Madappa N. Kundranda

Novel Diagnostic and Predictive Biomarkers in Pancreatic Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts have been dedicated to finding the appropriate serum and imaging biomarkers to help early detection and predict response to treatment of PDAC. Carbohydrate antigen 19-9 (CA 19-9) has been the most validated serum marker and has the highest positive predictive value as a stand-alone marker. When combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA 125), CA 19-9 can help predict the outcome of patients to surgery and chemotherapy. A slew of novel serum markers including multimarker panels as well as genetic and epigenetic materials have potential for early detection of pancreatic cancer, although these remain to be validated in larger trials. Imaging studies may not correlate with elevated serum markers. Critical features for determining PDAC include the presence of a mass, dilated pancreatic duct, and a duct cut-off sign. Features that are indicative of early metastasis includes neurovascular bundle involvement, duodenal invasion, and greater post contrast enhancement. 18-F-fluorodeoxyglucose (18-FDG) radiotracer uptake and changes following treatment may predict patient overall survival following treatment. Similarly, pretreatment apparent diffusion coefficient (ADC) values may predict prognosis with lower ADC lesions having worse outcome. Although these markers have provided significant improvement in the care of pancreatic cancer patients, further advancements can be made with perhaps better combination of markers or discovery of unique marker(s) to pancreatic cancer.

Promising new therapies in advanced pancreatic adenocarcinomas

Pancreatic ductal adenocarcinoma is a lethal disease due to late diagnosis, early metastasis and the lack of effective therapies. In patients with metastatic disease, 1-year survival ranges from 17 to 23% and 5-year survival is less than 5%. This necessitates an urgent need for developing more effective therapies. Targeting the neoplastic cells has been largely ineffective due to the dense stroma, which is a physical barrier for effective drug delivery and also a source for different factors that promote tumor progression and immunosuppression. In this review, we focus on understanding the complex biology of this tumor as it relates to the evaluation of previously failed molecularly targeted trials and review potential new therapies that are emerging in the treatment of metastatic pancreatic ductal adenocarcinoma.

Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options

BACKGROUND Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. MATERIALS AND METHODS We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). RESULTS Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples. CONCLUSION We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. IMPLICATIONS FOR PRACTICE Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA, NF1, CDKN2A, or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.

Signet-Ring Cell Carcinoma of the Colon: A Case Report and Review of the Literature

Background: Colorectal adenocarcinoma (CRC) is the third leading cause of death in the United States. One of the histologic subtypes of CRC is signet-ring cell carcinoma (SRCC), which has a distinct molecular and tumor biology from that of adenocarcinoma. Primary SRCC diagnosed at an early stage is very rare as most cases are detected at an advanced stage. Therefore, overall prognosis of SRCC is poor. Case Presentation: A 36-year-old female presented to her primary care physician with new-onset progressive right lower quadrant pain without any significant past medical or family history. Computed tomography scan of the abdomen and pelvis with contrast showed a 4.9 × 3.5 × 3.1 cm, lobulated, septated cystic mass arising from the cecum. The mass demonstrated wall enhancement and contained focal areas of coarse calcification. There was nodal involvement either locally or distally. The patient underwent right hemicolectomy, and pathology revealed a high-grade mucinous carcinoma with signet-ring cell variant invading through the muscularis propria and into the subserosal adipose tissue. The margins were negative for tumor, and no lymphovascular or perineural invasion was noted. None of the 14 resected pericolonic lymph nodes was positive for malignancy. Hence, she was staged as pT3, pN0, pMx-stage IIA. The appendix was not involved. Microsatellite instability testing showed the preservation of MLH1, PMS2, MSH2 and MSH6 proteins by IHC and PCR. Carcinoembryonic antigen level was within normal limits. Due to the patients young age, aggressive histology and microsatellite-stable status, adjuvant fluropyrimidine (5-FU)-based therapy with the single agent capecitabine was initiated. The patient completed 6 months of adjuvant therapy and has been disease free for approximately 18 months. Conclusion: Primary SRCC of the cecum is a rare disease. Given the poor prognosis of these patients, early-stage disease with microsatellite-stable patients should be considered for adjuvant 5-FU-based therapy in an attempt to prevent recurrence.

Metastatic Breast Cancer with Extensive Osseous Metastasis Presenting with Symptomatic Immune Thrombocytopenic Purpura and Anemia: A Case Report and Review of the Literature.

Background: Immune thrombocytopenic purpura (ITP) is a rare acquired bleeding disorder with an estimated incidence of 1 in 10,000 people in the general population. The association of ITP with breast cancer is an even rarer entity with very limited reports in the English literature. Case Presentation: We report a case of a 51-year-old female with no significant past medical history who presented with sudden onset of malaise, syncope, gingival bleed and epistaxis. She was found to have severe thrombocytopenia (platelet count 6,000/μl) and anemia (hemoglobin 7.2 g/dl). Her workup led to the diagnosis of metastatic ductal breast cancer with extensive bone metastasis. Bone marrow biopsy demonstrated myelophthisis which was initially thought to be consistent with her presentation of thrombocytopenia and anemia. Therefore, the patient was started on hormonal therapy for the treatment of her metastatic breast cancer. After 3 months of therapy, she did not improve and developed severe mucosal bleeding. Her clinical presentation was suspicious for ITP and immune-mediated anemia, and hence she was started on steroids and intravenous immunoglobulin. The patient had a dramatic response to therapy with normalization of her platelet count and hemoglobin within 2 weeks. Conclusion: To our knowledge, this is the first reported case of metastatic breast cancer presenting with symptomatic ITP and anemia, and both symptoms are postulated to be immune-mediated.

Chemotherapy re-challenge response rate in metastatic colorectal cancer

Background There are few treatment options in metastatic colorectal cancer (mCRC) after progression on standard chemotherapy. Third and fourth line therapies typically consist of regorafenib or trifluridine-tipiracil, however, clinical benefit of these medications is limited, as progression free survival is approximately 1.9 months for regorafenib (Grothey et al. 2013) and 2.0 months for trifluridine-tipiracil (Mayer et al. 2015). Another choice in this setting may include the re-initiation of previously used chemotherapy, therefore in this study we assessed the efficacy and tolerability of chemotherapy re-challenge. Methods This was a retrospective, cohort study assessing patients with mCRC who were 18-89 years of age and treated with re-challenge chemotherapy. Re-challenge chemotherapy was defined as re-initiation of oxaliplatin or irinotecan-based regimens at least nine months from the end of initial exposure. A minimum of four chemotherapy cycles was required to qualify as initial exposure. The key endpoints of this study were clinical benefit rate (CBR), defined as the proportion of patients with partial response or stable disease, and time to progression (TTP). Results A total of 67 chemotherapy re-challenges were accounted for in 51 patients. The overall CBR was 70.7%. Partial responses occurred in 50.7% cases. The TTP was 6.0 months. For the 51 cases of first re-challenge, the CBR was 75.5% and TTP was 6.5 months. Fourteen patients had a second re-challenge, and in these patients, the CBR was 61.5% and TTP was 4.1 months. Conclusions Oxaliplatin or irinotecan-based re-challenge should be considered as a third or fourth line treatment option in select patients with mCRC. CBR and especially TTP compare favorably to approved third line therapies such as regorafenib or trifluridine-tipiracil.

Synchronous primary adenocarcinoma of the lung and pancreas: a case series and review of the literature

Aim The frequency of pancreatic cancer in association with cancer of other organs ranges from 1 to 20%, with the most common ones being gastric, colon, thyroid and genitourinary. The presence of synchronous lung and pancreatic cancers is extremely rare. Case series Two patients with extensive smoking history and variable presentations were found to have simultaneous lung and pancreatic masses both lesions being different histologically and on immunohistochemical staining. After individualized treatment plans, the first patient remains free of disease and the second patient is being treated with a palliative intent. Conclusion The early recognition and treatment is important as there exists a significant survival difference in patients who have synchronous primaries as opposed to those with metastatic pancreatic adenocarcinoma.

Nab-paclitaxel plus gemcitabine in the treatment of metastatic pancreatic cancer: utility and experience from the clinic

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