Retrospective Evaluation of the Impact of Dose Escalation Using Pre-operative Simultaneous Integrated Boost Volumetric Modulated Arc Therapy on the Outcome of Locally Advanced Rectal Cancer Patients.

PURPOSE: Evaluating the outcome of pre-operative simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) concomitant with capecitabine in patients diagnosed with locally advanced rectal cancer (LARC) at King Faisal Specialist Hospital and Research Centre (KFSH&RC), Riyadh, Saudi Arabia, during the period January 2013-December 2019. RESULTS: A total of 134 patients were enrolled. The median age at diagnosis was 59 years. All patients received pre-operative concurrent chemo-radiation therapy (CCRT) using SIB-VMAT with oral capecitabine. Neoadjuvant chemotherapy was administered prior to CCRT in 32 patients (23.9%). The dose of radiation was 55 Gy in 94 patients (70.1%), while 40 patients (29.9%) received 50 Gy. All patients completed the CCRT treatment without breaks. No records of acute and late grade III and IV toxicities. Curative surgery was performed in all patients with a median interval of 11 (6-52) weeks between the end of CCRT and the date of surgery. No reported 30-day postoperative mortality and no grade III and IV Clavien-Dindo complications. PCR was reported in 26 patients (19.4%), while pathologically negative nodes (pN0) were achieved in 103 patients (76.9%). Adjuvant chemotherapy was utilized in 57 patients (42.5%). The 5-year local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were 93.2%, 67.1%, and 87.3%, respectively. Only tumor regression grade (TRG) was significantly correlated with LRFS, (p value 0.043). On multivariate analysis, only TRG and achievement of pN0 were significantly correlated with DFS (p value < 0.001). CONCLUSION: Dose escalation utilization (SIB-VMAT) in the pre-operative treatment of LARC is well tolerated and provides effective local control.

ABO-incompatible Pediatric Liver Transplantation With Antibody and B-cell Depletion-free Immunosuppressive Protocol in High Consanguinity Communities.

The success of orthotopic liver transplantation as a life-saving treatment has led to new indications and a greater competition for organ grafts. Pediatric patients with acute liver-related crises can benefit from orthotopic liver transplantation, but organ availability in the limited time can be a major obstacle. Crossing ABO blood group barriers could increase the organs available to such patients. Methods: From November 2010 to June 2015, 176 children aged 0.2-to18 y were transplanted in the King Faisal Specialist Hospital and Research Center. Out of those, 19 children were transplanted across blood group barriers (ABO incompatible). The underlying diseases were biliary atresia (n = 6); progressive familial intrahepatic cholestasis type 2 (n = 4); Crigler-Najjar syndrome (n = 3); hepatoblastoma (n = 2); and urea cycle disorder, Caroli disease, cryptogenic cirrhosis, and neonatal sclerosing cholangitis (n = 1 each). Immunosuppression consisted of basiliximab, mycophenolate, tacrolimus, and steroids. Pretransplant prophylactic plasmapheresis, high-dose immunoglobulins, and rituximab were not administered. Results: The grafts were from living donors (n = 17) and deceased donors (n = 2). Living donor morbidity was nil. The recipient median age was 21 mo (5-70 mo). After a median follow-up of 44 mo, 2 recipients (10%) died because of sepsis, 1 because of uncontrolled acute myeloid leukemia. The overall rejection rate was 7%, and no grafts were lost because of antibody-mediated rejection (AMR). HLA matching was 3.8 of 6 (A, B, DR), and there were 2 patients presented with acute cellular rejection, 1 patient with AMR, and 1 patient with biliary strictures. Conclusions: ABO incompatible liver transplantation is a feasible and life-saving option even with antibody and B-cell depletion-free protocol without increasing the risks for AMR. We speculate that this excellent result is most likely because of presence of relatively low titer ABO isoagglutinins and the high HLA match compatibility caused by habit of longstanding interfamilial marriages as typical of Saudi Arabia.

Efficacy of Everolimus Combined with 177Lu-Dotatate in the Treatment of Neuroendocrine Tumors.

Background: Both everolimus and peptide receptor radionuclide therapy (PRRT) are approved as monotherapies for advanced neuroendocrine tumors (NETs). Research in animal models showed synergism between the two treatment modalities. This study aimed to evaluate the safety and efficacy of combining everolimus and PRRT in the treatment of unresectable NETs. Methods: Adult patients (≥18 years) with progressing and unresectable histologically confirmed grade 1-2 NETs of all origins were enrolled. Everolimus was started at a 5 mg daily dose and was increased after the initial three patients to 10 mg daily. Patients were treated concurrently with 177Lu-DOTATATE at an 8-week interval, with planned four cycles. Safety was the primary endpoint, with response rate and progression-free survival (PFS) being secondary. Results: Eleven patients were enrolled. The trial was terminated early for poor accrual. The median age was 51 years (18-64), and 4 were males. The median number of cycles of 177Lu-DOTATATE was 3, and the median cumulative dose was 300 mCi. The most frequent grade 1-2 toxicities were stomatitis (90.9%) and nausea (72.7%). Less frequent were fatigue (63.6%), anorexia, diarrhea, and skin changes (each at a 36.4% rate). Grade 3 toxicities occurred in 36% (fatigue, infection, pneumonitis, neutropenia, and stroke). No patient developed grade 4 toxicity. Treatment was stopped because of progression in three patients, and toxicity in another three patients, in addition, in four patients due to therapy interruption and in one patient who developed stroke. One patient achieved partial response, and nine had stable disease. One patient developed disease progression. At a median follow-up of 18.9 months, three died and one was lost to follow-up. The median PFS was 23.3 months. Conclusions: The combination of everolimus at a dose of 10 mg daily and 177Lu-DOTATATE appears not to be feasible. A larger trial at a lower dose of everolimus is warranted.

Neoadjuvant concurrent chemoradiotherapy using infusional gemcitabine in locally advanced rectal cancer: A phase II trial.

INTRODUCTION: Gemcitabine is a well-known radiosensitizer. Herein, we tested the efficacy and toxicity of preoperative concurrent infusional gemcitabine and radiotherapy in locally advanced rectal cancer. PATIENTS AND METHODS: This was a phase II, single-arm trial. Eligible patients had a diagnosis of rectal adenocarcinoma with clinical stage T3-T4 and/or nodal involvement, age ≥18 years, and no prior chemotherapy or radiotherapy. Patients received preoperative radiation at a dose of 50.4-54 Gy over 28 days with concurrent infusional gemcitabine administered at a dose of 100 mg/m2 over the course of 24 h weekly for 6 weeks. The primary endpoint was pathological complete response (pCR). RESULTS: Forty patients were recruited. Only one patient did not complete therapy due to death. Eight patients did not undergo surgery, one died, two progressed to nonresectable disease, and five withdrew consent. Five patients progressed prior to surgery, with two having unresectable metastases and three having resectable liver metastases. One was found to have peritoneal metastasis during surgery. Out of the 32 patients who underwent surgery, seven achieved pCR at a rate of 20%. With a median follow-up of 30 months, four additional patients had a distant relapse (one had a subsequent local relapse). The 3-year event-free and overall survival rates were 70% and 85%, respectively. The commonest preoperative grade 3-4 toxicity included lymphopenia (50%), neutropenia (41%), anemia (15%), diarrhea (12%), abdominal pain (12%), and proctitis (8%). CONCLUSION: Concurrent preoperative chemoradiotherapy using infusional gemcitabine for locally advanced rectal cancer achieved an encouraging degree of local control with manageable toxicity.

Loss of ZNF677 expression is a predictive biomarker for lymph node metastasis in Middle Eastern Colorectal Cancer.

Zinc-finger proteins are transcription factors with a "finger-like" domain that are widely involved in many biological processes. The zinc-finger protein 677 (ZNF677) belongs to the zinc-finger protein family. Previous reports have highlighted the tumor suppressive role of ZNF677 in thyroid and lung cancer. However, its role in colorectal cancer (CRC) has not been explored. ZNF677 protein expression was analyzed by immunohistochemistry in a large cohort of 1158 CRC patients. ZNF677 loss of expression was more frequent in CRC tissues (45.3%, 525/1158), when compared to that of normal tissue (5.1%, 11/214) (p < 0.0001) and was associated with mucinous histology (p = 0.0311), advanced pathological stage (p < 0.0001) and lymph node (LN) metastasis (p = 0.0374). Further analysis showed ZNF677 loss to be significantly enriched in LN metastatic CRC compared to overall cohort (p = 0.0258). More importantly, multivariate logistic regression analysis showed that ZNF677 loss is an independent predictor of LN metastasis in CRC (Odds ratio = 1.41; 95% confidence interval 1.05-1.87; p = 0.0203).The gain- and loss-of-function studies in CRC cell lines demonstrated that loss of ZNF677 protein expression prominently increased cell proliferation, progression of epithelial-mesenchymal transition and conferred chemoresistance, whereas its overexpression reversed the effect. In conclusion, loss of ZNF677 protein expression is common in Middle Eastern CRC and contributes to the prediction of biological aggressiveness of CRC. Therefore, ZNF677 could not only serve as a marker in predicting clinical prognosis in patient with CRC but also as a potential biomarker for personalized targeted therapy.

PD-L1 Expression Is Associated with Deficient Mismatch Repair and Poor Prognosis in Middle Eastern Colorectal Cancers.

Several clinical trials are investigating the use of immune-targeted therapy with Programmed death ligand-1 (PD-L1) inhibitors for colorectal cancer (CRC), with promising results for patients with mismatch repair (MMR) deficiency or metastatic CRC. However, the prognostic significance of PD-L1 expression in CRC is controversial and such data are lacking in CRC from Middle Eastern ethnicity. We carried out this large retrospective study to investigate the prognostic and clinico-pathological impact of PD-L1 expression in Middle Eastern CRC using immunohistochemistry. A total of 1148 CRC were analyzed for PD-L1 expression. High PD-L1 expression was noted in 37.3% (428/1148) cases and was correlated with aggressive clinico-pathological features such as high malignancy grade (p < 0.0001), larger tumor size (p = 0.0007) and mucinous histology (p = 0.0005). Interestingly, PD-L1 expression was significantly higher in patients exhibiting MMR deficiency (p = 0.0169) and BRAF mutation (p = 0.0008). Furthermore, the expression of PD-L1 was found to be an independent marker for overall survival (HR = 1.45; 95% CI = 1.06 - 1.99; p = 0.0200). In conclusion, the results of this study indicate that PD-L1 expression could be a valid biomarker for poor prognosis in Middle Eastern CRC patients. This information can help in decision-making for anti-PD-L1 therapy in Middle Eastern CRC, especially for patients with MMR deficient tumors.

Gastric wall metastases from hepatocellular carcinoma: case report and review of the literature.

A 69-year-old male patient who had a history of well-differentiated hepatocellular carcinoma (HCC) post right hepatectomy presented a year later with iron-deficiency anemia. His anemia work-up included upper endoscopy that revealed multiple gastric polyp a biopsy from the largest demonstrated metastatic hepatocellular carcinoma. His magnetic resonance imaging (MRI) showed a gastric "polyp" without evidence of local HCC recurrence within the liver. His subsequent dual imaging with Choline/fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) confirmed the gastric metastases and in addition revealed other sites of unexpected metastatic disease in the right adrenal and the bone that was asymptomatic. Patient was started on sorafenib and currently he is alive one-and-half-year postdetection of his metastatic disease under palliative care. This case showed that the possibility of gastric metastases should be kept in mind when confronted with anemia in HCC patient and also highlight the complementary role of molecular imaging modality along with MRI in the metastatic work-up for hepatocellular carcinoma postcurative resection.

Clonal Evolution and Timing of Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, where ~50% of patients develop metastasis, despite current improved management. Genomic characterisation of metastatic CRC, and elucidating the effects of therapy on the metastatic process, are essential to help guide precision medicine. Multi-region whole-exome sequencing was performed on 191 sampled tumour regions of patient-matched therapy-naïve and treated CRC primary tumours (n = 92 tumour regions) and metastases (n = 99 tumour regions), in 30 patients. Somatic variants were analysed to define the origin, composition, and timing of seeding in the metastatic progression of therapy-naïve and treated metastatic CRC. High concordance, with few genomic differences, was observed between primary CRC and metastases. Most cases supported a late dissemination model, via either monoclonal or polyclonal seeding. Polyclonal seeding appeared more common in therapy-naïve metastases than in treated metastases. Whereby, treatment prompted for the selection of distinct resistant clones, through monoclonal seeding to distant metastatic sites. Overall, this study reinforces the importance of early clinical detection and surgical excision of the CRC tumour, whilst further highlighting the clinical challenges for metastatic CRC with increased intratumour heterogeneity (either due to early dissemination or polyclonal metastatic spread) and the underlying risk of future therapeutic resistance in treated patients.

Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update.

There is a growing interest in standardizing gene-disease associations for the purpose of facilitating the proper classification of variants in the context of Mendelian diseases. One key line of evidence is the independent observation of pathogenic variants in unrelated individuals with similar phenotypes. Here, we expand on our previous effort to exploit the power of autozygosity to produce homozygous pathogenic variants that are otherwise very difficult to encounter in the homozygous state due to their rarity. The identification of such variants in genes with only tentative associations to Mendelian diseases can add to the existing evidence when observed in the context of compatible phenotypes. In this study, we report 20 homozygous variants in 18 genes (ADAMTS18, ARNT2, ASTN1, C3, DMBX1, DUT, GABRB3, GM2A, KIF12, LOXL3, NUP160, PTRHD1, RAP1GDS1, RHOBTB2, SIGMAR1, SPAST, TENM3, and WASHC5) that satisfy the ACMG classification for pathogenic/likely pathogenic if the involved genes had confirmed rather than tentative links to diseases. These variants were selected because they were truncating, founder with compelling segregation or supported by robust functional assays as with the DUT variant that we present its validation using yeast model. Our findings support the previously reported disease associations for these genes and represent a step toward their confirmation.

Mycobacterium tuberculosis DNA in living donor transplanted livers and donor-related tuberculosis in recipients: A retrospective longitudinal cohort study.

OBJECTIVES: Mycobacterium tuberculosis DNA has been detected in multiple organs in people without active tuberculosis or a history of tuberculosis. Molecular testing for metabolic activity has suggested that M tuberculosis DNA represents viable bacilli. Whether transplanted organs with M tuberculosis DNA can result in tuberculosis in recipients has not been assessed. METHODS: Biopsies obtained at the time of living donor liver transplantation were tested for the presence of M tuberculosis DNA using in situ PCR. The cohort of recipients was longitudinally followed for the development of tuberculosis. RESULTS: Living donor liver transplantation was performed for 270 patients. Mean age was 33 years (median: 41 years, range: 1-80 years). Recipients were followed for a mean of 68 months (median: 72 months, range: 1-138 months) after transplantation. Mycobacterium tuberculosis DNA was detected in 25 of 155 donated livers (16%) with liver biopsies available for testing. None of the recipients of these livers received tuberculosis chemoprophylaxis and only one (4%) developed tuberculosis 15 months after transplantation. Among the entire cohort of 270 patients, post-transplant tuberculosis was diagnosed in four patients (1.48%) at an incidence rate of 2.61 cases per 1000 transplant-years. No factors associated with developing tuberculosis were identified, including positive M tuberculosis DNA in transplanted livers. CONCLUSIONS: Mycobacterium tuberculosis DNA in living donor transplanted livers did not result in tuberculosis despite post-transplant immunosuppression.

Early Hepatocellular Carcinoma Associated With Fibrocystic Liver Disease in a 10-Year-Old Child: A Case Report.

BACKGROUND: Fibrocystic liver-kidney disease is caused by a group of rare and genetically diverse disorders that are associated with kidney cysts or dysplasia and ductal plate malformation in the liver. There have been several reports of liver neoplasias arising in hepatobiliary fibrocystic diseases. However, most were cholangiocarcinoma; cases involving hepatocellular carcinoma (HCC) are rare, and all the reported cases are related with adults. CASE REPORT: A 10-year-old girl with a history of repeated gastrointestinal bleeding underwent banding and sclerotherapy multiple times and had a history of a Portosystemic shunt without any significant benefit. She was referred to us as a case of fibrocystic liver disease with decompensated liver disease for liver transplantation. The patient underwent living donor liver transplantation, and the explanted liver histopathology report is documented. The explant liver weighed 838 g and measured 21 × 13 × 8.5 cm with the attached gallbladder measuring 7 × 3 × 0.2 cm (in wall thickness). The external surface was covered with multiple white nodules ranging in size from 0.4 to 1 cm. Serial slicing revealed an ill-defined, yellow, soft lesion (4 × 2.5 × 2.5 cm) localized in the subcapsular area of the left lobe (segment 4). The rest of the cut surface was green and nodular (cirrhotic). Microscopy from largest nodule was consistent with early hepatocellular carcinoma.The rest of the liver was cirrhotic, and the morphology was consistent with fibrocystic disease of liver. CONCLUSION: We report a rare case of HCC associated with fibrocystic liver disease. When diagnosing fibrocystic liver disease without known risk factors, the presence of HCC must be considered, and vice versa. To our knowledge, this is the first reported case of HCC associated with fibrocystic liver disease in a 10-year-old child.

Dose Escalation with Simultaneous Integrated Boost (SIB) Using Volumetric Modulated Arc Therapy (VMAT) in Rectal Cancer.

PURPOSE: Assess feasibility-rate of PCR, short-term toxicity after neoadjuvant concurrent chemoradiation (NACRT) delivered via simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT) technique for locally advanced rectal cancer. METHODS: Retrospective evaluation of patients with locally advanced rectal cancer treated with VMAT-SIB technique preoperatively at an academic tertiary care center in Riyadh, Saudi Arabia between February 2013 and March 2017. RESULTS: One hundred patients with depth of invasion staged as T3/T4 or T2 in 93 and seven patients, respectively. Lymph node metastasis was staged as N1/N2 or N0 in 87 and 13 patients, respectively. Circumferential radial margin (CRM) was involved radiologically prior to treatment in 50 patients. A dose of 55 or 50 Gy was given to 71 and 29 patients, respectively. All treatments were completed without interruption. Grade 3/4 toxicity was not observed. Low anterior resection and abdominoperineal resection were performed with negative proximal, distal, and radial margins in 72 and 28 patients, respectively. There were no immediate significant postoperative complications. Histologically, no residual tumor (grade 0) was noted in 20 patients (pCR). Regression grade 1, 2, and 3 were noted in 31, 34, and 15 patients. Average number of lymph nodes retrieved in the surgical specimen was 12 (range 6-22). Lymph nodes were negative for cancer in 80 patients. CONCLUSION: Dose escalation with SIB-VMAT as NACRT for rectal cancer is feasible. Moreover, it can increase the rate of pathological complete response with a favorable toxicity profile. Clinical benefit of this approach needs to be validated in a larger cohort of patients with longer follow-up.

A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.

BACKGROUND: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer. Earlier studies have reported the incidence of BRAF mutations in the range of 5-20% in colorectal carcinomas (CRC) and are predominantly seen in the serrated adenoma-carcinoma pathway characterized by microsatellite instability (MSI-H) and hypermethylation of the MLH1 gene in the setting of the CpG island methylator phenotype (CIMP). Due to the lack of data on the true incidence of BRAF mutations in Saudi Arabia, we sought to analyze the incidence of BRAF mutations in this ethnic group. METHODS: 770 CRC cases were analyzed for BRAF and KRAS mutations by direct DNA sequencing. RESULTS: BRAF gene mutations were seen in 2.5% (19/757) CRC analyzed and BRAF V600E somatic mutation constituted 90% (17/19) of all BRAF mutations. BRAF mutations were significantly associated with right sided tumors (p = 0.0019), MSI-H status (p = 0.0144), CIMP (p = 0.0017) and a high proliferative index of Ki67 expression (p = 0.0162). Incidence of KRAS mutations was 28.6% (216/755) and a mutual exclusivity was noted with BRAF mutations (p = 0.0518; a trend was seen). CONCLUSION: Our results highlight the low incidence of BRAF mutations and CIMP in CRC from Saudi Arabia. This could be attributed to ethnic differences and warrant further investigation to elucidate the effect of other environmental and genetic factors. These findings indirectly suggest the possibility of a higher incidence of familial hereditary colorectal cancers especially Hereditary non polyposis colorectal cancer (HNPCC) syndrome /Lynch Syndrome (LS) in Saudi Arabia.

Pancreatic metastasis arising from a BRAF(V600E)-positive papillary thyroid cancer: the role of endoscopic ultrasound-guided biopsy and response to sorafenib therapy.

BACKGROUND: Lungs and bones are the most common sites for distant metastases from papillary thyroid cancer (PTC). Metastases to the pancreas are extremely rare. Here we present a man with pancreatic metastases from PTC, report our experience with sorafenib therapy, and discuss the role of endoscopic ultrasound (EUS)-guided biopsy in its diagnosis. PATIENT FINDINGS: A 56-year-old man underwent total thyroidectomy, right-modified neck dissection, and radioactive iodine (RAI) remnant ablation for PTC at age 47 years (in 2002). Between 2002 and 2007, he had three more neck surgeries, two RAI therapies, and external beam radiotherapy for persistent and subsequently metastatic PTC. In 2008, a computed tomography/positron emission tomography (CT/PET) scan showed an 18F-fluorodeoxyglucose (FDG)-avid pancreatic focus. Magnetic resonance imaging (MRI) revealed a pancreatic nodule at the same location. An EUS-guided biopsy confirmed the diagnosis of pancreatic metastasis from PTC, and molecular studies showed positive BRAF(V600E) mutation. He was treated with sorafenib for 6 months. Although a lung CT scan done 2 months after initiation of sorafenib suggested stability of the disease, MRI studies done at 3 and 6 months showed clear progression with an increase in the size of the lung and pancreatic metastases. Subsequently, he developed liver, bone, and omental metastases. He died in July 2011, 9 years and 8 months after the initial diagnosis of PTC and 20 months after discovery of the pancreatic metastasis. SUMMARY: A middle-aged man with PTC developed lung metastases despite multiple surgeries and RAI therapies. Seven years after the initial diagnosis, a pancreatic metastasis was accidentally discovered. Both the metastasis and the primary thyroid tumor are positive for BRAF(V600E) mutation. The lung and pancreatic metastases progressed while the patient was receiving sorafenib for 6 months, and the patient died 20 months after diagnosis of pancreatic metastasis. CONCLUSION: PTC rarely metastasizes to the pancreas. In this patient, an FDG PET scan and EUS-guided biopsy played important roles in the diagnosis. PTC metastases to the pancreas usually occur in otherwise advanced disease. In the patient presented here, sorafenib may have slowed disease progression but the overall utility of tyrosine kinase inhibitors in pancreatic metastases from PTC is not clear.

Paget disease of the bone: does it exist in Saudi Arabia?

Paget disease of the bone is a chronic disease characterized by accelerated bone turnover with abnormal repair leading to expansion, pain and deformities. The disease is common in the West, but little if any information is available on its existence in the Arab world, including Saudi Arabia. We present four cases of Saudi patients with Paget disease with variable presentations. The first case, a 63-year-old woman with a history of papillary thyroid cancer, presented with bone, shoulder and chest wall pain and foci of uptake in the ribs and skull that were thought to be metastases, indicating the possibility of diagnostic difficulty in a patient with history of malignancy. Bone biopsy confirmed the diagnosis of Paget disease. The second case was a 47-year-old asymptomatic woman with an elevated alkaline phosphatase of 427 U/L, a common presentation but at an unusual age. Plain x-rays and bone scan confirmed the diagnosis. The third case was a 43-year-old man who presented with hearing impairment and right knee osteoarthritis, unusual presentations at a young age leading to a delay in diagnosis. The fourth case was a 45-year-old man who presented with sacroiliac pain and normal biochemical values, including a normal alkaline phosphatase. Bone biopsy unexpectedly revealed features of Paget disease, which evolved over time into a classical form. A common feature in all except the first case was the relatively young age. Paget disease does exist in Saudi Arabia, and it should be considered in the differential diagnosis of similar cases.