Complete Tumor Clearance Research Articles

Application of indocyanine green near infrared fluorescence imaging in the surgical treatment of hepato-cellular carcinoma

Objective To investigate the clinical application of indocyanine green (ICG) near infrared fluorescence imaging in the surgical treatment of hepatocellular carcinoma (HCC). Method The prospective study was adopted. The clinicopathologic data of 24 patients with HCC who underwent surgical resection at the General Hospital of PLA from October 2014 to February 2015 were collected. Intravenous injection of ICG (0.5 mg/kg) was performed before surgery (range, 20.0-120.0 hours, mean, 47.5 hours). After free liver in open surgery, tumor lesions were displayed by fluorescent detector probe and completely resected under the guidance of the probe. The residual liver in vivo was detected, especially resection margin, and rapid frozen pathological examination of suspected lesions were conducted during operation. Fluorescence imaging of isolated tumor specimens was performed, the results of which were analyzed with results of pathological examination. Fluorescence imaging characteristics of the preoperative tumor, new lesions and isolated tumor specimens were observed. The follow-up using outpatient examination and telephone interview was performed for 1 year up to October 2015. The enhanced rescan of computed tomography (CT) and laboratory reexamination were performed every 3 months, and recurrence rate and mortality were recorded. Measurement data with normal distribution were represented as average (range). Result (1) Twenty-four primary lesions in 24 patients were detected by preoperative imaging examination. Of the 24 primary lesions, 19 showed fluoresce on the liver surface with an average depth of 0.36 cm (range, 0.00-0.65 cm) and an average diameter of 6.20 cm (range, 1.20-9.00 cm), 5 didn't show fluoresce with an average depth of 1.52 cm (range, 0.90-2.60 cm) and an average diameter of 4.60 cm (range, 1.50-7.80 cm). (2) Thirteen new suspicious lesions were detected in the residual liver, with an average depth of 0.30 cm (range, 0.00-0.60 cm) and an average diameter of 0.65 cm (range, 0.20-1.20 cm). The results of intraoperative rapid frozen pathological examination showed that cirrhotic liver nodule was diagnosed in 4 patients, cancer in 3 patients (1 with high-differentiated tumor and 2 with moderate-differentiated tumor), dysplasia in 2 patients, inflammatory changes in 2 patients and fatty degeneration in 2 patients. (3) Isolated tumor specimens from 24 patients were cut along the center, with strong fluoresce on the sections. Eleven high-differentiated tumors showed tumor tissue imaging, 2 of 9 moderate-differentiated tumors showed tumor tissue imaging and 7 of 9 moderate-differentiated tumors showed annular fluorescent imaging of tumor peripheral tissue, 4 poor-differentiated tumors showed annular fluorescent imaging of tumor peripheral tissue. (4) All the 24 patients were followed up for 1 year without death, and 3 of 24 patients had tumor recurrences with an average recurrence time of 8.3 months (range, 5.0-11.0 months) and received comprehensive treatment as the main treatment of surgery. Conclution ICG mediated near infrared fluorescence imaging during the surgery can not only display the primary tumor location clearly, but also detect small lesions which are invisible by routine preoperative imaging examination or during operation, with an advantage of complete tumor clearance. Key words: Liver neoplasms; Indocyanine green; Near-infrared; Fluorography; Surgical procedures, operative

Aneurysmal bone cyst of C2 treated with novel anterior reconstruction and stabilization.

Aneurysmal bone cysts (ABC) form 1% of primary bone tumors. Reported incidence rates are no more than 1.4 to 1,00,000. ABC of spine frequently involves posterior elements and commonly affects the lumbar spine (45%). We present a case of C2 ABC for the challenges it poses due to the rarity of the lesion, tedious to access location, dilemmas relating to the suitable approach for tumor resection and technically demanding stabilization and reconstruction strategy post resection. Clinical data analysis was performed to discuss a method of novel anterior column reconstruction following resection of a C2 aneurysmal bone cyst in a 8 year old child with anterior and posterior elements being involved. An 8-year-old girl with an aneurysmal bone cyst of the C2 vertebra underwent staged surgery following pre-operative embolisation. First a posterior approach tumor excision with posterior instrumented fusion was performed. Following which, using a modified anterior retropharyngeal approach anterior tumor excision and fibular graft reconstruction between the C1 lateral mass and C2 body was performed. Complete tumor clearance and stable reconstruction was successfully achieved in our patient. Patient showed excellent clinical outcome with radiological fusion. Preoperative embolisation in the treatment of ABC has supplemental advantage by reducing blood loss. Modified anterior retropharyngeal approach allows satisfactory clearance for C1-2 lesion and fibular strut graft between the C1 lateral mass and C2 body can provide a stable graft placement with good chance of fusion. Instability and spinal deformity, whether preexisting or post-excision, should be corrected with reconstruction and stabilization to offer best chance of cure in such cases.

Abstract B014: BGB324, a selective small molecule inhibitor of the receptor tyrosine kinase AXL, enhances immune checkpoint inhibitor efficacy

Abstract Signaling via the AXL receptor tyrosine kinase is a key suppressor of anti-tumor innate immune response. AXL is expressed on several cells associated with the suppressive tumor immune microenvironment including natural killer cells, dendritic cells and tumor-associated macrophages. AXL is also an important regulator of tumor plasticity related to epithelial-to-mesenchymal transition (EMT) that contributes to anti-tumor immune evasion. Hence AXL signaling contributes uniquely to tumor intrinsic and microenvironmental immune suppression in tumors. We therefore evaluated whether blocking AXL signaling with BGB324, a selective clinical-stage small molecule Axl kinase inhibitor, enhances the effect of immune checkpoint blockade in syngeneic cancer mouse models that display limited immunogenicity. We measured the effect of BGB324 in combination with anti-CTLA-4 and anti-PD-1 in the mammary adenocarcinoma 4T1/Balb/C syngeneic mouse model. BGB324 (50 mg/kg bid) significantly enhanced responsiveness to anti-CTLA-4/anti-PD-1 treatment (10 mg/kg of each, 4 doses) in Balb/C mice bearing 4T1 tumors. The combination of BGB324 + anti-CTLA-4/anti-PD-1 resulted in complete tumor clearance in 46.1 % of mice versus complete tumor clearance in 11.7 % of the mice treated with anti-CTLA-4/anti-PD-1 (p = 0.0087). BGB324 + anti-CTLA-4/anti-PD-1 treated tumors displayed enhanced CD8+ T cell tumor infiltration. Combination of BGB324 with immune checkpoint inhibitors is being evaluated in additional models, and detailed interrogation of AXL-dependent immune effector cell activity in tumors is in progress. In conclusion, AXL inhibition represents a unique opportunity to target anti-tumor immune suppressive mechanisms and supports clinical translation of BGB324 in combination with cancer immunotherapy in human cancer. Citation Format: Gro Gausdal, Kjersti Davidsen, Katarzyna Wnuk-Lipinska, Kathleen Wiertel, Monica Hellesøy, Magnus Blø, Lavina Ahmed, Linn Hodneland, Sergej Kiprijanov, Rolf A Brekken, James B Lorens. BGB324, a selective small molecule inhibitor of the receptor tyrosine kinase AXL, enhances immune checkpoint inhibitor efficacy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B014.

Neurological Recovery in Two Patients with Cauda Equina Syndrome Secondary to L5 Lumbar Spine Giant Cell Tumour after Treatment with Denosumab without Surgery.

We report two patients with cauda equina syndrome (CES) secondary to L5 giant cell tumour (GCT) who achieved good neurological recovery after treatment with denosumab without surgery. The first patient was a 26-year-old man with L5 GCT causing CES who regained bowel and urinary control, muscle power improvement from grade 2 to grade 4 and Oswestry disability index (ODI) improvement from 48 to 23 after denosumab treatment. The second patient was a 25-year-old woman with L5 GCT causing CES who regained bowel and urinary control, muscle power improvement from grade 0 to grade 4 and ODI improvement from 42 to 20 after denosumab treatment. The usage of denosumab in the treatment of patients with CES due to GCT allows potential neurological recovery without any surgical intervention. If surgery is not contraindicated, more time is obtained to prepare the patient preoperatively to attain safer surgery and to achieve complete tumour clearance.

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer

There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)-based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC-1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8(+) T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8(+) T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by αSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials.

Total pancreatectomy for primary pancreatic neoplasms: renaissance of an unpopular operation.

To assess the long-term survival and quality of life in total pancreatectomies and to identify risk factors for perioperative morbidity and mortality. Total pancreatectomy may be required in locally advanced or centrally located pancreatic neoplasms to achieve complete tumor clearance, but available data on short- and long-term results are limited. A total of 434 consecutive total pancreatectomies for primary pancreatic or periampullary tumors were performed between October 2001 and September 2012 at the authors' institution and were prospectively documented and analyzed. Long-term outcome was assessed using Kaplan-Meier and quality of life analysis (EORTC-QLQ-C30 and PAN26). Uni- and multivariate analysis was performed to identify perioperative risk factors and predictors for long-term survival. Extended total pancreatectomies were performed in 54% of cases, with arterial and portal vein resections in 15% and 32%, respectively. Overall 30-day and in-hospital mortality rates were 3.7% and 7.8%, respectively. High blood loss, long operative time, and arterial resections were independently associated with increased perioperative mortality (P ≤ 0.018). In malignant disease, median and 5-year survival were good for standard total pancreatectomies (28.6 months and 24.3%, respectively) and were significantly impaired after vascular resections (P < 0.001). Poor tumor grading, high American Joint Commission on Cancer tumor stage, age more than 70 years, and an R1 resection were independent prognostic parameters. Long-term global quality of life was comparable with a matched healthy control group. Standard total pancreatectomy, if needed, is associated with good long-term outcome in pancreatic cancer. Marked surgical morbidity and impaired survival associated with vascular resections reflect the invasiveness of extended total pancreatectomies and the underlying advanced malignant disease.

Superior Mesenteric Artery-First Approach in Radical Antegrade Modular Pancreatosplenectomy for Borderline Resectable Pancreatic Cancer: A Technique to Obtain Negative Tangential Margins

Early superior mesenteric artery (SMA) dissection from behind the head of the pancreas using an “artery-first approach” has been considered a safe and efficient technique in performing a pancreaticoduodenectomy for pancreatic cancer when SMA involvement is suspected. The goal of this approach for the resection of pancreatic head cancer is complete surgical removal of the tumor, ie, a no-residual-tumor (R0) resection, because the prognostic significance of complete tumor clearance at the resection margins has been demonstrated. Meanwhile, the preoperative diagnostic accuracy of various imaging studies in detecting vascular invasion, especially in borderline resectable pancreatic cancers, is unsatisfactory. For example, the specificity of a CT scan ranges from 67% to 91% due to difficulties in exact differentiation between cancer infiltration and fibrosis or tumor-mimicking adhesions. Therefore, surgical exploration is usually carried out in patients who are categorized as having borderline resectable disease because of the suspicion of arterial infiltration on the basis of imaging criteria. The biggest advantage of the artery-first approach is that it allows surgeons to make a final decision regarding resectability before reaching the “point of no return” during surgery. Many studies have therefore focused on this technique in performing a pancreaticoduodenectomy for cancers of the head of the pancreas, but its significance in pancreatosplenectomy has not been fully discussed. In 2003, Strasberg and colleagues demonstrated a new surgical procedure for cancers of the body and tail of

American Thyroid Association statement on preoperative imaging for thyroid cancer surgery.

The success of surgery for thyroid cancer hinges on thorough and accurate preoperative imaging, which enables complete clearance of the primary tumor and affected lymph node compartments. This working group was charged by the Surgical Affairs Committee of the American Thyroid Association to examine the available literature and to review the most appropriate imaging studies for the planning of initial and revision surgery for thyroid cancer. Ultrasound remains the most important imaging modality in the evaluation of thyroid cancer, and should be used routinely to assess both the primary tumor and all associated cervical lymph node basins preoperatively. Positive lymph nodes may be distinguished from normal nodes based upon size, shape, echogenicity, hypervascularity, loss of hilar architecture, and the presence of calcifications. Ultrasound-guided fine-needle aspiration of suspicious lymph nodes may be useful in guiding the extent of surgery. Cross-sectional imaging (computed tomography with contrast or magnetic resonance imaging) may be considered in select circumstances to better characterize tumor invasion and bulky, inferiorly located, or posteriorly located lymph nodes, or when ultrasound expertise is not available. The above recommendations are applicable to both initial and revision surgery. Functional imaging with positron emission tomography (PET) or PET-CT may be helpful in cases of recurrent cancer with positive tumor markers and negative anatomic imaging.

Hyaluronic Acid as a Marker of Sinusoidal Obstruction Syndrome after Oxaliplatin-based Chemotherapy for Colorectal Liver Metastases: Don’t Forget the Tumor

A few decades ago, patients with colorectal cancer liver metastases were considered incurable, and treatment was mainly supportive. Treatment options for patients with metastatic colorectal cancer have changed greatly since then, as has the outcome of these patients. Although in the past survival of these patients was within the range of a few months, with no 5-year survivors, current studies report median survival rates of 20–25 months and 5-year survival rates of 30–60 %. What has happened? Numerous studies have taught us that in selected patients, surgical resection of metastases prolongs survival. As hepatic resection has evolved to a safe procedure even in patients requiring extended, complex, and/or two-stage resection for complete tumor clearance, its use has increased and has added to the improved long-term outcome. However, only approximately 15 % to 20 % of patients are initially amenable to potentially curative resection; therefore, further factors must have played a role in the marked improvement in survival. The development and increased use of effective chemotherapeutic regimens has contributed significantly to the treatment results we are currently documenting for metastatic colorectal cancer. Several phase III trials proved that the addition of oxaliplatin or irinotecan to the backbone of 5-fluorouracil (5-FU) and folinic acid is able to achieve objective response rates of 40–50 %. The antitumor activity of these combined chemotherapy regimens has clearly improved median survival rates compared to historic data of patients who received 5-FU monotherapy, which was the standard of care in the late 1980s. Moreover, these improved regimens rendered the disease of a higher proportion of patients resectable. Resectability rates in firstline chemotherapy trials with palliative intent range from 5 to 15 % and go up to 30 % in patients with more limited yet still unresectable disease receiving chemotherapy for the intent of downstaging. Furthermore, the addition of biological agents such as bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), and cetuximab or panitumumab, monoclonal antibodies against the epidermal growth factor receptor, seem to further enhance response and resectability rates. Although the effectiveness of modern chemotherapy protocols in patients with metastatic colorectal cancer is undisputed, issues associated with these regimens, such as acquired resistance and increased toxicity, remain important future challenges for interdisciplinary management. In particular, liver toxicity related to the administration of irinotecanand oxaliplatin-containing regimens represents a significant concern; their development may interfere with the planned treatment concept. It has been demonstrated that preoperative chemotherapy correlates with significantly higher perioperative complications. Furthermore, the development of histological alterations in the liver parenchyma may impede the antitumor effects of systemic therapies. The pathological changes of the liver are specific to the administered agents. Irinotecan has been associated with chemotherapy-associated steatohepatitis. Oxaliplatin has been more frequently reported to cause hepatic injury, which typically manifests as sinusoidal obstruction syndrome (SOS) and occurs in up to 50 % of patients who receive an oxaliplatin-based regimen. SOS is considered to Society of Surgical Oncology 2013

478. Total Gastrectomy with Pancreatoduodenectomy for Advanced Gastric Cancer

Background: Treatment of gastric cancer, with tumor invading the pancreatic head or duodenum stays an open problem. This situation sounds dire if complete tumor clearance could be achieved by combination of pancreatoduodenectomy with total gastrectomy. Some favourable results after this procedure have been reported recently.

Fungating Thyroid Cancer: A Complex Clinical Scenario

Most research reporting the management of advanced thyroid cancer focuses on major aerodigestive system or vessel involvement. In the present study, we investigated patients with locally advanced thyroid cancers who presented with malignant skin infiltration. The term fungating thyroid cancer (fTC) has been used to describe such a condition. The study was based on prospective collection of clinical, laboratory, imaging, and pathological data of all patients admitted to the head and neck and endocrine surgery unit, Main University Hospital, Alexandria School of Medicine, during the period April 2005-March 2011. Eleven patients were referred with fTC, eight of whom had undergone subtotal thyroidectomy for an undiagnosed well-differentiated thyroid cancer (DTC) in another institution. The final pathological diagnosis showed (DTC, n = 3), poorly differentiated thyroid cancer (n = 5), anaplastic cancer (n = 2), and medullary thyroid cancer (n = 1). Extensive resections and reconstruction using flaps (pectoralis major, n = 6; deltopectoral, n = 1; sternocleidomastoid, n = 1) were undertaken. Complete tumor clearance (R0) was achieved in one patient and the others had microscopic (R1, n = 6) or macroscopic (R2, n = 1) residual disease. The three patients who did not undergo operation died within one month of presentation. The latest review of the eight patients who did undergo operation ranged from 3 to 6 months, but their survival remains unknown as access for follow-up was limited.

Phase I Dose-Escalation Study of SCH 900776 in Combination with Cytarabine (Ara-C) in Patients with Acute Leukemia

Abstract 1531Checkpoint kinase (Chk1) is a serine-threonine kinase that is activated via phosphorylation in response to DNA damage and is critical to the regulation of cell cycle progression. Ara-C triggers sequential activation of ATR kinase and Chk1 ex vivo to induce the S phase slowing that accompanies Ara-C treatment. Inhibition of Chk1 may abrogate S phase slowing, thereby preventing repair of Ara-C-induced DNA damage and potentiating the antitumor activity of Ara-C. The Hsp90 inhibitor tanespimycin (17-AAG) has been shown to enhance the cytotoxicity of Ara-C in part through Chk1 downregulation (RA Mesa et al., Blood 2005). While a phase I trial of Ara-C plus 17-AAG resulted in decreased blast cell Chk1 phosphorylation, drug toxicities precluded the clinical use of tanespimycin (SH Kaufmann et al., Haematologica, in press 2011). We have now tested the selective Chk1 inhibitor SCH 900776 (SCH 776) in combination with Ara-C in a Phase I dose-escalation trial in 24 adult patients with relapsed and refractory acute leukemias.AML (21)ALL (2)CML-BC (1)Male/Female9/121/11/0Age (range)57 (23–73)30, 6336Previous Ara-C1901Relapsed810No. Prior CRs2 (1–3)20Prior Stem Cell Transplant600Refractory1311No. Prior Regimens2 (1–4)33Prior Stem Cell Transplant100Secondary AML800MDS/MPD600Treatment-Related200Adverse Genetics1311Single cytogenetics310Complex cytogenetics1101Patients received Ara-C 667 mg/m2 on days 1–3 and 10–12 via 72-hour IV infusion along with SCH 776 on days 2, 3, 11, and 12 over 15 min IV starting at 10 mg/m2 (n=3) escalated to 20 mg/m2 (n=3), 40 mg/m2 (n=6), 56 mg/m2 (n=6), and flat dose of 140 mg (n=6) administered over 30 min IV. Maximal administered dose was achieved at 140 mg due to grade 3 prolonged QTc interval (n=1) and grade 3 hand-foot skin reaction (n=1). None of the expected mucosal or marrow toxicities of timed sequential Ara-C were exacerbated by SCH 776. Complete tumor clearance from day 14 bone marrow was detected in 13/24 (54%). CR plus CRi occurred in 7 patients (29%), with 6 of those CRs occurring at 40 mg/m2 or higher (response rate 40% for ≥ dose level 3). Examination of sequential samples of marrow blasts harvested pretreatment (day 0), 24 hours after initial Ara-C infusion prior to SCH 776 (day 2), and 2 hours after the second SCH 776 administration (day 3) demonstrated increased phosphorylation of Chk1 at Ser317 or Ser345 beginning at 40 mg/m2 consistent with the presence of unrepaired damage and further ATR activation. Pharmacokinetic (PK) data in each cohort showed lack of significant accumulation of SCH 776 in plasma. We plan for a randomized Phase II trial with 100 mg flat dose (or equivalent of 56 mg/m2) of SCH 900776 to assess any contributions to net Ara-C cytotoxicity and efficacy in relapsed and refractory acute leukemias. Disclosures:Gore:Celgene: Consultancy, Equity Ownership, Research Funding. Loechner:Merck Research Laboratories: Employment. Horowitz:Merck Research Labs: Employment, stock. Karp:Schering Merck: Research Funding.

Escalation Trial of Clofarabine Followed by Escalating Dose of Fractionated Cyclophosphamide in Adults with Relapsed or Refractory Acute Leukemias,

Abstract 3615 Background:The prognosis of patients with relapsed/refractory acute leukemias (RRAL) continues to be very poor, with a complete remission (CR) rate of ≤ 30% and a one-year disease-free survival of ≤ 10%. Consequently, there is no standard of care for the treatment of RRAL at the current time. Clofarabine (CLO) is a second-generation purine nucleoside analog that has shown activity against RRAL. The administration of CLO followed by Cyclophosphamide (Cy) enhances the DNA damage induced by Cy and increases AML/ALL blast apoptosis rates. We previously published a phase I study in RRAL patients in which a timed-sequential approach using CLO followed by Cy (days 1–3/8-10 or 1–2/8-9) resulted in promising clinical responses, but was associated with unacceptable toxicity (Karp, Blood 2007). Given the lengthy marrow aplasia, which was a dose-limiting toxicity (DLT), we conducted another phase I dose-escalation trial of CLO followed by escalating doses of fractionated Cy in adults with RRAL using an infusion schedule of 4 consecutive days (CLO-Cy × 4). Methods:One cycle of CLO-Cy was defined as 28 days. In order to assess the impact of CLO on Cy induced DNA damage, a 50% dose of CY was given alone on day zero and the remaining 50% was given after CLO on day 1. Thereafter, full dose Cy was given after CLO days 2–4. Full daily Cy doses ranged from 600–800mg/m2/day (total 2.4–3.2gms/m2). CLO was administered days 1 through 4 at 10 mg/m2/day for dose levels 1 and 2, 15 mg/m2/day for dose level 3, and 20 mg/m2/day for dose level 4. Results:Between 12/07 and 3/09, 26 adults (age 18 yrs) were entered on study. An additional 14 patients (pts) were enrolled between 4/09 and 3/10 in an expansion cohort determined by the phase 1 trial (dose level 1). 40 pts (28 AML [4 relapsed, 24 refractory], 12 ALL [3 relapsed, 9 refractory]) were given 45 cycles of CLO-Cy (5 pts received 2 cycles each). The average age was 48.5 years (range 22–73 years). The median number of prior regimens was 2 (range 1–5), including 6 who had prior allogeneic stem cell transplant. Of pts with AML, 21 (75%) had adverse cytogenetics, while 8 pts with ALL (67%) had adverse cytogenetics (2 with Philadelphia-positive ALL). The most common side effects were grade 3 and 4 hematologic toxicity. 6 pts (15%) died within 60 days of induction, 2 from septic complications and 4 from progressive disease. The average time to recovery of absolute neutrophilic count (ANC) of ≥ 500 was 40 days (range 31–78). 7 pts developed bacteremia and 2 developed fungemia. 10 pts developed grade 3 pneumonias, of which 7 were probably fungal. 5 pts developed pericardial/pleural inflammation or effusions (1=grade 3). 3 pts had reversible non-oligouric acute renal failure, but only one developed tumor lysis syndrome. Elevated liver function tests were noticed in 4 pts (2 grade 3). CLO-cytokine release syndrome (3 pts), hand-foot syndrome (3 pts), CLO-induced fever (1 pt), and mucositis (1 pt) were all ≤ grade 2. On day 14, 24 pts achieved complete tumor clearance, 4 pts had minimal disease, and 9 pts had residual disease. Of the 40 pts, 13 pts had an objective response (33%) with 11 CR, 2 PR. Of the 11 CR, 6 were in pts with non-adverse cytogenetics and 5 in pts with adverse cytogenetics. For AML, overall response rate (OR) was 25% (7/28) with 5 CR and 2 PR. For ALL, OR was 50% (6/12), all CR. At dose level 1 (total of 21 pts), OR was 48% (8 CR, 2 PR). Notably, the clinical responses were not dependent on the dose level. Among clinical responders, median pretreatment total white blood cell (WBC) was 3,310 (260–29,560) and median absolute lymphocyte count (ALC) was 1,737 [252–5948]. Median pretreatment IgG was 998 (226–1930), IgM was 67 (29–191), and IgA was 53 (<7–349). Median % decline in the ALC was 99%. The median % decline in IgG from D0 to D30 was 3%, for IgA was 4% and for IgM was 37%. Mean time to ALC recovery (ALC>200) was 47 days (32–85). Conclusions:This 4-day regimen of CLO followed by Cy demonstrated activity and tolerability in this heavily pretreated patient population with RRALs, with an OR of 33% (13/40). While the numbers are small, CLO-Cy may have particular activity in relapsed ALL. Immune reconstitution analysis showed profound and protracted decline in ALC without significant effects on IgG and IgA but perhaps with negative impact on early immunoglobulin responses (IgM). Further immunologic correlates should accompany clinical studies using CLO. Disclosures:Karp:Genzyme: Research Funding.

Antibiotic control of tumor-colonizingSalmonella entericaserovar Typhimurium

Systemic administration of Salmonella enterica serovar Typhimurium (S. typhimurium) into tumor-bearing mice results in preferential colonization of tumors and causes shrinkage and sometimes complete tumor clearance. However, in spite of these beneficial antitumor effects, the systemic administration of a bacterial pathogen raises serious safety concerns as well. Addressing those concerns, here, we demonstrate that tumor-colonizing Salmonella can be readily controlled by systemic administration of the antibiotic - ciprofloxacin. Treatment was most effective when started early postinfection. This was achieved at the expense of the efficacy of tumor therapy. In many of the mice treated in such a way, tumors re-grew again. Nevertheless, some mice were able to clear the tumor despite the start of antibiotic treatment only 24 h after the start of infection. Furthermore, we could demonstrate that such mice had elicited a specific antitumor immune response. Thus, S. typhimurium-mediated tumor therapy might be applied safely when combined with early antibiotic treatment. However, the therapeutic power of the bacteria needs to be enhanced in order to provide a more effective therapeutic tool.

Full-thickness Skin Graft After Nail Complex Resection for Malignant Tumors

Melanoma in situ and early squamous cell carcinoma can be treated successfully with excision with narrow margins. However, as the extent of disease is known only after pathologic examination of the entire lesion, the appropriate initial surgical margin is a dilemma. Lesions that involve the nail complex present an additional challenge for surgeons-whether to excise the nail complex partially or completely. The ideal form of reconstruction is also in question. We elect to completely excise the nail complex with immediate reconstruction using a full-thickness skin graft, allowing complete tumor clearance and preserving the distal phalanx. We retrospectively reviewed records of patients who had undergone complete nail complex excision and immediate skin grafting. We assessed the need for additional procedures for positive resection margins, full-thickness skin graft take on the bare bone of the distal phalanx, and final aesthetic appearance. Our study included 9 patients who had surgery on a total of 10 digits. One patient underwent repeat resection with distal phalanx disarticulation after pathologic assessment revealed a positive margin for an invasive tumor No patients had a local recurrence. Two patients required a second procedure-one for excision of a nail remnant and another for excision of an epidermal inclusion cyst. All patients were satisfied with the results, with none wanting further nail reconstruction, and all returned to presurgery use of the hand. This technique is effective for managing melanoma in situ and early squamous cell carcinoma that affect the nail complex.

Influence of infection route and virulence factors on colonization of solid tumors bySalmonella entericaserovar Typhimurium

Administration of facultative anaerobic bacteria such as Salmonella enterica serovar Typhimurium as anticancer treatment holds a great therapeutic potential. Here, we tested different routes of application of S. typhimurium with regard to tumor colonization and therapeutic efficacy. No differences between intravenous and intraperitoneal infection were observed, often leading to a complete tumor clearance. In contrast, after oral application, tumor colonization was inefficient and delayed. No therapeutic effect was observed under such conditions. We also showed that tumor invasion and colonization were independent of functional Salmonella pathogenicity island (SPI) 1 and SPI 2. Furthermore, tumor invasion and colonization did not require bacterial motility or chemotactic responsiveness. The distribution of the bacteria within the tumor was independent of such functions.

Two-Stage Resection for Bilobar Colorectal Liver Metastases: R0 Resection Is the Key

Two-stage liver resection (2-SLR) is used clinically in conjunction with portal vein embolization for bilobar disease to increase the number of patients suitable for liver resection. The long-term outcomes after 2-SLR for multiple bilobar colorectal liver metastases (CLM) was examined. Patients who sought care between November 2003 and April 2006 with multiple CLM considered suitable for 2-SLR were prospectively followed. Clinicopathological data were collected. Surgical outcomes were defined as complete clearance of tumor (R0/R1/R2), postoperative morbidity (within 3 months), 30 day mortality, disease-free survival (DFS), and overall survival (OS). A total of 131 patients with CLM underwent liver resection during the study period, 38 of whom were planned for a 2-SLR for multiple bilobar disease. Only 33 (87%) completed the 2-SLR with a curative intent. Five patients did not undergo stage II resection because of disease progression. The postoperative morbidity was 11 and 33% after stage I and stage II liver resections, respectively. Five patients (13%) encountered postoperative complications specific to liver surgery. The median interval from stage II resection to disease recurrence in the R0 group was 18 months versus 3 months in the R1/R2 group (P < 0.001). R0 resection with curative intent versus R1/R2 noncurative resection has a significantly longer period of DFS (P < 0.001) and OS (P = 0.04). The 2-SLR combined with portal vein embolization is an effective and safe method for resecting previously unresectable multiple bilobar CLM. However, a positive resection margin leads to poor DFS and OS.

Xeroderma pigmentosum.

To describe the features of Xeroderma pigmentosum observed in the stage 3 of the disease. Case series. Mayo Hospital Lahore, from December 2001 to September 2008. All patients diagnosed with Xeroderma pigmentosum stage 3 in the outpatient department of the study centre, were included. The age at first presentation, tumour sites, histology, recurrence rate, new tumour formation rate and the number of biopsies taken in a single session were recorded. The follow-up time was seven years. There were 25 patients including 15 males and 10 females. The mean age at initial presentation with the tumour was 20.4 years. The maximum number of biopsies taken from one patient during the same operation was 15 (mean=4). Complete tumour clearance was achieved in 15 patients and 3 patients were inoperable. Altogether, 70% tumours were basal cell carcinomas (BCC). The average interval for the development of a new tumour was 6 months. Twenty (80%) of the tumours were on the face, one was on the back and 3 on the forearms. Thirteen patients had ocular complications. Fifteen had a first degree relative afflicted. All wounds were closed primarily or with split grafts. There was a family history. The tumours were mostly BCCs. The rate of new tumour formation and recurrence was exceptionally high.

Can Antitumor Immunity Help to Explain “Oncogene Addiction”?

"Oncogene addiction" refers to the process of tumor cell death that can occur after inactivation of a single oncogene. In this issue of Cancer Cell , Rakhra et al. argue that complete tumor clearance after molecular targeted therapies requires a functioning immune system, pointing the way toward radically new combination therapies.

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals.