Maternal, obstetrical, and neonatal outcomes in celiac disease.

OBJECTIVES: Some studies have suggested a link between celiac disease (CD) and adverse maternal, obstetrical, and neonatal outcomes. Using a large database, we evaluated the effect of CD on pregnancy outcomes. METHODS: We conducted a retrospective cohort study using the National Inpatient Sample (NIS) of all deliveries from 2015 to 2019 in the United States. Using ICD-10 codes, we identified pregnant patients who had CD and those who did not. A multivariate logistic regression was used to generate odds ratios (ORs) with 95% confidence intervals (CIs) for maternal, obstetrical, and neonatal outcomes. RESULTS: Of 12,039,222 deliveries between 2015 and 2019, there were 10,555 births in women with CD. Pregnant women with CD were more likely to be white and older compared to those without CD. Pregnant women with CD were significantly more likely to carry a diagnosis of gestational hypertension (OR 1.26; 95% CI 1.04-1.52), preeclampsia (1.28; 1.08-1.53), and severe preeclampsia (1.62; 1.25-2.09). They were less likely to have a full-term uncomplicated delivery (OR 0.11; 95% CI, 0.05-0.20), while being more likely to require device-assisted delivery (1.25; 1.04-1.50) and sustain 3rd or 4th degree vaginal lacerations (1.56; 1.21-2.02). Babies of pregnant women with CD were more likely to be small for gestational age (SGA) (OR 1.29; 95% CI 1.03-1.61). CONCLUSIONS: CD in pregnancy appears to be associated with increased adverse maternal, obstetrical, and neonatal outcomes. Clinicians should discuss these increased risks with CD patients who are planning to conceive.

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases.

Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35-3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95-5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.

Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events.

BACKGROUND: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. METHODS: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. RESULTS: We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). CONCLUSION: Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).

Postoperative Apical Ballooning Syndrome Following Orthotopic Liver Transplantation.

As the mainstay of therapy for end-stage liver disease (ESLD), orthotopic liver transplantation (OLT) has complex effects on multiple organ systems. We present a representative case of acute heart failure with apical ballooning syndrome following OLT and review its mechanisms. Recognition of this and other potential cardiovascular and hemodynamic complications of OLT are essential to periprocedural anesthesia management. Once an acute phase of the condition is stabilized, conservative treatment and resolution of physical or emotional stressors usually allow for rapid resolution of symptoms, typically recovering systolic ventricular function within one to three weeks.

Multiple high-grade and rare immune-related adverse events in a colon cancer patient with genomic and cytokine profiling.

We report a case of multiple high-grade and rare immune-related adverse events (irAEs) in a patient with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A middle-aged MSI-H mCRC patient with metastases to the lungs and lymph nodes received several lines of chemotherapy and immunotherapy and developed five different high-grade irAEs during immunotherapy, including lymphadenitis, pneumonitis, hypophysitis, thyroiditis and transverse myelitis. Genomic profiling revealed high tumor mutational burden of 43 Muts/Mb. Cytokine profiling showed a threefold increase in MMP-9 shortly prior to the onset of lymphadenitis and a fourfold increase of Ang-1 1 week after the resolution of lymphadenitis. Further studies are warranted to investigate the association of MSI-H mCRC with irAEs and the role of cytokines in predicting irAEs.

Immune-related adverse events (irAEs) are a potential side effect of taking immunotherapy treatment for cancer. We report a case of a patient with a highly mutated form of metastatic colon cancer who developed five unique and severe irAEs while receiving immunotherapy. The patient developed inflammation of the lymph nodes, lungs, pituitary gland, thyroid and spinal cord. Genetic testing showed that the tumor was highly mutated (43 Muts/Mb). Analysis of cell signaling proteins called cytokines revealed that MMP-9 sharply increased before the onset of lymphadenitis and Ang-1 sharply increased after its resolution. Further research is needed to understand the relationship between highly mutated colon cancer and irAEs as well as the role of cytokines in predicting the onset and resolution of irAEs.

The clinical potential of circulating immune cell counts in primary gastric lymphoma.

BACKGROUND: High neutrophil-lymphocyte ratio (NLR) is linked to poor overall survival (OS) in gastrointestinal tract cancers. This study explores the clinical value of NLR, in addition to absolute lymphocyte count (ALC) and other hematologic parameters in association with distant metastases and OS in primary gastric lymphoma (PGL) patients. METHODS: Clinical data of 139 PGL patients who received treatment at King Hussein Cancer Center (KHCC), Amman-Jordan were retrospectively evaluated. Using data from complete blood count (CBC) tests, the following hematologic parameters: absolute neutrophil count (ANC), ALC, absolute eosinophil count (AEC), absolute monocyte count (AMC), NLR, platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR) were assessed in association with the following clinical outcomes: presence or absence of baseline distant metastases and OS. We conducted univariate and multivariate analyses assessing the various hematologic parameters in association with distant metastases. RESULTS: Univariate and multivariate analyses indicated that patients with an elevated NLR (>3.14) displayed more baseline distant metastases compared to patients with a low NLR (≤3.14), (P value: 0.02 and 0.018, respectively). High baseline ALC (>1,819/µL) was associated with lower baseline distant metastases (P value: 0.04). In the OS analysis, high baseline ANC (>5,100/µL), NLR (>2.75), and PLR (>0.16) were associated with poor OS, (P value: 0.027, 0.016, and 0.011 respectively). CONCLUSIONS: High NLR and ALC were associated with baseline distant metastases. High baseline ANC, NLR, and PLR were associated with poor OS. Hematologic parameters might be potentially helpful in assessing and correlating NLR with the response success to treatment in PGL.

Early 3+3 Trial Dose-Escalation Phase I Clinical Trial Design and Suitability for Immune Checkpoint Inhibitors.

PURPOSE: Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation. EXPERIMENTAL DESIGN: We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3-5 adverse events (G3-5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models. RESULTS: A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3-5 AEs was 34% with a significant 27% reduced risk in lower doses (P = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3-5 AEs was 20.1% which was lower in non-small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (P ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose-response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3-5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (P = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (P = 0.01), a relationship that was not observed in NSCLC. CONCLUSIONS: Our analysis shows a lack of consistent dose-toxicity or dose-response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.

Hematological Indices of Distant Metastases and Prognostic Nomogram in Gastro-Pancreatic and Biliary Tract Cancers.

PURPOSE: The predictive value of inflammatory parameters as indicators of poor overall survival (OS) has been well studied in various tumors. This study aimed to explore the association of neutrophil-lymphocyte ratio (NLR), among other parameters in upper gastro-intestinal tract tumors with distant metastases and OS. PATIENTS AND METHODS: Retrospective analysis was done for 945 patients (males n= 539, 57.0%) with a median of 57 years (range 19-90 years) treated at King Hussein Cancer Center (KHCC) for gastric (n=501), pancreatic (n=355), and biliary (n=89) carcinoma. NLR, and other parameters were calculated at primary presentation, and the association between the parameters with baseline distant metastases and OS was studied. The optimal cutoff value of NLR was based on receiver operating characteristic curve (ROC) analysis. A prognostic nomogram was then constructed to explore how accurately the OS can be predicted. RESULTS: Patients with high baseline NLR (>3.2) had more distant metastases on presentation than patients with low NLR (≤3.2), (p-value <0.001). Age older than 57 years was associated with poor median OS (8.7 versus 10.6 months, p-value= 0.04). In addition, the location of the tumor as stomach versus biliary tract (Odds Ratio 0.443 95% CI 0.281-0.699), and pancreas versus biliary tract (Odds Ratio 1.193, 95% CI 0.749-1.902, p-value <0.001) proved to be significant. In multivariate analysis, age older than 57 years (p-value =0.0033, HR 0.792, 95% CI 0.678-0.925), location of the tumor (p-value <0.0001), presence of distant metastasis (p-value <0.0001, HR 2.063, 95% CI 1.760-2.419), and NLR (p-value <0.0001, HR 1.045, 95% CI 1.028-1.062) remained significant. Nomogram confirmed the significance of NLR as an independent prognostic factor for OS (HR = 1.62, 95% CI: 1.31-2.01, p-value <0.0001). CONCLUSION: Our results suggested that high baseline inflammatory markers are associated with distant metastases and poor OS. The utilization of this association in management of cancer patients still warrants further investigation.

Novel platform leveraging electronic medical record (EMR) to triage patients admitted with high-grade immune-related adverse events (irAEs) to the immune-toxicity (ITOX) service.

BACKGROUND: The incidence of high-grade immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) is increasing due to the rapid expansion of indications for their use. There is an urgent need for a feasible approach of identifying patients with high-grade irAEs to ensure early detection and proper management of this unique set of toxicities. METHODS: We established one of the first inpatient services that are specifically devoted to mitigating irAEs. The service uses a multidisciplinary approach with consulting service from experts in managing irAEs. We are leveraging the electronic medical record (EMR) to triage patients who are admitted to the hospital and have received or are currently receiving ICIs. A list of patients with ICI exposure is generated daily by EMR and then curated manually to identify patients with potential irAEs. RESULTS: A total of 129 patients with high-grade irAEs were admitted between June 2018 and June 2019. The most common irAEs were colitis (32%), pneumonitis (30%), and hepatitis (14%). Eighty five per cent of the patients had grade 3 irAEs and 15% had grade 4-5. About half of the patients had received ICI monotherapy; 30% had received combination of ICIs and non-ICIs; and 19% had received a combination of ICIs. Only 9% of patients had steroid-refractory irAEs requiring other immunosuppressive agents. The average length of stay for irAE-related admission was 11 days with a readmission rate due to recurrent irAEs of 26% within a year. CONCLUSION: We demonstrated the feasibility of using the EMR to accurately triage patients with suspected irAEs to a dedicated immune-toxicity service. Our model is adaptable in major academic centers and could have a major impact on quality of care and future clinical research addressing irAEs.

The clinical value of peripheral immune cell counts in pancreatic cancer.

BACKGROUND: Elevated neutrophil-lymphocyte ratio (NLR) is linked to poor overall survival (OS) in pancreatic cancer. We aim to investigate the association of the various hematologic markers, in particular NLR among others, with distant metastases, a common feature in pancreatic cancer. METHODS: Clinical data from 355 pancreatic cancer patients managed at King Hussein Cancer Center (Amman-Jordan) have been reviewed. We examined the relationship between absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute eosinophilic count (AEC), absolute monocytic count (AMC), NLR, monocyte to lymphocyte ratio (MLR) and platelet to lymphocyte ratio (PLR) with the presence of baseline distant metastases and OS. Receiver Operating Characteristic (ROC) curve analysis was plotted to identify the NLR optimum cutoff value indicative of its association with distant metastases. RESULTS: On univariate and multivariate analyses patients whom on presentation had high NLR (≥3.3) showed more baseline distant metastases compared to patients with low NLR (<3.3), (p-value: <0.0001 and <0.0001, respectively). Patients with high baseline ANC (≥5500/µL), AMC (≥600/µL), MLR (≥0.3) had more baseline distant metastases in comparison to patients with lower values (p-value: 0.02, 0.001, and <0.0001, respectively). High ANC, NLR, MLR, and PLR and low ALC were associated with poorer OS, (p-value: <0.0001, <0.0001, <0.0001, 0.04, and 0.01, respectively). CONCLUSION: This study presents additional evidence of the association of some of the hematologic markers; in particular ANC, NLR, AMC, and MLR, with baseline distant metastases and poor outcome in pancreatic cancer. Whether these immune phenomena can help in identifying patients at higher risk for the subsequent development of distant metastases is unknown.

Frequency of Mismatch Repair Protein (MMRP) Deficiency among Young Jordanians Diagnosed with Colorectal Carcinoma (CRC).

PURPOSE: Microsatellite instability (MSI) caused by mismatch repair protein (MMRP) deficiency is detected in 15% of sporadic colorectal cancers (CRCs). Our aim is to investigate the frequency of MMRP deficiency in young CRC patients, using immunohistochemical analysis. METHODS: This study targeted cases of CRC at King Hussein Cancer Center from 2004 until 2012 in patients 45 years of age or younger at the time of diagnosis. Clinicopathological data was obtained from 155 patients' records. Immunohistochemistry for MLH1, MSH2, PMS2, and MSH6 proteins was performed on paraffin-embedded tissue containing carcinoma. RESULTS: The median age of patient at diagnosis was 38 years. A total of 29 (19%) cases showed deficient MMRP(dMMRP)expression. Loss of expression of PMS2 was seen in 17 cases, 12 cases of which showed loss of MLH1 expression. Loss of expression of MSH6 was seen in 10 cases, 9 of which showed loss of MSH2 expression. One case (3.4%) showed loss of all four MMR proteins, and another case (3.4%) showed loss of PMS2/MLH1 and MSH6. There was a significant association between abnormal MMR protein expression and tumor location proximal to splenic flexure (p value 0.000), pathologic features suggestive of microsatellite instability (p value 0.000), P53 negativity (p value 0.000), and stage (p value 0.02). Patients with dMMRP CRC appeared to have a significantly better overall survival compared to patients with proficient MMRP(pMMRP)(p value 0.02). Loss of MSH2/MSH6 was significantly associated with positive family history of cancer (p value = 0.020). CONCLUSIONS: The prevalence of dMMRP tumors in this age group appears to be similar to international literature. dMMRP tumors tends to be associated with earlier stages and better outcomes compared to pMMRP cases. dMMRP can serve as a biomarker for better prognosis. These results are of value in directing the clinical management of young patients with CRC.

Hematologic markers of distant metastases in gastric cancer.

BACKGROUND: High neutrophil-lymphocyte ratio (NLR) is associated with poor overall survival (OS) in gastric cancer. This study evaluates whether NLR, in addition to other parameters including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute eosinophil count (AEC), absolute monocyte count (AMC), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) are associated with distant metastases, a common and poor prognostic feature of gastric cancer. METHODS: Clinical data from 502 gastric cancer patients treated at King Hussein Cancer Center (Amman, Jordan) have been retrospectively reviewed. We examined the association between ANC, ALC, AEC, AMC, NLR, MLR and PLR with the baseline distant metastases and OS. Receiver operating characteristic (ROC) curve analysis was utilized to determine the optimal NLR cutoff value for association with distant metastases. RESULTS: Univariate and multivariate analyses showed that patients with high baseline NLR (≥3.9) had more distant metastases on presentation than patients with low NLR (<3.9), (P value: 0.0001 and 0.0005, respectively). Furthermore, patients with high baseline ANC (≥6,015/µL), AEC (≥215/µL), PLR (≥0.15) had more distant metastases in comparison to patients with low baseline ANC (<6,015/µL), AEC (<215/µL), PLR (<0.15) (P value: 0.024, 0.001, and 0.001, respectively). High ANC, NLR, MLR and PLR are associated with poor OS (P value: 0.046, 0.0003, 0.027, and <0.0001, respectively). CONCLUSIONS: High ANC, AEC, NLR, and PLR are associated with distant metastases on presentation in gastric cancer. In the era of cancer immunotherapy, whether these immune phenomena predict the response of gastric cancer to immunotherapy is unknown.

Cancer Immunotherapy: An Updated Overview of Current Strategies and Therapeutic Agents.

After several years of discouraging results, immunotherapy finally becomes a powerful, clinically valid and approved treatment for numerous types of cancer. Immunotherapy involves treatment approaches that work in various ways; some boost the body's immune system while others help guide and direct the immune cells to attack cancer cells specifically. In this review article, we summarize the current cancer immunotherapy strategies; immune checkpoint blockade, adoptive cellular therapy, cancer vaccines, oncolytic viruses, and the monoclonal antibodies and discuss the recent progress and future trends of the combination therapies.

Hematologic Markers of Lung Metastasis in Stage IV Colorectal Cancer.

BACKGROUND: Many studies showed an association between absolute neutrophil count (ANC), absolute monocyte count (AMC), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) with poor overall survival (OS) in patients with cancer. However, only a few studies were conducted to further investigate this association in colorectal cancer (CRC). METHODS: Clinical data from 299 stage IV CRC patients treated at King Hussein Cancer Center from 2004 to 2012 have been retrospectively reviewed. We examined the association between ANC, AMC, MLR, PLR, and NLR with lung metastasis in stage IV CRC. Receiver Operating Characteristic (ROC) curve analysis was operated to determine the optimal NLR cutoff value. Univariate and multivariate analysis were performed. RESULTS: The ROC value of 3.4 was determined as the cutoff value of NLR to study the association. Univariate and multivariate analysis showed that patients with high baseline NLR (≥ 3.4) had more baseline lung metastasis than patients with low NLR (< 3.4) (p = 0.0001, p = 0.0151, respectively). Also, baseline NLR correlated significantly with the presence of lymphovascular invasion (p = 0.001). In patients with no baseline lung metastasis, high post-treatment NLR was associated with consequent development of lung metastasis (p = 0.0227). Other markers including ANC, AMC, MLR, and PLR were significantly associated with lung metastasis at time of diagnosis (p = 0.0006, p = 0.0006, p = 0.0187, and p = 0.001, respectively). CONCLUSION: Results are suggesting that different hematologic markers obtained from a cheap test (CBC) could potentially be used to predict the likelihood of lung metastasis in stage IV CRC. Prospective studies are needed to further assess the immune cells' role in tumor metastasis promotion.