Distal Pancreatectomy with En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Adenocarcinoma Following Neoadjuvant Therapy

Background

Celiac trunk encasement by adenocarcinoma of the pancreatic body is generally regarded as a contraindication for surgical resection. Recent studies have suggested that a subset of stage III patients will succumb to their disease in the absence of distant metastases. We hypothesized that patients with stage III tumors invading the celiac trunk, who are free of distant disease following neoadjuvant therapy, may derive prolonged survival benefit from aggressive surgical resection.

Methods

We performed a retrospective review of distal pancreatectomies with en bloc celiac axis resection for pancreatic adenocarcinoma.

Results

Eleven patients underwent a distal pancreatectomy with en bloc celiac axis resection after completing neoadjuvant chemoradiation therapy. Median operative time was 8?h, 14?min, and median estimated blood loss was 700?ml. Median length of stay was 9?days. Five patients (45%) had postoperative complications; three were Clavien grade I. Four patients (35%) had pancreatic leaks; two were ISGPF grade B, and two were grade A. There were two 90-day perioperative deaths. Ten patients had R0 resections (91%). After a median follow-up of 41?weeks, six patients recurred. Four of the five patients with SMAD4 loss recurred, and two of the five patients with intact SMAD4 recurred. Median disease-free and overall survival were 21?weeks and 26?months, respectively.

Conclusions

Resection of pancreatic body adenocarcinoma with celiac axis resection is technically feasible with acceptable perioperative morbidity and mortality.     

Oral health needs in individuals with trisomy 18 and trisomy 13: Implications for dental professionals

The purpose of this study was to examine oral health needs and dental care in individuals with trisomy 18 and trisomy 13 (full, mosaic, partial and other, mixed types). Primary feeding method was also examined. Data was collected from a parent‐completed, mixed method survey (TRIS Survey). Mean age in months was 120.2 (range 38 to 394 months) and 133 (range 36 to 405 months), respectively, for trisomy 18 and trisomy 13 individuals. Results indicated the majority of individuals received routine dental care from their family dentist. Approximately 80% in both groups needed some form of specialized dental care. Close to 25% and 30% of trisomy 18 and trisomy 13 individuals, respectively, required hospital admission for specialized dental care. Responses indicated the presence of excessive plaque and tooth decay across the groups with a higher incidence for individuals with trisomy 13. Although not the primary form of intake, over half of the individuals received oral feedings. Implications for dental care and management are provided along with the need for additional research to confirm or disconfirm this study's findings.     

Sequential second free fibula flap for the reconstruction of metachronous osteoradionecrosis of the mandible

Osteoradionecrosis (ORN) of the mandible is a potentially catastrophic complication of external beam radiation therapy for head and neck malignancies. A 55-year-old man treated with chemoradiation for base-of-tongue cancer presented with a necrotic left mandibular body and underwent left mandibulectomy with right free fibula osteocutaneous flap reconstruction. Two and a half years later, he presented with right mandibular body ORN and underwent a second mandibular resection and subsequent reconstruction with a left fibula osteocutaneous free flap fixed in the midline to the previously placed contralateral fibula. He recovered well from all procedures. To the best of our knowledge, we report the first case of a patient with metachronous ORN of the mandible requiring resection and subsequent reconstruction with sequential free fibula flaps. Even in the presence of prior microvascular reconstructions, patients can successfully undergo additional reconstructive procedures to restore their function, appearance, and quality of life.     

Genetic modification of scAAV‐equine‐BMP‐2 transduced bone‐marrow‐derived mesenchymal stem cells before and after cryopreservation: An “off‐the‐shelf” option for fracture repair

Optimizing the environment of complex bone healing and improving treatment of catastrophic bone fractures and segmental bone defects remains an unmet clinical need both human and equine veterinary medical orthopaedics. The objective of this study was to determine whether scAAV‐equine‐BMP‐2 transduced cells would induce osteogenesis in equine bone marrow derived mesenchymal stem cells (BMDMSCs) in vitro, and if these cells could be cryopreserved in an effort to osteogenically prime them as an “off‐the‐shelf” gene therapeutic approach for fracture repair. Our study found that transgene expression is altered by cell expansion, as would be expected by a transduction resulting in episomal transgene expression, and that osteoinductive levels could still be achieved 5 days after recovery, and protein expression would continue up to 14 days after transduction. This is the first evidence that cryopreservation of genetically modified BMDMSCs would not alter the osteoinductive potential or clinical use of allogeneic donor cells in cases of equine fracture repair. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1310–1317, 2019.     

The challenges of promoting osteogenesis in segmental bone defects and osteoporosis

Conventional clinical management of complex bone healing scenarios continues to result in 5–10% of fractures forming non‐unions. Additionally, the aging population and prevalence of osteoporosis‐related fractures necessitate the further exploration of novel ways to augment osteogenesis in this special population. This review focuses on the current clinical modalities available, and the ongoing clinical and pre‐clinical research to promote osteogenesis in segmental bone defects, delayed unions, and osteoporosis. In summary, animal models of fracture repair are often small animals as historically significant large animal models, like the dog, continue to gain favor as companion animals. Small rodents have well‐documented limitations in comparing to fracture repair in humans, and few similarities exist. Study design, number of studies, and availability of funding continue to limit large animal studies. Osteoinduction with rhBMP‐2 results in robust bone formation, although long‐term quality is scrutinized due to poor bone mineral quality. PTH 1‐34 is the only FDA approved osteo‐anabolic treatment to prevent osteoporotic fractures. Limited to 2 years of clinical use, PTH 1‐34 has further been plagued by dose‐related ambiguities and inconsistent results when applied to pathologic fractures in systematic human clinical studies. There is limited animal data of PTH 1‐34 applied locally to bone defects. Gene therapy continues to gain popularity among researchers to augment bone healing. Non‐integrating viral vectors and targeted apoptosis of genetically modified therapeutic cells is an ongoing area of research. Finally, progenitor cell therapies and the content variation of patient‐side treatments (e.g., PRP and BMAC) are being studied. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1559–1572, 2018.     

Mutational analysis of VACM-1/cul5 exons in cancer cell lines

VACM-1, a cul-5 gene product, functions via an E3 ligase complex and when overexpressed, has an antiproliferative effect in many cell types. Overexpression of VACM-/cul5 cDNA mutated at the PKA-specific phosphorylation site at Ser730 reversed this phenotype. These effects are associated with the appearance of larger M(r) species subsequently identified as a Nedd8-modified VACM-1/cul5. Although decreased levels of VACM-1 mRNA detected in several cancers and cancer cell lines may explain the progression of cell growth, possible genetic and epigenetic changes in its sequence have not been analyzed. We hypothesized that in rapidly proliferating cells, VACM-1/cul5 may be mutated at either the PKA-specific phosphorylation site or the consensus neddylation site. We used RT-PCR and PCR, to amplify and to sequence mRNA and genomic DNA, respectively. To date we have sequenced all 19 coding exons of the VACM-1/cul5 gene in T47D breast cancer cells, U138MG glioma cells, ACHN renal cancer cells, and OVCAR-3 ovarian cancer cells. Our results indicate that in those cells VACM-1/cul5 is not mutated at the putative phosphorylation or the neddylation site. We have found one silent mutation in the genomic DNA isolated from U138MG, ACHN, and OVCAR-3 cell lines, but not from T47D cells. Our work suggests that in T47D breast cancer cells biologic activity of VACM-1/cul5 may be regulated by posttranslational modifications.