Association of Pancreatic Adenocarcinoma Location With DNA Damage Response Status and Response to Platinum-Based Therapy.

PURPOSE: Pancreatic adenocarcinoma is an aggressive disease with poor clinical outcomes. Primary pancreatic tumors originating from the head of the pancreas (H) have different prognostic implications than tumors arising from the body and tail (BT). This is thought to be largely due to anatomic differences, as molecular underpinnings of survival have not been fully explored. We hypothesized that differences in the primary site of H and BT tumors might account for differential molecular outcomes and response to chemotherapy. METHODS: Retrospective data from a single high-volume academic center were analyzed for hypothesis generation. A large-scale, real-world retrospective cohort of 2015 patients with next-generation sequencing (NGS) results were analyzed from a Real-World Evidence database. Progression-free survival (PFS) was evaluated from the initiation of first line of therapy for advanced disease until discontinuation because of progression. HR and P values were computed via Cox regression between first-line FOLFIRINOX and gemcitabine/nanoparticle albumin-bound (gem/nab) paclitaxel. Differences in frequencies of genomic alterations between H and BT were analyzed by Fisher's exact test. RESULTS: Genomic alterations in the DNA damage response (DDR) pathway (such as BRCA1, BRCA2, and PALB2) were enriched (unadjusted P value = .00244) in BT tumors (21.7% of 618) relative to H tumors (15.6% of 942) where BRCA2 was a top contributor within this pathway. Median PFS in BT tumors on first-line FOLFIRINOX was longer than first line gem/nab-paclitaxel (P = .006393); this difference was not identified in H tumors (P = .5546). CONCLUSION: DDR pathway alterations including BRCA1/BRCA2/PALB2 are known predictors of increased benefit from platinum-based chemotherapy. NGS testing for germline and somatic mutations remains important in pancreatic ductal adenocarcinoma, especially in BT tumors where DDR pathway alterations may be more common than in H tumors.

TOMM20 as a Potential Prognostic Biomarker in Chordoma: Results From a High-Volume, Single-Center Study.

OBJECTIVES: As few large studies identify correlative biomarkers in chordoma, our objective was to use our large, single-center chordoma tumor bank to identify novel signaling pathways. METHODS: Clinical and pathologic data for 73 patients with chordoma were retrospectively collected. Tumor microarrays were built from 61 archived chordoma specimens; immunohistochemistry for TOMM20, TIGAR, and MCT1 were performed; and semiquantitative analysis of staining intensity and percentage of positive tumor cells was performed. Average composite scores of MCT1, TIGAR, and TOMM20 expression were compared by disease status and anatomic location. RESULTS: Higher expression of TOMM20 was seen in recurrent and metastatic chordomas compared with primary lesions. Comparing composite scores of primary lesions in patients with primary disease only vs those with recurrent disease showed that TIGAR and TOMM20 expressions are significantly higher in primary lesions, followed by a history of recurrence. A TOMM20 composite score of greater than or equal to 3 significantly decreased overall survival (hazard ratio [HR], 5.83) and recurrence-free survival (HR, 8.95). CONCLUSIONS: Identifying novel signaling pathways that promote chordoma growth and recurrence is critical for developing targeted therapy for chordoma. TOMM20 may be a biomarker associated with chordoma disease progression.

Metabolic Pathways and Targets in Chondrosarcoma.

Chondrosarcomas are the second most common primary bone malignancy. Chondrosarcomas are characterized by the production of cartilaginous matrix and are generally resistant to radiation and chemotherapy and the outcomes are overall poor. Hence, there is strong interest in determining mechanisms of cancer aggressiveness and therapeutic resistance in chondrosarcomas. There are metabolic alterations in chondrosarcoma that are linked to the epigenetic state and tumor microenvironment that drive treatment resistance. This review focuses on metabolic changes in chondrosarcoma, and the relationship between signaling via isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), hedgehog, PI3K-mTOR-AKT, and SRC, as well as histone acetylation and angiogenesis. Also, potential treatment strategies targeting metabolism will be discussed including potential synergy with immunotherapies.

Obesity in early onset breast cancer in African American patients.

Obesity is a modifiable risk factor in breast cancer patients and is predictive of disease outcomes in early-onset breast cancer survivors. The purpose of this review is to summarize the current evidence in the association between early-onset breast cancer and obesity, specifically in African-American women. Reviewing the molecular mechanisms and social determinants of disease in this population can provide a foundation for future interventions in prevention, detection, and treatment aiming at improving outcomes for young breast cancer patients.

An update on angiogenesis targeting in head and neck squamous cell carcinoma.

Angiogenesis is an integral aspect of the growth and proliferation of solid tumors, including head and neck squamous cell carcinoma (HNSCC), and has potential implications in prognosis and treatment of both localized and recurrent/metastatic HNSCC. Therefore, there has been a significant interest in utilizing anti-angiogenic agents either alone or in combination with currently approved and emerging therapies. A phase III randomized trial (E1305) of chemotherapy with or without bevacizumab in the first-line treatment of recurrent/metastatic HNSCC showed an increased response rate and longer progression-free survival but fell short in demonstrating a statistically significant improved survival with bevacizumab. Moreover, toxicity, especially bleeding, was increased. Nevertheless, the study of other anti-angiogenic agents and novel combinations with other therapies, including immunotherapy, remains of interest. Several clinical trials are currently underway.

Comprehensive review of acute oesophageal necrosis.

Acute oesophageal necrosis, also known as 'black oesophagus', is a rare condition characterised by the black discolouration of the oesophageal mucosa on endoscopy and involves the distal oesophagus in majority of cases but may also extend proximally. A number of conditions are found to be associated with it and it is thought to occur due to a combination of hypovolaemia and inadequate oesophageal protective mucosal barrier function. Gastric secretions may have a direct effect on the oesophageal mucosa. We present a case of a woman who presented with haematemesis and significant hypotension after a session of haemodialysis. Black oesophagus was confirmed on esophagogastroduodenoscopy. She was given two units of packed red blood cells and one unit of platelets, and started on a pantoprazole infusion. However, despite rigorous attempts at resuscitation the patient failed to recover.

Posterior reversible encephalopathy syndrome (PRES) after bevacizumab therapy for metastatic colorectal cancer.

Posterior reversible encephalopathy syndrome (PRES) is an increasingly recognizable neuro-clinical syndrome. Clinical and neurological manifestations of PRES include hypertension, headache, encephalopathy, seizures, and symmetrical white matter changes on brain MRI. Most common precipitants of PRES are acute medical illness, hypertensive crisis, eclampsia, immunosuppressive therapy, and chemotherapy. Bevacizumab is a monoclonal antibody that halts angiogenesis by inhibiting vascular endothelial growth factor. It has gained widespread popularity in oncology world especially for metastatic and recurrent cancers due to its inherent ability to stop angiogenesis; a vital step for tumor growth. Bevacizumab has also been implicated as the cause of PRES due to dysregulation of the blood-brain barrier. We are reporting a case of PRES induced by Bevacizumab in a patient of colorectal cancer.

A deadly prescription: combination of methotrexate and trimethoprim-sulfamethoxazole.

Methotrexate (MTX) is a chemotherapeutic synthetic(s) phase cell cycle inhibitor, and its role has evolved as an immunological agent in autoimmune diseases like rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, etc. Trimethoprim-sulfamethoxazole (TS) is one of the most widely prescribed antibiotics commonly used for urinary tract infections, exacerbations of chronic bronchitis, traveler's diarrhea, and pneumocystis pneumonia. Both MTX and TS can have significantly overlapping side effects involving dermatologic, renal, and hematological systems, and the combination of these can be deadly. Our case is about the combination of MTX and TS that leads to mucocutaneous ulceration, leukopenia, and renal insufficiency. The purpose of this case is to increase awareness of potentially significant toxicity from the combination of MTX with TS. Abbreviations: MTX: methotrexate; TS: trimethoprim-sulfamethoxazole; ED: emergency department; IV: intravenous; GI: gastrointestinal; NSAIDs: nonsteroidal anti-inflammatory drugs.

Image-guided high-dose-rate intracavitary brachytherapy in the treatment of medically inoperable early-stage endometrioid type endometrial adenocarcinoma.

PURPOSE: The purpose of this case series is to describe the treatment and outcomes of a cohort of patients with inoperable early-stage endometrioid endometrial cancer with 3D image-guided high-dose-rate (HDR) intracavitary brachytherapy. MATERIALS AND METHODS: A review was performed of patients with early-stage endometrial cancer who underwent primary radiation treatment between 2010 and 2016. Staging and treatment planning were performed CT, pelvic ultrasound, and pelvic MRI. Gross tumor volume (GTV) was defined as the MRI or ultrasound demonstrated endometrial stripe width, with the entire uterine corpus, cervix, and proximal vagina representing the clinical target volume (CTV). Dosimetry calculations were performed in each fraction of HDR brachytherapy. RESULTS: Eight patients received external beam radiation therapy followed by intracavitary HDR brachytherapy. Seven patients underwent intracavitary HDR brachytherapy alone. In all patients, mean cumulative dose to 90% (D90) of GTV was 95.99 Gy in equivalent dose in 2 Gy fractions (EQD2, α/ß = 10). Mean cumulative D90 EQD2 to CTV was 51.64 Gy. Average follow-up was 29 months. Four patients died from concurrent disease(s) at an average of 2.83 years after completion of treatment. Except for 1 (6.6%) patient who recurred at 9 months following completion of treatment, all patients remained disease-free for the remainder of follow-up. CONCLUSIONS: In patients who are poor surgical candidates and have early-stage endometrioid type endometrial carcinoma, image-guided HDR intracavitary brachytherapy carries minimal side effects and a high response rate.