Ileo-colonic lymphoma: presentation, diagnosis, and management.

PURPOSE OF REVIEW: The gut-associated lymphoid tissue (GALT), the bulk of which is located in the ileo-colonic region comprises the lymphoid cells of the gastrointestinal tract and confers specific immunological responses. Repetitive antigenic stimulation of these cells predispose to a monoclonal proliferation of this tissue and the eventual development of lymphoma. The gastrointestinal tract is the most commonly involved site of extranodal lymphomas. This review will focus primarily on lymphomas of the ileo-colonic region (defined as the terminal ileum, the colon, and the rectum). We will discuss the epidemiology, pathogenesis, and presentation as well as current practices in diagnosis and management. RECENT FINDINGS: Despite the majority of the GALT to be located in the ileo-colonic region of the gut, the lymphomas in this location are relatively rare. However, the overall annual incidence of ileo-colonic lymphomas is steadily increasing. This entity has a varied spectrum of clinical presentations. Ileo-colonoscopy with adequate targeted biopsies can serve as a gold standard for definitive diagnosis. Ileo-colonic lymphomas may be managed with chemotherapy alone while surgery is reserved for highly aggressive tumors or clinical emergencies. Radiation is not a preferred adjuvant treatment for lymphomas in this location of the gut. Adequate endoscopic surveillance measures and tools to potentially prevent recurrence and improve the overall prognosis of this disease are lacking. SUMMARY: Ileo-colonic lymphomas are rare and can present with varied symptoms and signs. Endoscopy with adequate sampling can aid in making a definitive diagnosis. Chemotherapy can be highly effective in management while surgery is indicated for emergency presentations. Adequate endoscopic surveillance tools are lacking, yet imperative to prevent recurrence and improve prognosis.

Clinicopathologic Features, Treatment Response, and Outcomes of Immune Checkpoint Inhibitor-Related Esophagitis.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have provided practice-changing outcomes in treating many cancers, ICI-related gastrointestinal toxicity can limit their use. Upper gastrointestinal toxicity is not common nor as well described as lower gastrointestinal toxicity. We aimed to characterize the clinical presentation, endoscopic and histologic features, treatment response, and outcomes of ICI-related esophagitis. METHODS: We retrospectively studied patients at The University of Texas MD Anderson Cancer Center in whom esophagitis developed after receiving ICIs from June 2011 through January 2020. We included patients with endoscopic evidence of esophagitis and excluded those with other obvious causes of esophagitis. A chi-square test was used to assess associations between categorical variables. The Mann-Whitney U test was used to compare differences between continuous variables. RESULTS: Of 657 consecutive patients who underwent esophagogastroduodenoscopy (EGD) during or within 6 months of completing ICI-based therapy, 21 (3%) had esophagitis deemed to be from ICIs. Of these patients, 1 (5%) received an inhibitor of CTLA-4 alone, 15 (71%) received anti-PD-1 or PD-L1 monotherapy, and 5 (24%) received a combination of these. Median time from ICI initiation to onset of esophagitis was 4 months. Upon evaluation with EGD, only 3 patients (14%) had isolated esophageal involvement; 18 (86%) had concurrent involvement of the stomach, duodenum, or both. Most patients (67%) were treated with proton pump inhibitors, and 4 (19%) received steroids (prednisone or budesonide). The mortality rate was 38% (median follow-up, 15 months). CONCLUSIONS: Esophagitis associated with ICI use is rare. The diagnosis is one of exclusion because its clinical presentation appears similar to that of inflammation resulting from other causes. It often occurs in conjunction with other upper gastrointestinal toxicity. Symptoms are mild and respond well to nonimmunosuppressive treatment, with few severe complications.

Clinical Characteristics and Outcomes of Oral Mucositis Associated With Immune Checkpoint Inhibitors in Patients With Cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy predisposes patients to immune-related adverse events (irAEs). Data are limited regarding the incidence, management, and outcomes of one such irAE: mucositis. In this study, we evaluated the clinical characteristics, disease course, treatment, and outcomes of ICI-mediated mucositis. METHODS: This was a retrospective, single-center study of patients who received ICI therapy and developed oral mucositis at The University of Texas MD Anderson Cancer Center from January 2009 to September 2019. Inclusion criteria included age ≥18 years, a diagnosis of oral mucositis and/or stomatitis based on ICD-9 and ICD-10 codes, and therapy using CTLA-4 or PD-1/L1 inhibitors alone or combined with other agents. RESULTS: We identified 152 patients with a mean age of 60 years, 51% of whom were men. Of the sample patients, 73% had stage IV cancer, with melanoma the most common (28%). Median time from ICI initiation to mucositis was 91 days. The most common clinical presentation of mucositis was odynophagia and/or oral pain (89%), 91% developed CTCAE grade 1-2 mucositis, and 78% received anti-PD-1/L1 monotherapy. Compared with anti-PD-1/L1-based therapy, anti-CTLA-4-based therapy was more frequently associated with earlier onset of mucositis (73 vs 96 days; P=.077) and a lower rate of symptom resolution (76% vs 92%; P=.029); 24% of patients required immunosuppressive therapy, which was associated with longer symptom duration (84 vs 34 days; P=.002) and higher mucositis recurrence rate (61% vs 32%; P=.006). ICI interruption was associated with worse survival (P=.037). Mucositis recurrence, immunosuppressant use, and presence of other irAEs did not affect survival. CONCLUSIONS: For ICI-mediated mucositis, a diagnosis of exclusion has not been well recognized and is understudied. Although the clinical symptoms of mucositis are mostly mild, approximately 25% of patients require immunosuppression. Mucositis recurrence can occur in approximately 39% patients. Our results showed that ICI interruption compromises overall survival.

Endoscopic vacuum therapy for treatment of spontaneous and iatrogenic upper gastrointestinal defects.

BACKGROUND/AIMS: Endoscopic vacuum therapy (EVT) can heal a variety of defects within the gastrointestinal (GI) tract via applying negative pressure, which reduces the defect size, aspirates the infected fluid, and promotes granulation tissue. Here we present our experience with EVT as it relates to both spontaneous and iatrogenic upper GI tract perforations, leaks, and fistulas. METHODS: This retrospective study was conducted at four large hospital centers. All patients who underwent EVT between June 2018 and March 2021 were included. Data on multiple variables were collected, including demographics, defect size and location, number and intervals of EVT exchanges, technical success, and hospital length of stay. Student t-test and the chi-squared test were used to analyze the data. RESULTS: Twenty patients underwent EVT. The most common defect cause was spontaneous esophageal perforation (50%). The most common defect location was the distal esophagus (55%). The success rate was 80%. Seven patients were treated with EVT as the primary closure method. The mean number of exchanges was five with a mean interval of 4.3 days between exchanges. The mean length of hospital stay was 55.8 days. CONCLUSION: EVT is a safe and effective initial management option for esophageal leaks and perforations.

Diarrhea and colitis related to immune checkpoint inhibitor and BRAF/MEK inhibitor therapy.

Background: Immune checkpoint inhibitor (ICI) therapy can be complicated by gastrointestinal adverse events (AEs). Similarly, gastrointestinal AEs have been reported with the use of serine/threonine-protein kinase B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitor therapy. We investigated the characteristics and management of gastrointestinal AEs related to sequential ICI and BRAF/MEK inhibitor therapy. Methods: We identified 255 adult cancer patients who received both BRAF/MEK inhibitor therapy and ICI therapy between 2014 and 2021. Thirty-two eligible patients had gastrointestinal AEs after receiving both therapies and were categorized based on the order of their administration. Their clinical characteristics, evaluation, treatment and outcomes were compared. Results: Of the 32 eligible patients, 18 (56.3%) received ICI therapy followed by BRAF/MEK inhibitors (early ICI group), and 14 (44.8%) received BRAF/MEK inhibitor therapy followed by ICI (early BRAF/MEK inhibitor group). Compared with the early BRAF/MEK inhibitor group, the early ICI group had higher rates of grade 3-4 diarrhea (50.0% vs. 14.3%, P=0.047) and grade 3-4 colitis (38.9% vs. 0%, P=0.010). The early ICI group had a later onset of colitis (347.5 vs. 84.5 days, P=0.011) and a higher rate of hospitalization at initial colitis presentation (100% vs. 71.4%, P=0.028). Patients in the early ICI group were more likely to have diarrhea or colitis recurrence (69.2% vs. 9.1%, P=0.019) and re-hospitalization for colitis (38.9% vs. 0%, P=0.010). Conclusion: The sequential exposure of BRAF/MEK therapy after ICI may contribute to a more aggressive clinical profile of gastrointestinal toxicities that may warrant a more aggressive management strategy.

Characteristics, treatment, and outcome of diverticulitis after immune checkpoint inhibitor treatment in patients with malignancies.

PURPOSE: Immune checkpoint inhibitors (ICIs) are efficacious for treating various malignancies. In addition to immune-related adverse events (irAEs), growing evidence suggests that ICIs might also be associated with diverticulitis. We aim to assess the clinical presentations and management of colonic diverticulitis among cancer patients after ICI treatment. METHODS: A retrospective study was conducted on ICI-treated adult cancer patients between 01/2010 and 06/2020. Patients were grouped based on when diverticulitis developed relative to ICI treatment, either before (controls) or after (cases). Patient clinical characters, treatment, and outcomes were compared between both groups. RESULTS: 77 eligible patients were included: 63 patients developed diverticulitis after ICI exposure (46 had initial episode after ICI exposure, 17 had a history of diverticulitis prior then recurred after ICI exposure), and 14 had diverticulitis before ICI exposure. Diverticulitis occurred after a median of 129 days after ICI initiation. Clinical characteristics overlapped with traditional diverticulitis. 93% of patients had symptom resolution after treatment, while 23.8% experienced complications. These patients exhibited higher rates of hospitalization (87% vs 48%, P = 0.015) and surgery/interventional radiology procedures (27% vs 0, P = 0.002), and worse overall survival (P = 0.022). History of diverticulitis was not associated with a more severe disease course. Immunosuppressants (e.g., corticosteroids) were rarely required unless for concurrent ICI-mediated colitis. CONCLUSION: Colonic diverticulitis can occur after ICI therapy at very low incidence (0.5%). Its clinical presentation, evaluation, and management are similar to traditional diverticulitis, but associated with higher complication rates requiring surgical intervention and has lower overall survival.

Esophageal Perforation Successfully Treated With EVT.

Esophageal perforation is rare and carries high morbidity and mortality. A high degree of suspicion is needed for timely diagnosis and treatment. A 54-year-old man presented with fever and confusion. Imaging revealed air in the hepatic inferior vena cava and concern for a fistula between the distal esophagus and the inferior vena cava. An upper endoscopic evaluation revealed a dental floss pick penetrating the distal esophagus. The foreign body was removed, and endoluminal vacuum therapy was used to close the perforation. Endoluminal vacuum therapy is an emerging therapy to treat full-thickness gastrointestinal injuries.

Clostridioides difficile infection in cancer patients receiving immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but are associated with immune-mediated diarrhea and colitis (IMDC). Clostridioides difficile infection (CDI) can cause infectious diarrhea with overlapping symptoms. Thus, we sought to elucidate the characteristics of CDI in patients treated with ICI, in the context of IMDC. Methods: We conducted a retrospective, single-center study of adult cancer patients (N=421) with ICI exposure from 2015-2020 and a positive stool nucleic acid amplification test and/or enzyme immunoassay for CDI. Baseline characteristics, treatments, and outcomes were compared between patients with and without concurrent IMDC. Results: Forty-one eligible patients were included, 27 with concurrent IMDC and 14 without. Twenty-seven patients were taking programmed death-1 or its ligand inhibitors and 14 were taking cytotoxic T-lymphocyte-associated antigen 4 inhibitors. Patients with concurrent CDI and IMDC had a longer symptom duration (20 vs. 5 days, P=0.003) and a higher rate of grade 3-4 diarrhea (41% vs. 7%, P=0.033). Among patients with concurrent IMDC, preceding antibiotics (P=0.050) and proton pump inhibitors (PPI) (P=0.038) were used more frequently among individuals who developed CDI after immunosuppressant exposure. Thirty-eight patients received antibiotics for CDI, while 5 required fecal microbiota transplantation for concurrent CDI & IMDC. Conclusions: CDI is common in ICI-treated cancer patients, especially those with IMDC requiring immunosuppressants. Antibiotics did not alter the need for immunosuppressants in those with concurrent IMDC. Use of PPI and antibiotics while receiving immunosuppressants for IMDC was associated with a greater risk of CDI. Further large-scale studies are warranted to clarify the role of CDI, antibiotics and immunosuppression treatment in IMDC patients.

Cytomegalovirus infection among patients with cancer receiving immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs), used for the treatment of solid and hematologic malignancies, come with the risk of immune-related adverse events (irAEs). Opportunistic infections (e.g., cytomegalovirus [CMV]) mimic irAE symptoms and are understudied in this population. We aimed to describe the incidence, characteristics, treatment and outcomes of CMV infection in ICI-treated patients. Methods: We conducted a single-center retrospective review of all adult patients who were CMV-positive after ICI therapy between 06/2011 and 05/2020. A CMV-positive non-ICI cohort was matched to the ICI group based on age, sex and cancer type. Variables of interest were collected through electronic medical records. Results: The study population comprised 192 patients overall. CMV infection incidence was 7.7% in ICI patients and 12.9% in non-ICI patients (P<0.001). Rates of infection clearance (83% vs. 50%, P=0.002) and recurrence (20% vs. 3%, P=0.037) were higher in ICI patients with hematologic vs. solid tumors, despite similar treatments. All-cause mortality was higher in solid rather than hematologic malignancies in ICI patients (83% vs. 54%, P=0.009); CMV-related mortality was low (3-4%) in both groups. Conclusions: CMV infection occurred in about 7.7% of the ICI-treated cancer population. The infection can be disseminated in multiple organs and has a wide spectrum of clinical symptoms. ICI-treated patients with a hematologic malignancy had higher viral clearance and recurrence than those with solid tumors. In this study, CMV itself did not lead to high mortality in cancer patients. Further study is needed to investigate the role of CMV infection in patients' irAEs and cancer outcome.