Luminal Gastrointestinal Manifestations of Cystic Fibrosis.

PURPOSE OF REVIEW: People with cystic fibrosis (CF) are living longer. General age-related and CF-specific gastrointestinal symptoms are increasingly recognized. In this article, we review the latest data on luminal gastrointestinal manifestations in CF. RECENT FINDINGS: People with CF have increased incidence of gastroesophageal reflux disease symptoms and often prescribed proton-pump inhibitors (PPI). PPI use may increase risk of pulmonary exacerbations. Evidence to support gastric fundoplication to improve pulmonary outcomes is limited. Features of intestinal dysmotility are common. There are distinct differences in the gut microbiome in the CF population which may have clinical implications. CF is a possible hereditary digestive cancer syndrome, particularly in regard to colorectal cancer (CRC) with earlier incidence of CRC and advanced colonic neoplasia. Early screening colonoscopy is warranted in the CF population. Gastrointestinal manifestations in CF are prevalent across all digestive organs. More study on the effect of interventions for symptomatic treatment and cancer screening is needed.

Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease.

Background: Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN and drug resistance, the so-called hypermetabolizers. Our aim was to identify the effect of normal-to-high TPMT activity on 6-TGN concentrations in an inflammatory bowel disease population. Methods: A retrospective chart review of patients aged ≥18 with inflammatory bowel disease, on azathioprine, with documented TPMT activity and 6-TGN concentration was performed. Correlations were evaluated via the Spearman rho correlation coefficient. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for confounders. Relationships between TPMT activity, drug dose, and 6-TGN levels were defined via average causal mediation effects. Results: One hundred patients were included. No correlation was observed between TPMT activity, azathioprine dosing, and metabolite concentrations. Overall, 39% of the cohort had a therapeutic 6-TGN level of >230 pmol/8 × 108 red blood cells (RBCs). No patient under 1 mg/kg achieved a therapeutic 6-TGN level, whereas 42% of patients taking 2.5 mg/kg did. The median 6-TGN concentration was higher for those in remission (254 pmol/8 × 108 RBCs, interquartile range: 174, 309) versus those not in remission (177 pmol/8 × 108 RBCs, interquartile range: 94.3, 287.8), though not significantly (P = 0.08). Smoking was the only clinical factor associated with 6-TGN level. On multivariate linear regression, only age, azathioprine dose, and obese body mass index were predictive of metabolite concentration. Conclusions: Variations within the normal range of TPMT activity do not affect 6-TGN concentration.

Case report of synchronous post-lung transplant colon cancers in the era of colorectal cancer screening recommendations in cystic fibrosis: screening "too early" before it's too late.

BACKGROUND: The increasing life expectancy of individuals with Cystic Fibrosis (CF) is likely to be associated with new age-related challenges, colorectal cancer (CRC) most notably; recent consensus recommendations for CRC screening published in 2018 represent an important early step in addressing the emerging awareness of CF as a gastrointestinal cancer syndrome. These recommendations, however, need to be further refined based on more systematic data. We discuss an illustrative first-ever case of synchronous CRC arising in a post-lung transplant individual with CF within the recommended surveillance interval after a well-documented prior normal colonoscopy. CASE PRESENTATION: A 51-year-old female individual with homozygous F508del CF, presents to clinic with abdominal discomfort and intermittent blood in stools. She had previously undergone bilateral lung transplantation 18 years earlier, as well as two kidney transplants related to immunosuppression-related nephrotoxicity. A diagnostic colonoscopy was performed which revealed the presence of two separate synchronous colon cancers in the cecum and transverse colon; she had undergone a colonoscopy three years prior to this exam which was structurally normal. Endoscopic quality indicators, including a good quality bowel preparation, colonoscopic withdrawal time > 12 min, and quarterly Adenoma Detection Rate (ADR) ranging from 50 to 70% for both male and female patients for the endoscopist from both colonoscopic exams, as well as secondary retrospective comparative review of the pertinent case images, diminish the risk for a "missed" cancer or advanced lesion on the index exam. These cancers did not demonstrate any immunohistochemical features suggestive of Lynch Syndrome, though the rapid progression to cancer within the surveillance interval (possibly non-polypoid in nature) is similar. This cancer presentation within the newly-established recommended colon cancer screening interval warrants concern. CONCLUSIONS: This case prompts serious discussion regarding the length of surveillance intervals in the post-transplant CF population (a population at 20-30 times greater risk for CRC compared to the general non-CF population), as well as the importance of documenting endoscopic quality benchmarks, particularly if a narrative of interval CRC development continues to develop with further prospective monitoring and multi-center experience.

Cystic Fibrosis & disorders of the large intestine: DIOS, constipation, and colorectal cancer.

Since 1966 when the Cystic Fibrosis Foundation Patient Registry (CFFPR) was founded, clinicians have witnessed significant advances in both the quality and quantity of life for patients living with Cystic Fibrosis (CF). As patients with CF live longer and fuller lives, increasing encumbrances from gastrointestinal manifestations of CF will be observed. This article serves to discuss "below the diaphragm" concerns involving the large intestine (Distal Intestinal Obstruction Syndrome, Constipation, and Colorectal Cancer). Avenues for development and implementation of clinical care protocols, particularly regarding proactive management of known associated conditions and cancer screening, will continue to be refined in the coming years. It falls to the multidisciplinary CF care team to be actively engaged in addressing these concerns effectively as priority shifts from relative acuity (typically related to early nutrition and lung function) to the travails of longevity as the CF population continues to age.

Infectious Disease Consultation for Staphylococcus aureus Bacteremia Improves Patient Management and Outcomes.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) is a common, severe infectious disease with accepted standards of care. METHODS: A retrospective cohort study of all 233 SAB cases at the Minneapolis Veterans Affairs Medical Center (MVAMC) between October 2004 and February 2008 was performed to measure the impact of Infectious Disease (ID) consultation on conformance to standards and patient outcomes. Outcomes were classified as survived without relapse, relapsed, or died without relapse. ID involvement was classified as consultation, curbside, or no involvement. RESULTS: ID involvement occurred in 179/233 cases (77%). Management conformed to accepted standards in 162/197 cases (82%) evaluable for conformance. ID involvement was associated with increased conformance in univariable analysis and multivariable analysis adjusted for propensity for ID consultation (OR 5.9, 95% CI 2.5 - 13.8). Relapse occurred in 14/156 cases (9%) in which therapy conformed to standards compared with 8/35 cases (23%) in which therapy did not conform to standards (p=0.045). Relapse was more common in older patients (OR 1.05, CI 1.01-1.09) and in cases without ID involvement (OR 3.02, CI 1.003-9.1). Death was associated with greater Charlson Index scores (OR 1.89, CI 1.4-2.5). Of 111 cases with definitely or possibly infected devices, relapse occurred in 9/92 cases (9.8%) in which the device was wholly or partially removed compared with 6/19 cases (32%) in which the device was left in place (p=0.02). CONCLUSIONS: ID involvement in SAB cases was associated with increased adherence to accepted standards and fewer relapses. ID consultation should be performed for all SAB cases.

The use of fine needle aspiration cytology for the distinction of pancreatic mucinous neoplasia.

Cytology frequently has some role in preoperatively distinguishing pancreatic mucus-producing neoplasia (intraductal papillary mucinous neoplasms [IPMNs] and mucinous cystic neoplasms [MCNs]) from other pancreatic cysts. We evaluated all cytologic specimens at our institutions from resected pancreatic cystic lesions for lesional extracellular and cellular material. Lesional extracellular material was identified in 32 of 38 of the cytologic samples from cystic pancreatic mucus-producing neoplasms (28 of 31 IPMNs and 4 of 7 MCNs). Lesional cellular material was seen in 22 of 38 cases (17 of 31 IPMNs and 5 of 7 MCNs). Lesional material was more commonly identified in higher grade and invasive lesions. Lesional extracellular material was seen in 3 of 14 samples of other pancreatic cysts, and lesional cellular material was seen in 6 of 14 cases.