United States

Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), significantly improving patient outcomes, particularly in the chronic phase (CML-CP). First-generation TKI imatinib and second-generation TKIs such as dasatinib and nilotinib have proven highly effective, achieving deep molecular responses like major molecular response (MMR). However, resistance or intolerance to TKIs results in treatment failure in 20%–25% of cases, despite an initial good response.
Methods: This clinical study involved ten CML patients, aged between 38 and 83 years, including 6 males and 4 females, receiving TKI therapy at our clinic. Patients were treated with imatinib, dasatinib, or nilotinib, depending on insurance approval. BCR-ABL levels were monitored through regular PCR tests, with relapse defined as a 10-log increase from a previous level. Potential causes of relapse, including non-compliance, side effects, and resistance development, were identified through medical records, patient interviews, and consultations.
Results: The study analyzed the causes of relapse in ten CML patients treated with TKIs:
Patient 1: Noncompliance and developed resistance to dasatinib, so was switched to imatinib, eventually achieving remission.
Patient 2: Switched from dasatinib to nilotinib for pleural effusion, achieving undetectable BCR-ABL levels.
Patient 3: Stable on imatinib with steady BCR-ABL levels.
Patient 4: Switched from dasatinib to nilotinib due to heavy vaginal bleeding.
Patient 5: Reached negative BCR-ABL on nilotinib, then switched to dasatinib due to GI side effects.
Patient 6: Responded well, BCR-ABL undetectable on Scemblix.
Patient 7: Non-compliance due to side effects of vomiting and nausea led to erratic BCR-ABL levels, switched from nilotinib to dasatinib, eventually achieving remission.
Patient 8: Non-compliance on imatinib due to insurance problems. Stable after switching from imatinib to nilotinib due to progression.
Patient 9: Non-compliant, fluctuating BCR-ABL levels.
Patient 10: Positive response to nilotinib, with significant reduction in BCR-ABL levels.
Conclusion: CML is a highly treatable hematological cancer with the use of TKIs. We employ highly sensitive PCR tests to detect even the slightest molecular relapse. Our study revealed that 7 out of 10 patients experienced a molecular relapse at some point during their treatment. The primary cause of relapse was non-compliance, followed by side effects, and, although rare, resistance to TKIs. Therefore, patient education and effective communication during consultations are crucial components of treatment.


AMA Research Challenge 2024 

Why Effective Treatments for CML Fail: Investigating Loss of Response

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poster

Introduction
Colon cancer is the third most common cancer worldwide, with signet ring cell carcinoma (SRCC) being a rare subtype accounting for 1-2% of cases. SRCC incidence is increasing among younger patients, and is associated with worse survival rates and poor treatment response compared to other colorectal cancers. This study aims to analyze SRCC’s epidemiology, metastatic patterns, and survival rates, focusing on early-onset cases using the SEER database to provide robust statistical insights.

Methods
The study is a retrospective analysis that utilizes a cohort from the Surveillance, Epidemiology, and End Results database from 2000-2020. This study uses several demographic and clinical factors that include age, race, median income, housing, tumor stage, tumor size, lymph node status, metastasis, and treatment modalities (surgery, radiation, chemotherapy). 

Results
The median age of onset is increasingly earlier, now at 41 years, with most cases occurring between 36-50 years. Common metastasis sites are other locations (38.3%), liver (8.9%), bone (4.2%), and lung (3.8%), with the rectum being the most frequent primary tumor site (29.1%). Predominantly affecting males (62.3%), the cohort includes white (50.6%), Hispanic (21.9%), and African American (12.3%) patients. Surgery with adjuvant chemotherapy is the most common treatment, while chemotherapy-only has the lowest 5-year survival rate (2.6%) and surgery-only the highest (40.2%). Multivariate analysis identifies tumor stage (H.R. 2.15, p <0.001), nodal status (H.R. 3.28, p <0.001), and tumor size (H.R. 2.08, p =0.013) as prognostic factors.

Conclusion

The study indicates a declining median age for young-onset SRCC, which often presents with distant metastasis and advanced-stage due to delayed symptom onset. Worse outcomes are linked to tumor location, nodal status, and size. These findings can guide clinicians in creating personalized treatment plans and risk stratification for SRCC patients.

Young-onset Colorectal with Signet Ring Cell Morphology; Clinicopathological Analysis and Patterns of Metastases in US Population

Abstract Title:
“Why Did They Die?” The Hidden Surge of Pulmonary Thromboembolism in Post-COVID
Saint Vincent and the Grenadines – A JoinPoint Regression Analysis (2013-2023)
Background:
Pulmonary thromboembolism (PTE) is a critical cardiovascular condition with significant
mortality risk. The COVID-19 pandemic has been associated with increased thromboembolic
events, likely due to virus-related hypercoagulability. This study investigates the trends and
demographic shifts in PTE-related mortality in Saint Vincent and the Grenadines over an 11-year
period, exploring both pre- and post-COVID eras.
Methods:
Data on PTE-related deaths from Kingstown, Saint Vincent and the Grenadines, were obtained
from the population-based death registration system. Crude mortality rates were calculated for
the period 2013-2023. Joinpoint regression analysis was employed to identify significant changes
in mortality trends. The analysis also explored demographic shifts across different age groups
and genders.
Results:
A total of 209 PTE-related deaths were recorded during the study period, with notable peak
significant stratifications seen as 56.5% of the cases being men and 24.9% occurring in
individuals aged 51-60 years. The crude mortality rate for PTE increased by 66.5% from the pre-
COVID era (2013-2019) to the COVID/post-COVID era (2020-2023). Joinpoint regression
analysis revealed a significant increase in the annual percent change (APC) of PTE mortality:
11.5% (95% CI −1.2 to 25.89, P = 0.99) for males and 13.85% (95% CI −2.58 to 33.07, P = 0.83)
for females. A peak in PTE mortality was observed in 2020, with a subsequent decline from
2021-2023.
Conclusion:
The mortality trend for PTE showed a marked increase during the COVID-19 era compared to
the pre-COVID period, particularly among males and those aged 51-60 years. Despite the
significant surge in 2020, a decline in crude mortality rates was noted from 2021-2023,
potentially attributable to various factors such as improved clinical management and increased
vaccine uptake. More research is needed to fully understand the impact these factors could have
played. This study underscores the need for targeted interventions to mitigate PTE risk and
improve outcomes in vulnerable populations during and after pandemics.
Keywords: Pulmonary embolism, Mortality trends, Crude mortality rate, Joinpoint regression,
COVID-19 impact, Saint Vincent and the Grenadines, Vaccine uptake.
Anderson E. Ikeokwu (M.D MPH)
Promise Okereke (M.D)
Hilary Daniel (MD)

“Why Did They Die?” The Hidden Surge of Pulmonary Thromboembolism in Post-COVID

Insulin Resistance Spawns Hypertriglyceridemia-induced Acute Pancreatitis and Diabetic Ketoacidosis: Unboxing a New Metabolic Crisis

Background
Insulin resistance (IR) in adipose tissue (Adipo-IR) is linked to uncontrolled lipolysis with free fatty acids (FFAs) dissipation, ectopic fat deposition and hypertriglyceridemia (HTG). As a valuable component in the metabolic syndrome, HTG increases the likelihood of atherosclerotic cardiovascular disease (ASCVD). By analyzing two cases with severe HTG in poorly controlled T2DM which provoked hypertriglyceridemic acute pancreatitis (HTGAP) and diabetic ketoacidosis (DKA), we suggest an Adipo-IR-induced new metabolic crisis of lipid and glucose metabolism underlying HTGAP and DKA.
Case Presentation
In this case series, case 1 involves a 48-year-old female with triglyceride of 3841 mg/dL and HbA1c 10.1%, while case 2 describes a 32-year-old male with triglyceride of 650 mg/dL initially which was up to 5359 mg/dL 9 months later with HbA1c 12%. Both had increased anion gap, positive ketones and elevated c-peptide with significant IR. Both developed significantly increased lipase with abdomen CT scan showing edematous pancreatitis. Both patients were admitted to the intensive care unit receiving continuous insulin and Lactated Ringer’s solution infusion. The DKAs were resolved in 24 hours and triglycerides gradually decreased to < 1000 mg/dL on days 5 to 6. Both were discharged with Fenofibrate, Atorvastatin and insulin therapy. 3-month follow-up showed well controlled triglyceride and HbA1c levels. Insulin injection was switched to oral hypoglycemic medications. 
Discussion
This scenario represents an acute crisis of lipid and glucose metabolism induced by Adipo-IR and its consequent over-activated lipolysis. Adipo-IR and over-activated lipolysis create a two-way feedback between white adipose tissue and liver (Hep-IR), which further damages pancreases with pancreatic self-hydrolysis leading to HTGAP. HTGAP further triggers counter-regulatory hormone worsening hyperglycemia and lipolysis and ultimately causing downward spiral of HTGAP-DKA. Acute management involves fluid resuscitation, insulin infusion, and nutrition management and complications prevention. Chronic management includes non-pharmacological measures and medications including Fibrates, Statin, Omega-3 fatty acids, Metformin and Sodium-glucose cotransporter-2 inhibitors. Further investigation is needed for clinically applicable assessment and stratification of Adipo-IR/Hep-IR axis.

Insulin Resistance Spawns Hypertriglyceridemia-induced Acute Pancreatitis and Diabetic Ketoacidosis: Unboxing a New Metabolic Crisis

Background: Vitamin B12 deficiency (B12D) is associated with multiple risk factors and comorbidities; however, there are no firm guidelines regarding screening for B12D in the population at risk. We aimed to identify the risk factors and comorbidities associated with B12D in an adult population.
Methods: Retrospective review of adult patients who received medical care in our large urban tertiary healthcare system between 1/1/2011 to 12/31/2020. Variables were compared between the group who had B12D and those who did not (NoB12D).
Results: Patients with B12D (n=2,666) were younger than the NoB12D group (n=2,334) (62.2±18.5 vs 76.5±7.6 years; P<0.001). There were significantly higher associations in B12D group compared to NoB12D group of female sex, recreational drug use, CHF, CVA, COPD, asthma, peripheral neuropathy (PN), subacute combined degeneration of spinal cord (SCD), dementia), mild cognitive impairment (MCI), GERD, gastritis, inflammatory bowel disease (IBD), small bowel resection (SBR), colorectal surgery (CRS), bariatric surgery (BS), depression, bipolar disorder, anxiety disorder, schizophrenia, anemia, use of NSAIDs, proton pump inhibitor (PPI), histamin-2 receptor antagonist (H2RA), and lithium. Compared to White race, Black and Hispanic races had higher odds of B12D (OR 1.43, 95% CI 1.02–2.01; P=0.040, and OR 3.15, 95% CI 2.23–4.45; P<0.001, respectively). Comorbidities with greater odds of B12D included COPD and asthma (OR 1.41, 95% CI 1.12–1.78; P=0.003), anemia (OR 253.72, 95% CI 164.66–390.93; P<0.001), PN and SCD (OR 2.78, 95% CI 2.16–3.58; P<0.001), dementia and MCI (OR 3.37, 95% CI 2.40–4.74; P<0.001), gastrointestinal disorders (GERD, gastritis, IBD, SBR, CRS and BS) (OR 2.38, 95% CI 1.95–2.90; P<0.001), PPI use (OR 2.81, 95% CI 1.88–4.20; P<0.001), and NSAID use (OR 1.40, 95% CI 1.08–1.81; P=0.011).
Conclusion: Younger age, female sex, Black and Hispanic races, recreational drug use, CHF, CVA, COPD, asthma, PN, SCD, dementia, MCI, GERD, IBD, SBR, colorectal surgery, bariatric surgery, depression, bipolar disorder, anxiety disorder, schizophrenia, anemia, use of PPI, H2RA, NSAIDs and lithium are associated with B12D.

Risk Factors and Comorbidities associated with Vitamin B12 Deficiency in an Adult Population

This systematic review examines the interplay between the MTHFR gene C677T genotype polymorphism, hyperhomocysteinemia (HHCY), and spontaneous cervical/vertebral artery dissection, a significant cause of ischemic stroke (IS) in young adults. Analyzing 11 studies involving 4,840 patients aged 18-45, the review highlights that HHCY contributes to vascular damage and tissue ischemia, often presenting with nonspecific symptoms such as neck pain or headache. The MTHFR C677T genotype is closely linked to elevated homocysteine levels, increasing stroke risk, yet remains underdiagnosed. Early detection and management through supplementation with vitamin B12, folates, and in severe cases, betaine, can mitigate these risks, underscoring the need for heightened clinical awareness to prevent severe outcomes.

The connection between enzyme MTHFR, homocysteine levels, and artery dissection in young adults.

Introduction
While delayed graft function (DGF) is less common after donation after brain death (DBD) than after circulatory death (DCD) in kidney transplantation (KT), this study investigated whether risk factors for DGF and post-transplant outcomes differ by donor type.
Methods
We analyzed all adult deceased donor kidney transplant recipients (DDKTR) at our center between 2005-2019, stratified by donor type (DBD vs. DCD). We assessed risk factors for DGF, acute rejection (AR), uncensored graft failure (UCGF), and death-censored graft failure (DCGF), within first year of transplant. 

Results
Among 2543 DDKTs, 804 (31%) were DCD. In both DBD and DCD recipients, older donor age, higher recipient BMI, and depleting induction agent increased the risk for DGF, while female recipient and preemptive transplant were protective. Additional risk factors in DBD but not in DCD recipients included higher terminal serum creatinine, higher KDPI, right donor kidney, and prolonged cold ischemia time (CIT). Female donors were protected against DGF in DCD only. DGF was linked to higher AR and UCGF risk, with no significant differences between DBD and DCD groups (AR: aHR 2.22 vs 2.37, p-interaction=0.65; UCGF: 3.04 vs 2.56; p-interaction=0.47). No adjusted DCGF data were available. 

Conclusion
DBD-KTs had more risk factors for DGF than DCD-KTs, including higher terminal creatinine, higher KDPI, right renal graft, and prolonged CIT. Female donors offered added protection against DGF in DCD-KTs. Despite higher DGF rates in DCD-KTs, the risk of adverse early outcomes after DGF development was similar between deceased donor types, suggesting DCD grafts remain a viable option despite DGF concerns.


Comparable Early Outcomes in Brain versus Circulatory Death Kidney Transplants After Delayed Graft Function

Does CKD modify the effects of GLP-1RA and SGLT2i on weight loss?

Background:
It is unknown whether CKD modifies the weight loss effects of GLP1-RA or SGLT2i. 

Methods:
In an active comparator, new user study, we examined the effects of CKD status on bodyweight loss in veterans with T2D on metformin who began insulin glargine (IG), SGLT2i, or GLP1-RA from 1/1/18 to 3/31/21. Previous use of study medications between 1/1/08 and 12/31/17 was an exclusion. Index date was the date of study drug prescription fill. Outpatient bodyweight closest to the index date and within 1 year prior was defined as baseline bodyweight. Bodyweight change after drug initiation was defined as the difference between baseline bodyweight and an average of all outpatient weights across 6-month intervals after the index date, up to 24 months.

Follow up was until 24 months after index date or until loss to follow-up or death, whichever came earliest. Inverse probability weights (IPW) for each pairwise drug comparison resulted in balance of baseline variables across the drug classes. In IPW mixed effects models, study drug classes were related to weight change at 24 months in pairwise comparisons in non-CKD and CKD (eGFR<60) subgroups. Effect modification was tested by comparing the regression coefficients for each of the pairwise comparisons in non-CKD and CKD subgroups.

Results:
In the non-CKD group (N = 124,963), the percentages of female patients for GLP1-RA, SGLT2i, and IG respectively were 9.7%, 4.4%, and 5.9%. Mean ages were 62, 65, and 63; baseline eGFRs were 87.3, 85.6, and 87.3; and baseline BMIs were 35.8, 33.4, and 32.6, respectively. In the CKD group (N = 25,124), the percentages of female patients for GLP1-RA, SGLT2i, and IG respectively were 6.1%, 3.4%, and 4.3%. Mean ages were 71, 72, and 71; baseline eGFRs were 48.7, 51.0, and 48.6; and baseline BMIs were 34.2, 32.2, and 31.8, respectively. 

Absolute bodyweight difference at 24 months for IG compared to GLP1-RA was 6.77 ± 0.22 lbs in the non-CKD group and 7.15 ± 0.48 lbs in the CKD group (interaction p-value = 0.476). Corresponding numbers for IG compared to SGLT2i were 6.13 ± 0.18 lbs and 6.18 ± 0.37 lbs (interaction p-value = 0.906) and SGLT2i compared to GLP1-RA were 0.64 ± 0.20 and 0.97 ± 0.45 (interaction p-value = 0.507). Percent bodyweight difference at 24 months for IG compared to GLP1-RA was 3.01 ± 0.10 in the non-CKD group and 3.31 ± 0.21 in the CKD group (interaction p-value = 0.219). Corresponding numbers for IG compared to SGLT2i were 2.75 ± 0.08 and 2.92 ± 0.17 (interaction p-value = 0.365) and SGLT2i compared to GLP1-RA were 0.26 ± 0.09 and 0.39 ± 0.21 (interaction p-value = 0.575). 

Conclusion:
Patients lost significantly more weight on GLP1-RA or SGLT2i compared to insulin glargine, but there was minimal difference in weight change at 2 years between SGLT2i and GLP1-RA. CKD status did not modify weight loss on SGLT2i or GLP1-RA.

Does CKD modify the effects of GLP1-RA and SGLT2i on weight loss?

Background
Renal transplantation, a cornerstone in modern medicine, offers a crucial solution for those grappling with end-stage renal diseases. However, organ transportation challenges necessitate innovative preservation methods. This study aims to enhance transplant viability by optimizing kidney preservation through advanced ultrasound technology. It continues previous work with our hemoglobin-based oxygen carrier (HBOC) compound, addressing oxygen deprivation during transport with the OxyVita organ storage device. Enhanced with sugars and amino acids, HBOC creates an extracellular storage solution that maintains high oxygen delivery and metabolism ex vivo, offering greater clinical value than current practices.

Methods
Current market organ preservation solutions rely on dissolved oxygen, lacking active transport, which leads to ischemic necrosis and ROS build-up. Over 24-48 hours, control kidneys will be submerged in the University of Wisconsin (UW) solution, while study kidneys will be submerged and perfused with OxyVita. The NextGen LOGIQ e ultrasound system will be used to screen for healthy kidneys at removal and guide fine-needle biopsies every two hours. The Fine Needle Recognition Mode software allows for precise sectioning from the renal cortex, generating accurate data on tissue necrosis. Additionally, ultrasound-guided fluid collection will provide insights into critical metabolites. Post-experiment, periodic ultrasound assessments will monitor the transplanted kidney’s condition. The methodology incorporates color-flow Doppler and contrast-enhanced ultrasound for detailed structural and functional assessments, delineating perfusion patterns, detecting structural aberrations, and preserving renal echogenicity and corticomedullary differentiation, providing a reliable basis for clinical application.

Results
Preliminary research shows OXYVITA optimizing its storage solution, currently aiming to reach a storage time between 24-48 hours. Preliminary studies conducted at the UWM School of Medicine in Olsztyn, Poland have evaluated the role of OxyVita as a component of an organ storage solution in the preservation of renal tissue. Results demonstrated that more than 20% greater preservation of renal structure using OxyVita solution compared to control solution.

Conclusion
This study aims to confirm that the OxyVita solution deters pathophysiological processes. Data from renal tissue histology and spectrophotometry will be enhanced by high-quality imaging and contrast signals from the NextGen LOGIQ e system, strengthening the histopathological and biochemical findings. Leveraging advanced ultrasound technology, our investigation spans diverse dimensions, including assessing organ morphometrics, delineating architectural pathologies, understanding perfusion dynamics, and providing precise visualizations crucial for comprehensive research analyses to unravel rejection mechanisms within the application of the OxyVita product. Ultimately, our goal is to extend the shelf-life of kidneys to increase their transplantation viability for a broader patient population.

Utilizing Advanced Ultrasound Technology to Optimize OxyVita for Enhanced Preservation and Extended Viability of Kidney Transplants During Organ Transportation

Background
Chronic Traumatic Encephalopathy (CTE) is a progressive neurodegenerative disease associated with repetitive head trauma, predominantly affecting contact sports athletes and military personnel. Given the high prevalence of traumatic brain injuries (TBI) managed by neurosurgeons, it is crucial to understand CTE's pathophysiology, clinical presentation, and management strategies to enhance patient outcomes.
Methods
A systematic review and meta-analysis were conducted following PRISMA guidelines.
Searches were performed in PubMed, Cochrane Library, Embase, and Google Scholar for studies published from January 2010 to May 2024. Inclusion criteria encompassed studies on CTE epidemiology, pathophysiology, clinical presentation, diagnostics, and therapeutics. Data extraction and quality assessment were conducted independently by two reviewers, with discrepancies resolved by a third reviewer.

Results
Fourteen studies met the inclusion criteria, totaling 2729 observations and 799 events of CTE. The pooled proportion of CTE cases was 72.82% (95% CI: 48.17% to 88.53%) using a random effects model, with substantial heterogeneity (I2 = 98.6%). Subgroup analysis indicated high pooled proportions among athletes (71.43%) and military personnel (74.29%). Sensitivity analysis confirmed the robustness of the findings.
The pathophysiology of CTE involves the accumulation of hyperphosphorylated tau
protein and chronic neuroinflammation, leading to significant neuronal damage.
Clinically, CTE presents with cognitive impairment, mood disorders, and behavioral
changes, complicating its diagnosis due to overlapping symptoms with other
neurodegenerative diseases. Current treatments focus on symptomatic management, with emerging therapies targeting tau pathology and neuroinflammation showing promise.

Conclusion
This meta-analysis underscores the significant prevalence of CTE among individuals
exposed to repetitive head trauma, highlighting the need for standardized diagnostic
criteria and personalized management approaches. Neurosurgeons are pivotal in
advancing diagnostic protocols and therapeutic strategies to improve outcomes for
patients with CTE. Further research is needed to enhance understanding and
management of CTE, ultimately benefiting the broader TBI patient population frequently
encountered in neurosurgical

Chronic Traumatic Encephalopathy in Neurosurgical Practice: Insights from a Systematic Review and Meta-Analysis

Introduction: Proximal junctional kyphosis (PJK) is a common complication following correction of adult spinal deformity (ASD) at the transition of fused and mobile motion segments. PJF represents PJK with vertebral fracture, soft-tissue disruption, and/or screw pullout at the upper instrumented vertebra (UIV) accompanied with neurological deficit. Coronal decompensation following long-segment fusion may contribute to the development of proximal junctional pathology. This study reports on the natural history of coronal imbalance in ASD patients that develop PJF after fusion of the thoracolumbar spine to the pelvis. 
Methods: A single-institution retrospective review was performed for 1180 ASD patients who underwent posterior instrumented fusion to the pelvis (2009-2021). Patients that developed PJF were grouped by the UIV: upper thoracic (UT, T2-T6, 10 patients), lower thoracic (LT, T8-T11, 35 patients), or lumbar spine (L, L1-L3, 8 patients). Radiographic parameters, including the major scoliotic curve (MSC), coronal and sagittal proximal junctional angle (cPJA/sPJA), and the coronal and sagittal C7 vertical angles (CVA/SVA), were recorded before primary surgery, before revision surgery for failure, and at both 6-week and final follow-up following revision. 
Results: From 1180 ASD patients, 54 (4.6%) developed PJF (59% female, mean age 65.0 ± 6.8 and BMI 30.3 ± 5.9). Mean follow-up after revision was 3.1 ± 2.7 years. The ΔMSC (UT –17.6 ± 24.7°, LT –11.5 ± 15.97°, L –5.7 ± 7.6°) was calculated as the difference in MSC before revision surgery and before primary surgery. The mean ΔcPJA (UT 0.5 ± 3.6°, LT 0.6 ± 24.7°, L 2.5 ± 8.1°), ΔsPJA (UT: 19.1 ± 11.0°, LT: 14.8° ± 4.0°, L: 16.0° ± 9.0°), ΔCVA (UT: -13.6 ± 35.5 mm, LT –8.1 ± 21.1 mm, L 3.3 ± 29.4 mm), and ΔSVA (UT: -42.8 ± 86.8 mm, LT: 15.9 ± 38.4 mm, L: 48.6 ± 58.5 mm) were also calculated in that manner. 
Conclusion: Proximal junctional pathology presents differently radiographically following PJF after instrumented fusion from the UT, LT, and L spine. In this study, patients with a UIV in the L spine develop more coronal tilt and sagittal imbalance after PJF than patients with an UIV in the UT and LT spine.

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Young-onset Colorectal with Signet Ring Cell Morphology; Clinicopathological Analysis and Patterns of Metastases in US Population

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