Publications by authors named "John Mullinax"

40 Publications

Management of Primary Retroperitoneal Sarcoma (RPS) in the Adult: An Updated Consensus Approach from the Transatlantic Australasian RPS Working Group.

Ann Surg Oncol 2021 Apr 14. Epub 2021 Apr 14.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Retroperitoneal soft tissue sarcomas comprise a heterogeneous group of rare tumors of mesenchymal origin that include several well-defined histologic subtypes. In 2015, the Transatlantic Australasian RPS Working Group (TARPSWG) published consensus recommendations for the best management of primary retroperitoneal sarcoma (RPS). Since then, through international collaboration, new evidence and knowledge have been generated, creating the need for an updated consensus document.

Methods: The primary aim of this study was to critically evaluate the current evidence and develop an up-to-date consensus document on the approach to these difficult tumors. The resulting document applies to primary RPS that is non-visceral in origin, with exclusion criteria as previously described. The relevant literature was evaluated and an international group of experts consulted to formulate consensus statements regarding the best management of primary RPS. A level of evidence and grade of recommendation were attributed to each new/updated recommendation.

Results: Management of primary RPS was considered from diagnosis to follow-up. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the 29 consensus statements included in this article, which were agreed upon by all of the authors. Whenever possible, patients should be enrolled in prospective trials and studies.

Conclusions: Ongoing international collaboration is critical to expand upon current knowledge and further improve outcomes of patients with RPS. In addition, prospective data collection and participation in multi-institution trials are strongly encouraged.
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http://dx.doi.org/10.1245/s10434-021-09654-zDOI Listing
April 2021

Expansion of tumor-infiltrating lymphocytes (TIL) from penile cancer patients.

Int Immunopharmacol 2021 May 23;94:107481. Epub 2021 Feb 23.

Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA; Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA; Center for Immunization and Infection Research in Cancer (CIIRC), Moffitt Cancer Center, Tampa, FL, USA. Electronic address:

Penile cancer is a rare but highly lethal cancer, and therapeutic options for patients presenting with lymph nodal disease are very limited. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) was shown to provide durable objective response in patients with metastatic melanoma and TIL have been expanded from solid tumors at rates between 70 and 90% depending on the specific diagnosis. We evaluated whether TIL could be expanded from surgical specimens of patients with penile cancer. Tumor samples from metastatic lymph nodes obtained at the time of inguinal lymph node dissection were collected, minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. The phenotype of expanded TILs was assessed by flow cytometry and their anti-tumor reactivity was assessed by IFN-γ ELISA. TIL were expanded from 11 out of 12 (91.6%) samples of metastatic lymph nodes. Expanded TIL were predominantly CD3 (mean 67.5%, SD 19.4%) with a mean of 46.8% CD8 T cells (SD 21.1%). Five out of 11 samples (45.4%) from expanded TIL secreted IFN-γ in response to autologous tumor. TIL expansion and phenotype of expanded T cell lymphocytes were independent of previous HPV infection and treatment with neoadjuvant chemotherapy. This is the first report demonstrating successful expansion of tumor-reactive TIL from penile cancer patients, which support development of ACT strategies using TIL for the treatment of advanced and recurrent penile cancer.
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http://dx.doi.org/10.1016/j.intimp.2021.107481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205103PMC
May 2021

Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma.

Blood 2021 May;137(19):2621-2633

Department of Blood and Marrow Transplant and Cellular Immunotherapy.

Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory large B-cell lymphoma (LBCL). This study evaluated whether immune dysregulation, present before CAR T-cell therapy, was associated with treatment failure. Tumor expression of interferon (IFN) signaling, high blood levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and high blood interleukin-6 and ferritin levels were each associated with a lack of durable response. Similar to other cancers, we found that in LBCL tumors, IFN signaling is associated with the expression of multiple checkpoint ligands, including programmed cell death-ligand 1, and these were higher in patients who lacked durable responses to CAR-T therapy. Moreover, tumor IFN signaling and blood M-MDSCs associated with decreased axi-cel expansion. Finally, patients with high tumor burden had higher immune dysregulation with increased serum inflammatory markers and tumor IFN signaling. These data support that immune dysregulation in LBCL promotes axi-cel resistance via multiple mechanistic programs: insufficient axi-cel expansion associated with both circulating M-MDSC and tumor IFN signaling, which also gives rise to expression of immune checkpoint ligands.
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http://dx.doi.org/10.1182/blood.2020007445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120145PMC
May 2021

Expanded Tumor-infiltrating Lymphocytes From Soft Tissue Sarcoma Have Tumor-specific Function.

J Immunother 2021 Feb-Mar 01;44(2):63-70

Immunology.

Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) can generate durable clinical responses in patients with metastatic melanoma and ongoing trials are evaluating efficacy in other advanced solid tumors. The aim of this study was to develop methods for the expansion of tumor-reactive TIL from resected soft tissue sarcoma to a degree required for the ACT. From 2015 to 2018, 70 patients were consented to an institutional review board-approved protocol, and fresh surgical specimens were taken directly from the operating room to the laboratory. Fragments of the tumor (1 mm3) or fresh tumor digest were placed in culture for a period of 4 weeks. Successfully propagated TIL from these cultures were collected and analyzed by flow cytometry. TIL were cocultured with autologous tumor and function was assessed by measurement of interferon-γ in the supernatant by enzyme-linked immunosorbent assay. Initial TIL cultures were further expanded using a rapid expansion protocol. Nearly all specimens generated an initial TIL culture (91% fragment method, 100% digest method). The phenotype of the TIL indicated a predominant CD3+ population after culture (43% fragment, 52% digest) and TIL were responsive to the autologous tumor (56% fragment, 40% digest). The cultured TIL expanded to a degree required for clinical use following rapid expansion protocol (median: 490-fold fragment, 403-fold digest). The data demonstrate the feasibility of TIL culture from fresh soft tissue sarcoma. The derived TIL have tumor-specific reactivity and can be expanded to clinically relevant numbers. An active ACT clinical trial using the methods described in this report is now approved for patients with metastatic soft tissue sarcoma.
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http://dx.doi.org/10.1097/CJI.0000000000000355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111686PMC
August 2019

Intraoperative Localization Using an Implanted Radar Reflector Facilitates Resection of Non-Palpable Trunk and Extremity Sarcoma.

Ann Surg Oncol 2021 Jun 18;28(6):3366-3374. Epub 2020 Oct 18.

Sarcoma Department, H. Lee Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.

Background: Resecting non-palpable soft tissue tumors presents a unique challenge, particularly with recurrent disease in which surrounding tissue has been surgically manipulated and often irradiated. SAVI SCOUT is a radar-based localization device that was developed for breast tumor localization and was recently FDA-approved for localization of soft tissue tumors. Application of this technology to soft tissue sarcoma has not been previously reported.

Methods: We assembled a single-institution retrospective case series of patients with trunk and extremity sarcomas resected by five sarcoma surgeons using SAVI SCOUT from December 2018 to May 2020. Reflectors were placed preoperatively using image-guidance, and the radar detector was used intraoperatively to localize the target lesion. Clinical variables were abstracted from the electronic medical record including treatment history, pathology, and early oncologic outcomes. Using a focused review, we compared margin status and recurrence rates with previously published cohorts.

Results: Ten SAVI SCOUT-localized sarcoma resections were performed. Eight were for locally recurrent disease, of which seven (83%) had prior radiation. The remaining lesions became non-palpable after neoadjuvant chemotherapy. SAVI SCOUT facilitated resection in all cases with a margin-negative resection rate (77%) comparable to prior cohorts. In this high-risk population with a median follow-up of 14 months, only one patient recurred locally 7.5 months after SAVI SCOUT-localized resection, requiring re-resection.

Conclusion: SAVI SCOUT technology facilitated resection of non-palpable recurrent sarcoma of the trunk and extremities in all ten cases attempted. In a high-risk patient population, the pattern of recurrence has been primarily distant with one instance of local tumor recurrence.
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http://dx.doi.org/10.1245/s10434-020-09229-4DOI Listing
June 2021

Trends and Predictors of Failure of Minimally Invasive Surgery for Gastric GIST.

J Gastrointest Surg 2021 05 15;25(5):1319-1322. Epub 2020 Oct 15.

Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3760, Bethesda, MD, 20892, USA.

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http://dx.doi.org/10.1007/s11605-020-04816-yDOI Listing
May 2021

Intrapelvic melanocytic schwannoma resection with computer-assisted navigation.

Radiol Case Rep 2020 Nov 22;15(11):2385-2390. Epub 2020 Sep 22.

Sarcoma Department, Moffitt Cancer Center, Tampa, FL.

Melanocytic schwannoma is a rare nerve tumor characterized by melanin-producing neoplastic Schwann cells. Wide surgical resection is the management of choice for this tumor; however, anatomical location and proximity to nerve roots can make locating this tumor and the surgical resection challenging. Here we describe the case of 49-year-old male with a melanocytic schwannoma in the presacral area adjacent to the second sacral nerve root that was managed by wide resection aided by computer-assisted navigation due to the difficulty in identifying its location intraoperatively. The utilization of computer-assisted navigation improves accuracy and precision through the creation of a virtual continuous tridimensional map, particularly useful when oftentimes tumor margins may seem equivocal and further resection would compromise the patient's functionality. The value of computer-assisted navigation for soft tissue tumor resections in orthopedic oncology is still in its infancy, though, in certain scenarios it may advance the technique for some soft tissue resections.
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http://dx.doi.org/10.1016/j.radcr.2020.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516168PMC
November 2020

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel.

Clin Cancer Res 2020 09 15;26(18):4823-4831. Epub 2020 Jul 15.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Purpose: One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).

Experimental Design: Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.

Results: We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.

Conclusions: These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501265PMC
September 2020

Tumor grade may be used to select patients with multifocal hepatocellular carcinoma for resection.

HPB (Oxford) 2020 07 13;22(7):1004-1010. Epub 2019 Nov 13.

Surgical Oncology Program, National Cancer Institute, National Institutes of Health, 10 Center Drive Bethesda, MD, 20892, USA. Electronic address:

Background: While resection is a recommended treatment for patients with stage 1 hepatocellular carcinoma (HCC), it remains controversial for multifocal disease. We sought to identify patients with multifocal HCC with survival after resection similar to patients with clinical stage 1 HCC.

Methods: The National Cancer Database was queried to identify patients that underwent resection for HCC.

Results: In this study, 2990 patients with a single tumor, and 1087 patients with multifocal disease confined to one lobe underwent resection. In the multifocal cohort, patients with clinical stage 3 (HR 1.54, CI 1.31-1.81, p < 0.0001) or 4 (HR 2.27, CI 1.57-3.29, p < 0.0001) disease, and those with moderately-differentiated (HR 1.32, CI 1.06-1.64, p = 0.012) or poorly differentiated/undifferentiated tumors (HR 1.53, CI 1.20-1.95, p = 0.0006) were associated with worse overall survival (OS). There was no difference in OS between patients with well-differentiated clinical stage 2 multifocal HCC and those with all grades of clinical stage 1 HCC (median of 84.8 (CI 66.3-107.2) vs 76.2 months (CI 71.2-81.3), respectively, p = 0.356).

Conclusions: Patients with well-differentiated, clinical stage 2 multifocal HCC confined to one lobe experience similar OS following hepatic resection to patients with clinical stage 1 disease. These findings may impact the management of select patients with multifocal HCC.
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http://dx.doi.org/10.1016/j.hpb.2019.10.1531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771330PMC
July 2020

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer.

Oncoimmunology 2018;7(9):e1476816. Epub 2018 Jul 23.

Department of Genitourinary Oncology, Moffitt Cancer Center and Research Institute, Tampa, USA.

Advanced bladder cancer patients have limited therapeutic options resulting in a median overall survival (OS) between 12 and 15 months. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) has been used successfully in treating patients with metastatic melanoma, resulting in a median OS of 52 months. In this study, we investigated the feasibility of expanding TIL from the tumors of bladder cancer patients. Primary bladder tumors and lymph node (LN) metastases were collected. Tumor specimens were minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. Expanded TIL were phenotyped by flow cytometry and anti-tumor reactivity was assessed after co-culture with autologous tumor digest and IFN-gamma ELISA. Of the 28 transitional cell bladder or LN tumors collected, 14/20 (70%) primary tumors and all of the LN metastases demonstrated TIL expansion. Expanded TIL were predominantly CD3 (median 63%, range 10-87%) with a median of 30% CD8 + T cells (range 5-70%). TIL secreted IFN-gamma in response to autologous tumor. Addition of agonisitic 4-1BB antibody improved TIL expansion from primary bladder tumors regardless of pre-treatment with chemotherapy. This study establishes the practical first step towards an autologous TIL therapy process for therapeutic testing in patients with bladder cancer.
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http://dx.doi.org/10.1080/2162402X.2018.1476816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140546PMC
July 2018

Loss of PDPK1 abrogates resistance to gemcitabine in label-retaining pancreatic cancer cells.

BMC Cancer 2018 Jul 31;18(1):772. Epub 2018 Jul 31.

Rare Tumor Initiative, Cancer for Cancer Research, National Cancer Institute, Building 10, Room 2B-38E, Bethesda, MD, USA.

Background: Label-retaining cancer cells (LRCC) have been proposed as a model of slowly cycling cancer stem cells (CSC) which mediate resistance to chemotherapy, tumor recurrence, and metastasis. The molecular mechanisms of chemoresistance in LRCC remain to-date incompletely understood. This study aims to identify molecular targets in LRCC that can be exploited to overcome resistance to gemcitabine, a standard chemotherapy agent for the treatment of pancreas cancer.

Methods: LRCC were isolated following Cy5-dUTP staining by flow cytometry from pancreatic cancer cell lines. Gene expression profiles obtained from LRCC, non-LRCC (NLRCC), and bulk tumor cells were used to generate differentially regulated pathway networks. Loss of upregulated targets in LRCC on gemcitabine sensitivity was assessed via RNAi experiments and pharmacological inhibition. Expression patterns of PDPK1, one of the upregulated targets in LRCC, was studied in patients' tumor samples and correlated with pathological variables and clinical outcome.

Results: LRCC are significantly more resistant to gemcitabine than the bulk tumor cell population. Non-canonical EGF (epidermal growth factor)-mediated signal transduction emerged as the top upregulated network in LRCC compared to non-LRCC, and knock down of EGF signaling effectors PDPK1 (3-phosphoinositide dependent protein kinase-1), BMX (BMX non-receptor tyrosine kinase), and NTRK2 (neurotrophic receptor tyrosine kinase 2) or treatment with PDPK1 inhibitors increased growth inhibition and induction of apoptosis in response to gemcitabine. Knockdown of PDPK1 preferentially increased growth inhibition and reduced resistance to induction of apoptosis upon gemcitabine treatment in the LRCC vs non-LRCC population. These findings are accompanied by lower expression levels of PDPK1 in tumors compared to matched uninvolved pancreas in surgical resection specimens and a negative association of membranous localization on IHC with high nuclear grade (p < 0.01).

Conclusion: Pancreatic cancer cell-derived LRCC are relatively resistant to gemcitabine and harbor a unique transcriptomic profile compared to bulk tumor cells. PDPK1, one of the members of an upregulated EGF-signaling network in LRCC, mediates resistance to gemcitabine, is found to be dysregulated in pancreas cancer specimens, and might be an attractive molecular target for combination therapy studies.
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http://dx.doi.org/10.1186/s12885-018-4690-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069886PMC
July 2018

T cell mediated immunity after combination therapy with intralesional PV-10 and blockade of the PD-1/PD-L1 pathway in a murine melanoma model.

PLoS One 2018 25;13(4):e0196033. Epub 2018 Apr 25.

Department of Immunology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

Intralesional (IL) injection of Rose Bengal (PV-10) induces regression of injected and uninjected lesions in several murine tumor models. In this study, we investigated the anti-tumor response of combining IL PV-10 with blockade of the PD-1 / PD-L1 pathway and the role of immune cell populations in eliciting this response. To investigate the role of T cell subsets in mediating an immune response, B16 or M05 melanoma-bearing mice received combination therapy as well as CD8+, CD4+, or CD25+ depleting antibodies. Tumor growth was measured. T cells were collected from spleens or tumors, and phenotype, activation markers, and reactivity were measured. Splenocytes from mice treated with combination therapy had increased OVA antigen-specific CD8+ T cells in M05-tumor-bearing mice. Depletion of CD4+ T cells or regulatory T cells (Tregs) in combination with IL PV-10 and anti-PD-1 antibody treatment resulted in an enhanced anti-tumor effect. Treatment with CD8+ depleting antibody abrogated anti-tumor immunity. These results support a clinical study for the safety and anti-tumor immune responses with combination therapy of IL PV-10 and PD-1/PD-L1 blockade.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196033PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918896PMC
July 2018

Combination of Ipilimumab and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.

Front Oncol 2018 2;8:44. Epub 2018 Mar 2.

Immunology Department, Moffitt Cancer Center, Tampa, FL, United States.

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for metastatic melanoma can be highly effective, but attrition due to progression before TIL administration (32% in prior institutional experience) remains a limitation. We hypothesized that combining ACT with cytotoxic T lymphocyte-associated antigen 4 blockade would decrease attrition and allow more patients to receive TIL.

Experimental Design: Thirteen patients with metastatic melanoma were enrolled. Patients received four doses of ipilimumab (3 mg/kg) beginning 2 weeks prior to tumor resection for TIL generation, then 1 week after resection, and 2 and 5 weeks after preconditioning chemotherapy and TIL infusion followed by interleukin-2. The primary endpoint was safety and feasibility. Secondary endpoints included of clinical response at 12 weeks and at 1 year after TIL transfer, progression free survival (PFS), and overall survival (OS).

Results: All patients received at least two doses of ipilimumab, and 12 of the 13 (92%) received TIL. A median of 6.5 × 10 (2.3 × 10 to 1.0 × 10) TIL were infused. At 12 weeks following infusion, there were five patients who experienced objective response (38.5%), four of whom continued in objective response at 1 year and one of which became a complete response at 52 months. Median progression-free survival was 7.3 months (95% CI 6.1-29.9 months). Grade ≥ 3 immune-related adverse events included hypothyroidism (3), hepatitis (2), uveitis (1), and colitis (1).

Conclusion: Ipilimumab plus ACT for metastatic melanoma is feasible, well tolerated, and associated with a low rate of attrition due to progression during cell expansion. This combination approach serves as a model for future efforts to improve the efficacy of ACT.
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http://dx.doi.org/10.3389/fonc.2018.00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840208PMC
March 2018

Pancreaticoduodenectomy in the surgical management of primary retroperitoneal sarcoma.

Eur J Surg Oncol 2018 06 5;44(6):810-815. Epub 2018 Feb 5.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: In retroperitoneal sarcoma (RPS), the optimal extent of resection must balance adequate disease control with potential for morbidity. We sought to study the frequency and outcomes after a Whipple procedure or pancreaticoduodenectomy (PD) in patients undergoing resection for primary RPS.

Methods: Participating referral centers within the Trans-Atlantic Retroperitoneal Sarcoma Working Group provided retrospective data from January 2007 to December 2016 for patients with primary RPS who underwent PD along with the total number of consecutive resections done during the same time period. Data from participating centers were combined for analysis.

Results: In total, 29 patients underwent PD among 2068 resections performed for primary RPS (1.4%). The predominant histologic subtypes were liposarcoma and leiomyosarcoma. All PD patients underwent concomitant resection of additional organs (median: 2, range: 1-5), including 13 patients (45%) who also received vena cava resection. Definitive evidence of microscopic invasion of the duodenum or pancreas was seen in 84% of patients. Postoperatively, 10 patients (34%) had major complications including 8 (28%) that developed a clinically-significant pancreatic leak. One postoperative death (3.4%) occurred. With a median follow-up of 4.8 years, 19 patients (66%) developed disease recurrence. The patterns of recurrence were dependent on histologic subtype.

Conclusion: Although infrequent, when PD is done for primary RPS, resection of additional organs is often required and major complication rates are moderate. The recurrence rate is overall high and the pattern of recurrence is dictated by histologic subtype.
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http://dx.doi.org/10.1016/j.ejso.2018.01.086DOI Listing
June 2018

The Changing Paradigm of Management of Liver Abscesses in Chronic Granulomatous Disease.

Clin Infect Dis 2018 04;66(9):1427-1434

Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryl.

Background: Chronic granulomatous disease (CGD) is a rare genetic disorder causing recurrent infections. More than one-quarter of patients develop hepatic abscesses and liver dysfunction. Recent reports suggest that disease-modifying treatment with corticosteroids is effective for these abscesses. Comparison of corticosteroid therapy to traditional invasive treatments has not been performed.

Methods: Records of 268 patients with CGD treated at the National Institutes of Health from 1980 to 2014 were reviewed. Patients with liver involvement and complete records were included. We recorded residual reactive oxygen intermediate (ROI) production by neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase germline mutation status, laboratory values, imaging characteristics, time to repeat hepatic interventions, and overall survival among 3 treatment cohorts: open liver surgery (OS), percutaneous liver-directed interventional radiology therapy (IR), and high-dose corticosteroid management (CM).

Results: Eighty-eight of 268 patients with CGD suffered liver involvement. Twenty-six patients with a median follow-up of 15.5 years (8.5-32.9 years of follow-up) had complete records and underwent 100 standard interventions (42 IR and 58 OS). Eight patients received a treatment with high-dose corticosteroids only. There were no differences in NADPH genotype, size, or number of abscesses between patients treated with OS, IR, or CM. Time to repeat intervention was extended in OS compared with IR (18.8 vs 9.5 months, P = .04) and further increased in CM alone (median time to recurrence not met). Impaired macrophage and neutrophil function measured by ROI production correlated with shorter time to repeat intervention (r = 0.6, P = .0019).

Conclusions: Treatment of CGD-associated liver abscesses with corticosteroids was associated with fewer subsequent hepatic interventions and improved outcome compared to invasive treatments.
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http://dx.doi.org/10.1093/cid/cix1012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248449PMC
April 2018

Isolated Limb Infusion: A Single-Center Experience with Over 200 Infusions.

Ann Surg Oncol 2017 Dec 10;24(13):3842-3849. Epub 2017 Oct 10.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Background: Isolated limb infusion (ILI) is a minimally invasive technique for delivering regional chemotherapy to an extremity for patients with locally advanced cutaneous malignancies and sarcoma.

Methods: A single-institution, prospectively collected database was analyzed for intention-to-treat with ILI.

Results: From 2007 to 2016, 163 patients underwent 205 procedures (201 were successfully completed), and four malignancies were treated: melanoma (72.1% of all ILIs), sarcoma (23.4%), squamous cell carcinoma (SCC; 2.0%) and Merkel cell carcinoma (MCC; 2.5%). A median grade II regional Wieberdink toxicity score was observed, with 88.1% of patients experiencing grade II or less. Median follow-up was 21.8 months, and overall response rate (ORR) was 59.0% for melanoma, 48.9% for sarcoma, 50.0% for SCC, and 60.0% for MCC. A significant difference (p = 0.04) between upper (76.9%) and lower extremity (55.1%) ORR was observed in patients with melanoma. When comparing responders with nonresponders, patients with melanoma had significantly longer in-field progression-free survival (IPFS; 14.1 vs. 3.2 months, p < 0.001), distant metastatic-free survival (DMFS; not reached vs. 25.8 months, p = 0.006), and overall survival (OS; 56.0 vs. 26.7 months, p = 0.0004). Sarcoma responders had a significantly longer IPFS (13.0 vs. 2.7 months, p < 0.0001), but no significant distant metastatic or OS advantage. Over a median follow-up of 19.3 months, sarcoma patients had an overall limb salvage rate of 68.4%.

Conclusion: ILI is a well-tolerated procedure for patients with locally advanced melanoma, sarcoma, and other cutaneous malignancies. ILI responders had a significantly longer time to IPFS, while melanoma responders also had a DMFS and OS advantage.
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http://dx.doi.org/10.1245/s10434-017-6107-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771340PMC
December 2017

Staged reconstruction brachytherapy has lower overall cost in recurrent soft-tissue sarcoma.

J Contemp Brachytherapy 2017 Feb 31;9(1):20-29. Epub 2017 Jan 31.

Radiation Oncology.

Purpose: Adjuvant brachytherapy (AB) with immediate (IR) and staged reconstruction (SR) are distinct treatment modalities available for patients with recurrent soft tissue sarcoma (STS). Although SR may offer local control and toxicity benefit, it requires additional upfront procedures, and there is no evidence that it improves overall survival. With the importance of value-based care, our goal is to identify which technique is more cost effective.

Material And Methods: A retrospective review of 22 patients with recurrent extremity STS treated with resection followed by AB alone. Hospital charges were used to compare the cost between SR and IR at the time of initial treatment, at 6-month intervals following surgery, and cumulative cost comparisons at 18 months.

Results: Median follow-up was 31 months. Staged reconstruction ( = 12) was associated with an 18-month local control benefit (85% vs. 42%, = 0.034), compared to IR ( = 10). Staged reconstruction had a longer hospital stay during initial treatment (10 vs. 3 days, = 0.002), but at 18 months, the total hospital stay was no longer different (11 vs. 11 days). Initially, there was no difference in the cost of SR and IR. With longer follow-up, cost eventually favored SR, which was attributed primarily to the costs associated with local failure (LF). On multivariate analysis, cost of initial treatment was associated with length of hospital stay (~$4.5K per hospital day, < 0.001), and at 18 months, the cumulative cost was ~175K lower with SR ( = 0.005) and $58K higher with LF ( = 0.02).

Conclusions: In recurrent STS, SR has a longer initial hospital stay when compared to IR. At 18 months, SR had lower rates of LF, translating to lower total costs for the patient. SR is the more cost-effective brachytherapy approach in the treatment of STS, and should be considered as healthcare transitions into value-based medicine.
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http://dx.doi.org/10.5114/jcb.2017.65641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346606PMC
February 2017

Isolated Limb Infusion as a Limb Salvage Strategy for Locally Advanced Extremity Sarcoma.

J Am Coll Surg 2017 Apr 15;224(4):635-642. Epub 2017 Feb 15.

Sarcoma Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Background: Treatment-resistant, locally advanced soft tissue sarcomas often require amputation for complete tumor extirpation. Isolated limb infusion (ILI) selectively delivers high-dose chemotherapy to the extremity in an attempt to achieve limb salvage. The aim of this study was to report perioperative and oncologic outcomes after ILI in patients with extremity soft tissue sarcomas.

Study Design: From 1994 to 2016, 77 patients underwent 84 ILIs at a total of 5 institutions. Melphalan and actinomycin D were circulated for 30 minutes after complete tourniquet occlusion of the limb, then actively washed out to prevent systemic exposure.

Results: The procedure was performed in an upper extremity on 19 patients (21 infusions) and in a lower extremity on 58 patients (63 infusions). The 3-month overall response rate (ORR) for the entire cohort was 58%, and there was a statistically significant difference (p = 0.03) between upper (37%) and lower extremity (66%) ORR. With median follow-up of 20.6 months (range 0.6 to 146.1 months), the overall limb salvage rate was 77.9%. For those who underwent amputation due to progression of disease, the median time to amputation was 4.5 months. With a median follow-up of 20.6 months, the median overall survival for the entire cohort was 44.3 months. The distant metastatic-free survival was longer for responders than nonresponders (p = 0.01), though the disease-specific survival was not different for the same groups (p = 0.2).

Conclusions: Isolated limb infusion for extremity soft tissue sarcoma results in an objective response for half of the patients who are otherwise facing amputation, and offers prolonged limb salvage for the vast majority of patients. The procedure is well tolerated without serious complications.
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http://dx.doi.org/10.1016/j.jamcollsurg.2016.12.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771304PMC
April 2017

Management of Truncal Sarcoma.

Surg Clin North Am 2016 Oct;96(5):1003-13

Sarcoma Department, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33606, USA. Electronic address:

The management of truncal sarcoma presents unique challenges to the treating physician for reasons specific to this tumor location. First, the reconstruction options after resection of the abdominal or chest wall require a balance between cosmesis and structural integrity due to the multiplanar forces exerted on this region. Second, the histologies that commonly arise in this region are often associated with high local recurrence rates, which often require complex decision making due to prior therapy. Finally, sarcomas of the trunk in the inguinal region involve those organs in the genitourinary system, of which resection can have significant psychosocial implications.
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http://dx.doi.org/10.1016/j.suc.2016.06.005DOI Listing
October 2016

Liver Label Retaining Cancer Cells Are Relatively Resistant to the Reported Anti-Cancer Stem Cell Drug Metformin.

J Cancer 2016 6;7(9):1142-51. Epub 2016 Jun 6.

1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;; 6. Department of Surgery, Saint Peter's Healthcare System, Rutgers University, New Brunswick, NJ 08901, USA.

Background & Aims: Recently, we reported that liver Label Retaining Cancer Cells (LRCC) can initiate tumors with only 10 cells and are relatively resistant to the targeted drug Sorafenib, a standard of practice in advanced hepatocellular carcinoma (HCC). LRCC are the only cancer stem cells (CSC) isolated alive according to a stem cell fundamental function, asymmetric cell division. Metformin has been reported to preferentially target many other types of CSC of different organs, including liver. It's important to know if LRCC, a novel class of CSC, are relatively resistant to metformin, unlike other types of CSC. As metformin inhibits the Sorafenib-Target-Protein (STP) PI3K, and LRCC are newly described CSC, we undertook this study to test the effects of Metformin on Sorafenib-treated HCC and HCC-derived-LRCC.

Methods: We tested various STP levels and phosphorylation status, associated genes' expression, proliferation, viability, toxicity, and apoptosis profiles, before and after treatment with Sorafenib with/without Metformin.

Results: Metformin enhances the effects of Sorafenib on HCC, and significantly decreased viability/proliferation of HCC cells. This insulin-independent effect was associated with inhibition of multiple STPs (PKC, ERK, JNK and AKT). However, Metformin increased the relative proportion of LRCCs. Comparing LRCC vs. non-LRCC, this effect was associated with improved toxicity and apoptosis profiles, down-regulation of cell death genes and up-regulation of cell proliferation and survival genes in LRCC. Concomitantly, Metformin up-regulated pluripotency, Wnt, Notch and SHH pathways genes in LRCC vs. non-LRCC.

Conclusions: Metformin and Sorafenib have enhanced anti-cancer effects. However, in contradistinction to reports on other types of CSC, Metformin is less effective against HCC-derived-CSC LRCC. Our results suggest that combining Metformin with Sorafenib may be able to repress the bulk of tumor cells, but as with other anti-cancer drugs, may leave LRCC behind leading to cancer recurrence. Therefore, liver LRCC, unlike other types of CSC, are relatively resistant to the reported anti-cancer stem cell drug metformin. This is the first report that there is a type of CSC that is not relatively resistant to the CSC-targeting drug. Our findings suggest that a drug targeting LRCC may be critically needed to target CSC and prevent cancer recurrence. These may significantly contribute to the understanding of Metformin's anti-cancer effects and the development of novel drugs targeting the relatively resistant LRCC.
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http://dx.doi.org/10.7150/jca.10047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911882PMC
June 2016

Implications of staged reconstruction and adjuvant brachytherapy in the treatment of recurrent soft tissue sarcoma.

Brachytherapy 2016 Jul-Aug;15(4):495-503. Epub 2016 May 12.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Electronic address:

Purpose: Prior studies illustrated a reduction in wound complications with the use of staged reconstruction (SR) and negative pressure wound therapy when treating soft tissue sarcoma (STS) with surgical resection followed by high-dose-rate adjuvant brachytherapy. The purpose of this study is to compare the outcomes of SR and immediate reconstruction (IR) brachytherapy in recurrent STS.

Methods And Materials: A retrospective review of 40 patients with recurrent STS of the local extremity and trunk treated with resection followed by adjuvant brachytherapy alone. Margin status was defined as positive (SM(+)) if there was microscopic involvement (R1) or ≤1 mm margin and negative (SM(-)) if >1 mm margin was obtained. SR and IR were compared regarding toxicity, local control, and limb preservation.

Results: Median followup was 27 months. When comparing the SR (n = 22) and IR (n = 18) cohorts, there was a significantly lower final SM(+) rate in SR (32% vs. 83%, p < 0.01). A 2-year local control benefit seen with SR (80% vs. 34%; p = 0.012) and a final SM(-) (81% vs. 39%; p = 0.023). SR was associated with less toxicity on multivariate analysis, including a 90% decrease in persistent edema, an 80% decrease in wound dehiscence, and a 94% decrease in nonhealing wounds, when compared to IR. Ten of 31 (32%) extremity cases required eventual amputation from either chronic wound complications (n = 4) or local recurrence (n = 6). SR predicted for a benefit in 2-year limb preservation (88% vs. 50%; p = 0.008).

Conclusion: In our series, the treatment with SR brachytherapy resulted in less morbidity and an improved final SM(-) rate. This technique translated to an improvement in both local control and limb preservation of recurrent STS.
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http://dx.doi.org/10.1016/j.brachy.2016.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771533PMC
July 2017

Robotic Whipple Procedure for Pancreatic Cancer: The Moffitt Cancer Center Pathway.

Cancer Control 2015 Jul;22(3):340-51

Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.

Background: Resection of malignancies in the head and uncinate process of the pancreas (Whipple procedure) using a robotic approach is emerging as a surgical option. Although several case series of the robotic Whipple procedure have been reported, detailed descriptions of operative techniques and a clear pathway for adopting this technology are lacking.

Methods: We present a focused review of the procedure as it applies to pancreatic cancer and describe our clinical pathway for the robotic Whipple procedure used in pancreatic cancer and review the outcomes of our early experience. A systematic review of the literature is provided, focusing on the indications, variations in surgical techniques, complications, and oncological results of the robotic Whipple procedure.

Results: A clinical pathway has been defined for preoperative training of surgeons, the requirements for hospital privileges, patient selection, and surgical techniques for the robotic Whipple procedure. The robotic technique for managing malignant lesions of the pancreas head is safe when following well-established guidelines for adopting the technology. Preliminary data demonstrate that perioperative convalescence may exceed end points when compared with the open technique.

Conclusions: The robotic Whipple procedure is a minimally invasive approach for select patients as part of multidisciplinary management of periampullary lesions in tertiary centers where clinicians have developed robotic surgical programs. Prospective trials are needed to define the short- and long-term benefits of the robotic Whipple procedure.
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http://dx.doi.org/10.1177/107327481502200313DOI Listing
July 2015

Jejunal diverticulosis found in a patient with long-standing pneumoperitoneum and pseudo-obstruction on imaging: a case report.

Gastroenterol Rep (Oxf) 2016 Nov 27;4(4):337-340. Epub 2015 Jul 27.

Department of Surgical Oncology, Moffitt Cancer Center, Tampa, FL, USA

Small bowel diverticulosis is a rare finding within the general population and jejunal diverticulosis, specifically, is even rarer. Clinical manifestations can range from post-prandial pain, constipation and malabsorption to serious complications, such as gastro-intestinal hemorrhage, perforation and acute intestinal obstruction. Here we describe the case of an 81-year-old gentleman who presented with a three-year history of abdominal pain and weight loss. Despite unremarkable physical examination and laboratory tests, persistent pneumoperitoneum and dilated loops of small bowel were found on imaging. Having been given a diagnosis of small bowel bacterial overgrowth, the patient underwent capsule endoscopy study for further evaluation of his small bowel. The capsule did not reach the colon and the patient never noted passing the capsule in his stool so, six months post-procedure, a computed tomography (CT) scan seemed to reveal the retained capsule. Subsequent exploratory laparotomy revealed 200 cm of atonic, dilated jejunum with impressive diverticula along the anti-mesenteric border. This case report is an example of an unusual set of presenting signs and symptoms of jejunal diverticulosis, including persistent pneumoperitoneum, pseudo-obstruction and small bowel bacterial overgrowth. A literature review has revealed that these signs have been present in other cases of jejunal diverticulosis, although the etiology and pathophysiology is not clearly understood.
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http://dx.doi.org/10.1093/gastro/gov033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193057PMC
November 2016

Impact of maximal cytoreductive surgery plus regional heated intraperitoneal chemotherapy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric origin: results of the GYMSSA trial.

J Surg Oncol 2014 Sep 5;110(3):275-84. Epub 2014 Jul 5.

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Background: A prospective randomized trial was conducted to compare the impact of systemic chemotherapy versus multi-modality therapy (complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic chemotherapy) on overall survival (OS) in patients with gastric carcinomatosis.

Methods: Patients with measurable metastatic gastric adenocarcinoma involving the peritoneum, and resectable to "no evidence of disease" were randomized to gastrectomy, metastasectomy, HIPEC, and systemic FOLFOXIRI (GYMS arm) or FOLFOXIRI alone (SA arm).

Results: Seventeen patients were enrolled (16 evaluable); 7 of 9 patients in the multi-modality GYMS arm achieved complete cytoreduction (CCR0). Median OS was 11.3 months in the GYMS arm and 4.3 months in the SA arm. Four patients in the GYMS arm survived >12 months, 2 patients close to 2 years at last follow-up, and 1 patient more than 4 years, with 2 of these patients still alive. No patient in the SA arm lived beyond 11 months. All patients surviving beyond 12 months in the surgery arm achieved complete cytoreduction and had an initial Peritoneal Cancer Index (PCI) of ≤ 15.

Conclusion: Maximal cytoreductive surgery combined with regional (HIPEC) and systemic chemotherapy in selected patients with gastric carcinomatosis and limited disease burden can achieve prolonged survival.
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http://dx.doi.org/10.1002/jso.23633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301031PMC
September 2014

Wnt and the cancer niche: paracrine interactions with gastrointestinal cancer cells undergoing asymmetric cell division.

J Cancer 2013 2;4(6):447-57. Epub 2013 Jul 2.

1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;

Objective: Stem-like cancer cells contribute to cancer initiation and maintenance. Stem cells can self-renew by asymmetric cell division (ACD). ACD with non-random chromosomal cosegregation (ACD-NRCC) is one possible self-renewal mechanism. There is a paucity of evidence supporting ACD-NRCC in human cancer. Our aim was to investigate ACD-NRCC and its potential interactions with the cancer niche (microenvironment) in gastrointestinal cancers.

Design: We used DNA double and single labeling approaches with FACS to isolate live cells undergoing ACD-NRCC.

Results: Gastrointestinal cancers contain rare subpopulations of cells capable of ACD-NRCC. ACD-NRCC was detected preferentially in subpopulations of cells previously suggested to be stem-like/tumor-initiating cancer cells. ACD-NRCC was independent of cell-to-cell contact, and was regulated by the cancer niche in a heat-sensitive paracrine fashion. Wnt pathway genes and proteins are differentially expressed in cells undergoing ACD-NRCC vs. symmetric cell division. Blocking the Wnt pathway with IWP2 (WNT antagonist) or siRNA-TCF4 resulted in suppression of ACD-NRCC. However, using a Wnt-agonist did not increase the relative proportion of cells undergoing ACD-NRCC.

Conclusion: Gastrointestinal cancers contain subpopulations of cells capable of ACD-NRCC. Here we show for the first time that ACD-NRCC can be regulated by the Wnt pathway, and by the cancer niche in a paracrine fashion. However, whether ACD-NRCC is exclusively associated with stem-like cancer cells remains to be determined. Further study of these findings might generate novel insights into stem cell and cancer biology. Targeting the mechanism of ACD-NRCC might engender novel approaches for cancer therapy.
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http://dx.doi.org/10.7150/jca.6896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726705PMC
July 2013

Colorectal cancer biomarkers and the potential role of cancer stem cells.

J Cancer 2013 15;4(3):241-50. Epub 2013 Mar 15.

1. Georgetown University Hospital, Washington, DC, USA.

Over 50% of patients with colorectal cancer (CRC) will progress and/or develop metastases. Biomarkers capable of predicting progression, risk stratification and therapeutic benefit are needed. Cancer stem cells are thought to be responsible for tumor initiation, dissemination and treatment failure. Therefore, we hypothesized that CRC stem cell markers (CRCSC) can identify a group of patients whom are at increased risk for recurrence or progression of disease. If proven correct, these CRCSC biomarkers may herald a paradigm shift in the treatment of this deadly disease. This manuscript reviews current CRC evidence based screening modalities, patient stratification, and summarizes the current state of biomarkers and discusses the novel concept of putative CRCSC's as prognostic biomarkers.
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http://dx.doi.org/10.7150/jca.5832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584837PMC
March 2013

Label-retaining liver cancer cells are relatively resistant to sorafenib.

Gut 2013 Dec 14;62(12):1777-86. Epub 2013 Feb 14.

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, , Bethesda, Maryland, USA.

Objective: The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib.

Methods: We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib.

Results: LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed.

Conclusions: Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.
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http://dx.doi.org/10.1136/gutjnl-2012-303261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993136PMC
December 2013

Survival after pancreatectomy for pancreatic adenocarcinoma is not impacted by performance status.

Am J Surg 2012 Nov;204(5):704-8

Department of Surgery, University of South Florida College of Medicine, Tampa, FL 33606, USA.

Background: Patients with the best performance status have the best prognosis after resection for pancreatic adenocarcinoma. This study was undertaken to determine the impact of performance status on survival after pancreatectomy for adenocarcinoma.

Methods: Patients with a Karnofsky Performance Score (KPS) status (KPS) ≥60 after pancreatectomy for adenocarcinoma were evaluated, and the impact of the KPS at 6 weeks after pancreatectomy on survival was determined using survival curve analysis.

Results: Recurrence was experienced by 84% of patients and negatively impacted patient survival. The median overall survival was 12 months, and the 2-year overall survival was 35%. The KPS after pancreatectomy did not impact survival when using survival curve analysis (P = .5740).

Conclusions: Performance status for patients with a KPS ≥60 after pancreatectomy does not impact survival. Patients with pancreatic adenocarcinoma without adjuvant therapy have poor overall survival, and KPS after pancreatectomy for adenocarcinoma should not be used to withhold therapy for these patients.
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http://dx.doi.org/10.1016/j.amjsurg.2012.01.016DOI Listing
November 2012