Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Radiation segmentectomy of hepatic metastases with Y-90 glass microspheres.

PURPOSE: To evaluate safety and efficacy of radiation segmentectomy (RS) with 90Y glass microspheres in patients with limited metastatic liver disease not amenable to resection or percutaneous ablation. METHODS: Patients with ≤ 3 tumors treated with RS from 6/2015 to 12/2017 were included. Target tumor radiation dose was > 190 Gy based on medical internal radiation dose (MIRD) dosimetry. Tumor response, local tumor progression (LTP), LTP-free survival (LTPFS) and disease progression rate in the treated segment were defined using Choi and RECIST 1.1 criteria. Toxicities were evaluated using modified SIR criteria. RESULTS: Ten patients with 14 tumors underwent 12 RS. Median tumor size was 3 cm (range 1.4-5.6). Median follow-up was 17.8 months (range 1.6-37.3). Response rates per Choi and RECIST 1.1 criteria were 8/8 (100%) and 4/9 (44%), respectively. Overall LTP rate was 3/14 (21%) during the study period. One-, two- and three-year LTPFS was 83%, 83% and 69%, respectively. Median LTPFS was not reached. Disease progression rate in the treated segment was 6/18 (33%). Median overall survival was 41.5 months (IQR 16.7-41.5). Median delivered tumor radiation dose was 293 Gy (range 163-1303). One major complication was recorded in a patient post-Whipple procedure who suffered anaphylactic reaction to prophylactic cefotetan and liver abscess in RS region 6.5 months post-RS. All patients were alive on last follow-up. CONCLUSION: RS of ≤ 3 hepatic segments can safely provide a 2-year local tumor control rate of 83% in selected patients with limited metastatic liver disease and limited treatment options. Optimal dosimetry methodology requires further investigation.

Diagnostic and treatment challenge of unrecognized subacute bacterial endocarditis associated with ANCA-PR3 positive immunocomplex glomerulonephritis: a case report and literature review.

BACKGROUND: Diagnosis and treatment of either ANCA disease or silent infection-related glomerulonephritis is complicated and is a huge treatment challenge when overlapping clinical manifestations occur. We report a case of ANCA-PR3 glomerulonephritis, nervous system involvement, hepatosplenomegaly and clinically silent subacute infectious endocarditis. CASE PRESENTATION: A 57-year-old man with known mitral valve prolaps was admitted for unexplained renal failure with signs of nephritic syndrome, hepatosplenomegaly, sudden unilateral hearing loss, vertigo, malaise, new onset hemolytic anemia and thrombocytopenia. Immunoserology revealed positive c-anti-neutrophil cytoplasm antibody (ANCA)/anti-proteinase 3 (anti-PR3), mixed type crioglobulinemia and lowered complement fraction C3. Head MRI showed many microscopic hemorrhages. Common site of infection, as well as solid malignoma were ruled out. In accordance with clinical and laboratory findings, systemic vasculitis was assumed, although the etiology remained uncertain (ANCA-associated, cryoglobulinemic or related to unrecognized infection). After kidney biopsy, clinical signs of sepsis appeared. Blood cultures revealed Streptococcus cristatus. Echocardiography showed mitral valve endocarditis. Kidney biopsy revealed proliferative, necrotizing immunocomplex glomerulonephritis. Half a year later, following intravenous immunoglobulins, glucocorticoids, antibiotic therapy and surgical valve repair, the creatinine level decreased and c-ANCA and cryoglobulins disappeared. A second kidney biopsy revealed no residual kidney disease. Four years after treatment, the patient is stable with no symptoms or signs of vasculitis recurrence. CONCLUSIONS: Here we describe the diagnostic and treatment challenge in a patient with unrecognized subacute bacterial endocarditis associated with ANCA-PR3 immunocomplex proliferative and crescentic glomerulonephritis. In patients with ANCA-PR3 immunocomplex glomerulonephritis and other overlapping manifestations suggesting systemic disease, it is important to recognize and aggressively treat any possible coexisting bacterial endocarditis, This is the most important step for a favorable patient outcome, including complete clinical and pathohistological resolution of the glomerulonephritis.

Changes in the multidisciplinary management of rectal cancer from 2009 to 2015 and associated improvements in short-term outcomes.

AIM: Significant recent changes in management of locally advanced rectal cancer (LARC) include preoperative staging, use of extended neoadjuvant therapies and minimally invasive surgery (MIS). This study was aimed at characterizing these changes and associated short-term outcomes. METHOD: We retrospectively analysed treatment and outcome data from patients with T3/4 or N+ LARC ≤ 15 cm from the anal verge who were evaluated at a comprehensive cancer centre in 2009-2015. RESULTS: In total, 798 patients were identified and grouped into five cohorts based on treatment year: 2009-2010, 2011, 2012, 2013 and 2014-2015. Temporal changes included increased reliance on MRI staging, from 57% in 2009-2010 to 98% in 2014-2015 (P < 0.001); increased use of total neoadjuvant therapy, from 17% to 76% (P < 0.001); and increased use of MIS, from 33% to 70% (P < 0.001). Concurrently, median hospital stay decreased (from 7 to 5 days; P < 0.001), as did the rates of Grade III-V complications (from 13% to 7%; P < 0.05), surgical site infections (from 24% to 8%; P < 0.001), anastomotic leak (from 11% to 3%; P < 0.05) and positive circumferential resection margin (from 9% to 4%; P < 0.05). TNM downstaging increased from 62% to 74% (P = 0.002). CONCLUSION: Shifts toward MRI-based staging, total neoadjuvant therapy and MIS occurred between 2009 and 2015. Over the same period, treatment responses improved, and lengths of stay and the incidence of complications decreased.

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

Involvement of the helix-loop-helix protein Id-1 in the glucocorticoid regulation of tight junctions in mammary epithelial cells.

Mammary epithelial cell-cell junctions undergo morphological and structural differentiation during pregnancy and lactation, but little is known about the transcriptional regulators that are involved in this process. In Con8 mammary epithelial tumor cells, we have previously documented that the synthetic glucocorticoid, dexamethasone, induces the reorganization of the tight junction and adherens junction and stimulates the monolayer transepithelial electrical resistance (TER), a reliable in vitro measurement of tight junction sealing. Western blots demonstrated that dexamethasone treatment rapidly and strongly stimulated the level of the Id-1 protein, which is a serum-inducible helix-loop-helix transcriptional repressor. The steroid induction of Id-1 was robust by 4 h of treatment and maintained over a 24-h period. Isopropyl-1-thio-beta-d-galactopyranoside-inducible expression of exogenous Id-1 in Con8 cells was shown to strongly facilitate the dexamethasone induction of TER in the absence of serum without altering the dexamethasone-dependent reorganization of ZO-1, beta-catenin, or F-actin. Ectopic overexpression of Id-1 in the SCp2 nontumorigenic mammary epithelial cells, which does not undergo complete dexamethasone-dependent tight junction reorganization, enhanced the dexamethasone-induced ZO-1 tight junction localization and stimulated the monolayer TER. Moreover, antisense reduction of Id-1 protein in SCp2 cells prevented the apical junction reorganization and dexamethasone-stimulated TER. Our results implicate Id-1 as acting as a critical regulator of mammary epithelial cell-cell interactions at an early step in the glucocorticoid-dependent signaling pathway that controls tight junction integrity.

Construction of an approximately 700-kb transcript map around the familial Mediterranean fever locus on human chromosome 16p13.3.

We used a combination of cDNA selection, exon amplification, and computational prediction from genomic sequence to isolate transcribed sequences from genomic DNA surrounding the familial Mediterranean fever (FMF) locus. Eighty-seven kb of genomic DNA around D16S3370, a marker showing a high degree of linkage disequilibrium with FMF, was sequenced to completion, and the sequence annotated. A transcript map reflecting the minimal number of genes encoded within the approximately 700 kb of genomic DNA surrounding the FMF locus was assembled. This map consists of 27 genes with discreet messages detectable on Northerns, in addition to three olfactory-receptor genes, a cluster of 18 tRNA genes, and two putative transcriptional units that have typical intron-exon splice junctions yet do not detect messages on Northerns. Four of the transcripts are identical to genes described previously, seven have been independently identified by the French FMF Consortium, and the others are novel. Six related zinc-finger genes, a cluster of tRNAs, and three olfactory receptors account for the majority of transcribed sequences isolated from a 315-kb FMF central region (between D16S468/D16S3070 and cosmid 377A12). Interspersed among them are several genes that may be important in inflammation. This transcript map not only has permitted the identification of the FMF gene (MEFV), but also has provided us an opportunity to probe the structural and functional features of this region of chromosome 16.

Assessment of pyrin gene mutations in Turks with familial Mediterranean fever (FMF).

Familial Mediterranean fever (FMF) is an autosomal recessive disease clinically characterized by recurrent short self-limited attacks of fever accompanied by peritonitis, pleurisy, and arthritis and can lead to amyloidosis and renal failure in the longer term. It is prevalent mainly in non-Ashkenazi Jews, Armenians, Turks, and Arabs. Due to the lack of an accurate diagnostic test, patients often experience years of attacks and invasive diagnostic procedures before the correct diagnosis is made and adequate treatment is begun. Recently, the gene responsible for FMF, denoted pyrin, has been cloned, and three disease mutations have been described (French FMF Consortium, 1997; International FMF Consortium, 1997). In the current study we assessed the spectrum of mutations in this gene in 16 unrelated families of Turkish origin. The three previously reported missense mutations (Met-Ile at codon 680, Met-Val at codon 694, and Val-Ala at codon 726) accounted for 29 of the 34 disease alleles. In one patient in whom no disease mutation was identified, the clinical picture was atypical enough to raise questions regarding the diagnosis. These results imply that the origin of FMF in Turkey is heterogeneous, that molecular diagnosis of FMF is possible in the majority of cases and clinically helpful, and that delineation of the undiscovered disease mutation(s) in the remaining cases remains a high priority.