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ObjectiveColorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the USA. The faecal microbiome may provide non-invasive biomarkers of CRC and indicate transition in the adenoma–carcinoma sequence. Re-analysing raw sequence and metadata from several studies uniformly, we sought to identify a composite and generalisable microbial marker for CRC.DesignRaw 16S rRNA gene sequence data sets from nine studies were processed with two pipelines, (1) QIIME closed reference (QIIME-CR) or (2) a strain-specific method herein termed SS-UP (Strain Select, UPARSE bioinformatics pipeline). A total of 509 samples (79 colorectal adenoma, 195 CRC and 235 controls) were analysed. Differential abundance, meta-analysis random effects regression and machine learning analyses were carried out to determine the consistency and diagnostic capabilities of potential microbial biomarkers.ResultsDefinitive taxa, including Parvimonas micra ATCC 33270, Streptococcus anginosus and yet-to-be-cultured members of Proteobacteria, were frequently and significantly increased in stools from patients with CRC compared with controls across studies and had high discriminatory capacity in diagnostic classification. Microbiome-based CRC versus control classification produced an area under receiver operator characteristic (AUROC) curve of 76.6% in QIIME-CR and 80.3% in SS-UP. Combining clinical and microbiome markers gave a diagnostic AUROC of 83.3% for QIIME-CR and 91.3% for SS-UP.ConclusionsDespite technological differences across studies and methods, key microbial markers emerged as important in classifying CRC cases and such could be used in a universal diagnostic for the disease. The choice of bioinformatics pipeline influenced accuracy of classification. Strain-resolved microbial markers might prove crucial in providing a microbial diagnostic for CRC.

Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.

Microbes colonizing colorectal cancer (CRC) tumors have the potential to affect disease, and vice-versa. The manner in which they differ from microbes in physically adjacent tissue or stool within the case in terms of both, taxonomy and biological activity remains unclear. In this study, we systematically analyzed previously published 16S rRNA sequence data from CRC patients with matched tumor:tumor-adjacent biopsies (n = 294 pairs, n = 588 biospecimens) and matched tumor biopsy:fecal pairs (n = 42 pairs, n = 84 biospecimens). Procrustes analyses, random effects regression, random forest (RF) modeling, and inferred functional pathway analyses were conducted to assess community similarity and microbial diversity across heterogeneous patient groups and studies. Our results corroborate previously reported association of increased Fusobacterium with tumor biopsies. Parvimonas and Streptococcus abundances were also elevated while Faecalibacterium and Ruminococcaceae abundances decreased in tumors relative to tumor-adjacent biopsies and stool samples from the same case. With the exception of these limited taxa, the majority of findings from individual studies were not confirmed by other 16S rRNA gene-based datasets. RF models comparing tumor and tumor-adjacent specimens yielded an area under curve (AUC) of 64.3%, and models of tumor biopsies versus fecal specimens exhibited an AUC of 82.5%. Although some taxa were shared between fecal and tumor samples, their relative abundances varied substantially. Inferred functional analysis identified potential differences in branched amino acid and lipid metabolism. Microbial markers that reliably occur in tumor tissue can have implications for microbiome based and microbiome targeting therapeutics for CRC.

Primary hyperparathyroidism (PHPT) is an excessive parathyroid hormone (PTH) production disorder, causing increased calcium levels. Commonly, these cases are asymptomatic and detected incidentally on routine labs. These patients are usually conservatively managed and monitored periodically, including bone and kidney health evaluation. Medical management of severe hypercalcemia secondary to PHPT includes IV fluids, cinacalcet, bisphosphonates, and dialysis, while the surgical treatment is parathyroidectomy. Patients suffering from heart failure with reduced ejection fraction (HFrEF) on diuretics and PHPT require a delicate balance of their volume status to prevent exacerbation of either condition. In patients with these two comorbidities on the opposite ends of the volume spectrum, it can lead to challenges in managing these patients. We present a case of a woman with repeated hospitalizations due to poor volume status control.  An 82-year-old female with primary hyperparathyroidism (diagnosed 17 years ago), HFrEF due to non-ischemic cardiomyopathy, sick sinus syndrome with a pacemaker, and persistent atrial fibrillation presented to the emergency department with worsening bilateral lower limb swelling for several months. The remaining review of systems was largely negative. Her home medication regimen included carvedilol, losartan, and furosemide. Vitals were stable, and the physical exam revealed bilateral lower extremity pitting edema. Chest x-ray revealed cardiomegaly with mild pulmonary vascular congestion. Relevant labs were NT pro-BNP at 2190 pg/mL, calcium at 11.2 mg/dL, creatinine at 1.0 mg/dL, PTH at 143 pg/mL, and Vitamin D, 25-hydroxy at 48.6 ng/mL. The echocardiogram showed an ejection fraction (EF) of 39%, grade III diastolic dysfunction, severe pulmonary hypertension, and mitral and tricuspid regurgitation. The patient received IV diuretics and guideline-directed treatment for congestive heart failure exacerbation. She was managed conservatively for her hypercalcemia and advised to maintain hydration at home. Spironolactone and Dapagliflozin were added to her regimen, and the Furosemide dose was increased at discharge.  The patient was re-admitted three weeks later with fatigue and decreased fluid intake. Vitals were stable; however, the physical exam revealed dehydration. Pertinent labs were calcium at 13.4 mg/dL, potassium at 5.7 mmol/L, creatinine at 1.7 mg/dL (baseline 1.0), PTH at 204 pg/mL, and Vitamin D, 25-hydroxy at 54.1 ng/mL. Repeat ECHO showed an ejection fraction (EF) of 15%. She was started on gentle IV fluids to correct the hypercalcemia while preventing volume overload. Hypercalcemia and acute kidney injury improved with hydration. She was put on Cinacalcet 30 mg, and home medications were adjusted for better volume control at discharge. This case highlights the complications of balancing the volume status with primary hyperparathyroidism and CHF. Worsening HFrEF resulted in a higher diuretic requirement, thereby worsening her hypercalcemia. With emerging data on the correlation between PTH and cardiovascular risks, it is becoming necessary to assess the risks and benefits of conservative management in asymptomatic patients. Current research has also shown that various patient demographics and comorbidities prevent the surgical management of PHPT. Hence, in suitable candidates, parathyroidectomy must be considered early in patients with asymptomatic hyperparathyroidism.

Disclosure: N. Mohan: None. M.S. Shah: None. Introduction: Primary hyperparathyroidism is a disorder of excessive parathyroid hormone production causing increased calcium levels, usually due to a parathyroid adenoma. Commonly these cases are asymptomatic and detected incidentally on routine labs. They can be managed conservatively with sufficient fluid intake and avoiding dehydration. Congestive heart failure patients on diuretics with primary hyperparathyroidism require a delicate balance of their volume status to prevent exacerbation of either condition. We present a case of a woman with repeated hospitalizations due to poor volume status control. Clinical Case: An 82-year-old female with congestive heart failure (CHF), primary hyperparathyroidism (diagnosed 17 years ago), sick sinus syndrome with a pacemaker, and persistent atrial fibrillation presented to the emergency room with worsening b/l lower limb swelling for a few months. The remaining review of systems was largely negative. At home, she was on Losartan, Furosemide, and Carvedilol. Vitals were stable and physical exam revealed b/l lower extremity pitting edema. Chest x-ray showed cardiomegaly with mild pulmonary vascular congestion. Pertinent labs were NT pro-BNP 2190, Calcium 11.3 mg/dL, PTH 143 pg/mL, and Vit D, 25-hydroxy 48.6 ng/mL. The patient was started on IV diuretics and her home medications for CHF exacerbation. ECHO showed EF 39%, grade III diastolic dysfunction, severe pulmonary hypertension, mitral and tricuspid regurgitation. She was managed conservatively for her hypercalcemia and advised to maintain hydration at home. Spironolactone and Dapagliflozin were added to her regimen, and Furosemide was increased at discharge. The patient was re-admitted three weeks later with fatigue and decreased fluid intake. Vitals were stable and physical exam revealed dehydration. Pertinent labs were Calcium 13.4 mg/dL, Potassium 5.7 mmol/L, Creatinine 1.7 mg/dL (baseline 1.0), PTH 204 pg/mL, and Vit D 54.1 ng/mL. Repeat ECHO showed EF 15%. She was started on gentle 0.9% NS IV fluid to correct the hypercalcemia while preventing volume overload. Hypercalcemia and acute kidney injury improved with hydration. She was put on Cinacalcet 30 mg and home medications were modified for better volume control at discharge. Conclusion: This case highlights the complications of balancing the volume status with primary hyperparathyroidism and CHF. This patient’s primary hyperparathyroidism was well-controlled for more than fifteen years on adequate hydration. However, worsening CHF resulted in a higher requirement for diuretics, thereby worsening her hypercalcemia. Even though parathyroidectomy is an established treatment modality, she was not a suitable candidate due to age and comorbidities. Hence, to prevent such complications, parathyroidectomy must be considered early in patients with heart disease and even in asymptomatic hyperparathyroidism. Presentation: Thursday, June 15, 2023

Introduction Immune Checkpoint inhibitors (ICI) have been associated with multiple endocrinopathies including hypothyroidism, hyperthyroidism, primary and secondary adrenal insufficiency, hypophysitis and type 1 diabetes. Unlike other adverse effects from ICI, endocrinopathies tend to be irreversible. There are limited reports on the interaction of Covid-19 vaccine in patients receiving ICI for cancer treatment. Clinical Case A 56 year old man with history of non-small cell lung cancer presents to the hospital with nausea, decreased appetite, fatigue and 30lb unintentional weight loss. He had been started on immunotherapy with pembrolizumab 4 months prior to symptom onset (total of 4 doses). His symptoms began the day after he received his first Covid-19 vaccine injection. At an outside hospital, his initial work up showed TSH of 0.02mcU/mL, free T3 of 8.3pg/mL and free T4 of 2.8ng/dL. Thyroid stimulating immunoglobulin (TSI) was negative and he did not undergo thyroid uptake scan due to recent contrast load for CT abdomen imaging. Patient was diagnosed with hyperthyroidism and started on methimazole 10mg daily. He presented to our hospital after two weeks at his oncologist's recommendation due to worsening symptoms and concern for failure to thrive. On admission, he was noted to have hypotension and tachycardia. Given the severity of his symptoms, we obtained an AM cortisol and ACTH. His baseline cortisol was 1.2mcg/dL, so he underwent a cosyntropin stimulation test. Patient was diagnosed with adrenal insufficiency given his subnormal response on cosyntropin stimulation test. He was treated with intravenous hydrocortisone 50mg every 8 hours and methimazole 20mg daily with dramatic clinical improvement within 24 hours. ACTH obtained prior to initiation of steroids subsequently resulted as undetectably low. Further hormonal work up including LH, FSH and IGF-1 were in the normal range with mildly elevated prolactin. MRI pituitary demonstrated a 4mm hypo-attenuation in the posterior pituitary. Discussion Thyroid dysfunction is the most common adverse effect occurring in up to 30% of patients on ICI. Although less common, hypophysitis has been documented in 0.6-3.2% of patients on ICI depending on the drug. Many patients present only with adrenal insufficiency especially in those treated with pembrolizumab. Additionally, not all cases will present with radiographic findings of enhancement or inflammation of the pituitary gland. We describe a patient who developed acute symptoms of hyperthyroidism and adrenal insufficiency within 24 hours of receiving his Covid vaccine. We hypothesize that the vaccination may have triggered ICI-induced hypophysitis and hyperthyroidism in our patient. Resolution is yet to be determined. Conclusion Hypopituitarism and hyperthyroidism can be life-threatening if undiagnosed and untreated. Patients on ICI should be closely monitored for adrenal insufficiency and other endocrinopathies after receiving Covid-19 vaccine. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.