two prexasertib-based regimens promote CSC eradication through a sequential mechanism involving the induction of elevated replication stress in a context in which cell cycle checkpoints usually activated during the replication stress response are abrogated. This leads to uncontrolled proliferation and premature entry into mitosis of replication-stressed cells, followed by the induction of mitotic catastrophe. CRC-SCs subjected to RAD51+CHK1 inhibitors or MRE11+CHK1 inhibitors are eventually eliminated, and CRC-SC tumorspheres inhibited or disaggregated, via a caspase-dependent apoptosis. These results support further clinical development of these prexasertib-based regimens in colorectal cancer patients.

Introduction: Iron deficiency is the most frequent cause of anemia, which afflicts 32.9% of the global population and is a significant cause of morbidity worldwide. Oral iron is the first-line therapy for treating iron deficiency anemia; intravenous(IV) iron is used when oral iron is inappropriate, poorly tolerated or ineffective. The major adverse effect associated with IV iron is infusion-related reactions (IRR), ranging from mild reactions mediated by complement activation-related pseudo-allergy to anaphylaxis. In this study, we sought to determine rates and severity of iron IRR, identify patient characteristics associated with IRR and report strategies for subsequent iron repletion in patients who have IRR. Methods: We conducted a retrospective chart review of all patients older than 18 years who received IV iron from 1/1/2016 to 7/20/2021 in the outpatient Classical Hematology clinic at Yale New Haven Hospital. Demographics, risk factors, details of reactions and follow up were noted. The primary outcomes analyzed included rates and severity of IRR based on nursing and provider documentation and graded according to a previously-published IRR severity classification (Rampton D et al, Haematologica 2014;99:1671). Secondary outcomes included identification of patient characteristics associated with IRR utilizing Chi-square or Fisher's exact test for unadjusted analysis and logistic regression for multivariable analysis (IBM SPSS version 28). Results: A total of 330 patients, including 298 females, received IV iron. The common formulations used were ferumoxytol, iron sucrose and iron dextran with 199 (60.3%), 49(14.8%), and 36 (10.9%) patients, respectively, receiving each of these. Comorbid conditions were present in 317 (96.1%) patients, including 114 (34.5%) with cardiovascular disease (CVS) and 71 (21.5%) with asthma. Beta blocker or angiotensin-converting enzyme inhibitor (ACEI) use was noted in 90 (27.3%) patients. A history of allergies to medications was present in 167 (50.6%) patients while 139 (42.1%) had other non-drug allergies. The common indications for infusion were anemia due to heavy menstrual bleeding (27.6%), gastrointestinal bleeding (17.2%) and pregnancy (6.9%). Iron IRR was noted in 58 (17.6%) patients, of whom 36 (62.1%) had previously tolerated IV iron. Of the 58 patients with IRR, the median age was 40.32 ± 14.6 years; 30 (51.7%) had allergies to medications, 34 (58.6%) had non-drug allergies, and 13 (22.4%) each had a history of CVS or asthma. Beta blocker or ACEI use was found in 12 (20.7%) patients. The reaction manifestations included gastrointestinal in 16 (27.6%) patients, cardiovascular in 24 (41.4%), bronchopulmonary in 34(58.6%), mucocutaneous in 28(48.3%), neurological in 21(36.2%) and autonomic in 30 (51.7%). The severity of reaction was mild in 22 (37.9%) patients, moderate in 23 (39.7%), and severe in 11 (19%). After a reaction, 28 (48.3%) patients subsequently tolerated a different formulation of IV iron, while 14 (24.1%) patients tolerated the same formulation of IV iron at a slower rate with premedication; 5 (8.6%) patients had a subsequent reaction to a different IV iron formulation. Multivariable regression analysis was performed to examine associations of iron IRR with history of allergies to medications, non-drug allergies, asthma, CVS, use of beta blockers or ACEI and sex. In this analysis, a history of non-drug allergies was significantly and independently associated with greater odds of IRR (odds ratio (OR) 2.40, 95% confidence interval (CI): 1.32-4.37, p=0.004) while a history of CVS was associated with lower odds of IRR (OR 0.46, 95% CI: 0.22-0.988, p=0.047). None of the parameters were found to have an association with the severity of IRR. Conclusion: Iron IRR occurred in 17.6% of patients receiving IV iron, with severe reactions occurring in 3.3% of all patients; these rates are higher than those previously reported in literature. A history of non-drug allergies is independently associated with greater odds of IRR, and additional precautions may be indicated to prevent IRR in such patients. An association of CVS with lower odds of reaction may reflect anti-inflammatory effects of widespread aspirin use in these patients. The majority of patients with iron IRR can subsequently tolerate the same or a different formulation of IV iron with slower rates of infusion and premedication. Figure 1 Figure 1. Disclosures Neparidze: Janssen: Research Funding; GlaxoSmithKline: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Objectives: This study aimed to evaluate the clinical and radiographic outcomes of the xenograft in the extraction socket following the surgical removal of impacted mandibular third molar. Patients & Methods: The study was conducted on sixty patients with asymptomatic bilateral impacted mandibular third molars. The molar on one side was extracted and xenograft (Bio-oss® Geistlich Pharma AG, Switzerland) was placed in the extraction socket (study side); the molar on the other side was extracted two weeks later and the extraction socket was left to heal naturally (control side).Results: Pain, maximal incisal opening and swelling were significantly improved in the study group when compared to the control group. Values of bone density were higher in the study group throughout the follow-up period.Conclusion: Incorporation of xenograft material plays an important role in increasing the alveolar bone density, enhancement of postoperative pain, swelling, range of mouth opening and gives better wound healing.