Nongeminomatous germ cell tumors (NGGCTs) are aggressive malignancies known for their rapid metastatic potential. Teratomas, a subtype of NGGCTs, can be classified as either mature (benign) or immature (malignant). Immature teratomas carry a higher metastatic risk than mature teratomas due to their embryonic-like tissue composition. Intracranial teratomas are rare in nature and can develop secondary malignancies, such as Wilms tumors. We report the case of a 70-year-old man with a history of prostate cancer who presented with neurological symptoms and was diagnosed with a Wilms tumor arising from an immature teratoma. A heterogenous morphology, including squamous, cartilaginous, and neural differentiation, was revealed upon surgical resection. Despite interventions, the patient experienced rapid disease progression and eventually passed away in hospice care 7 months after the initial diagnosis. This case highlights the complexity of diagnosing and managing NGGCTs, particularly when secondary malignancies arise. Ultimately, it underscores the need for careful diagnosis and precise therapeutic strategies to manage these tumors.

BACKGROUND:Lacrimal gland adenoid cystic carcinoma (LGACC) has historically been associated with a poor prognosis even with localized disease, with a survival of 56% at 5 years. In 1988, we treated the first patient with neoadjuvant intra-arterial cytoreductive chemotherapy (IACC). Since then, we have used this protocol as the standard approach. We aim to analyze the outcomes of patients with LGACC treated with the protocol and compare them to a population-based cohort to assess if IACC can improve survival. METHODS:We prospectively assessed all non-metastatic patients with LGACC treated with IACC at a single institution between 1988 and 2021. For a comparison group, we identified all non-metastatic patients with LGACC treated with excision from the Surveillance, Epidemiology, and End Results (SEER) registry. We calculated disease-specific survival using the Kaplan-Meier and Cox proportional-hazards modeling methods. RESULTS:Thirty-five non-metastatic patients with LGACC treated with IACC were identified at a single institution, and 64 patients with non-metastatic LGACC treated with excision were identified in the SEER database. The 5- and 10-year disease-specific survival rates for patients treated with IACC were 84% (95%CI 71-97) and 76% (95%CI 60-92), respectively. While the 5- and 10-year disease-specific survival rates for the population-based cohort were 72% (95%CI 62-82) and 46% (95%CI 32-60). The survival analysis favored IACC, with a 60% lower risk of death (HR: 0.4; 95%CI 0.2-0.9). CONCLUSION:IACC improves disease-specific survival in comparison to a population-based cohort treated with excision. Additional patients treated with IACC at multiple institutions are required to provide further external validity.

Supplementary Figure from Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in CTNNB1 or APC: A Multi-institutional Retrospective Study

Figure S1. Correlative Angiogenesis Biomarkers. A, levels of circulating endothelial cells in patients in schedule A and B at baseline (Pre-treatment). B, circulating endothelial precursor cells (EPCs) at baseline in patients in schedule A and B. C, baseline plasma angiogenic activity (PAA) at baseline in patients in schedule A and B.

Supplementary Figure from Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in <i>CTNNB1</i> or <i>APC</i>: A Multi-institutional Retrospective Study

AbstractPurpose:Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments.Experimental Design:We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan–Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen.Results:A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First- and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APC-mutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or “other” therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations.Conclusions:Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated.See related commentary by Greene and Van Tine, p. 3911

Abstract Purpose: To evaluate the safety, MTD, pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every 3 weeks in combination with daily sunitinib in patients with advanced solid tumors. Experimental Design: Eligible patients received either weekly (schedule A) or every 3 weeks (schedule B) ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m2; schedule B: 20, 30, or 40 mg/m2), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLT) were assessed during cycle 1. Results: The ixabepilone and sunitinib combination was fairly well tolerated. DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B). The most common grade 3–4 hematologic and nonhematologic adverse events were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response, while 13 patients had stable disease. Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Coadministration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in the clearance of ixabepilone. Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients. Weekly, but not every 3 weeks, ixabepilone led to a significant decrease in PAA postbaseline. Conclusions: Coadministration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients, particularly in patients with metastatic colorectal cancer. Clin Cancer Res; 22(13); 3209–17. ©2016 AACR.

T cell activation is initiated by signaling through the TCR after binding to MHC-presented antigen. Both positive and negative co-regulatory signaling can modify this original activating signal. T cell co-regulation is provided by receptors on the T cell surface membrane. Inhibitory signals are provided by CTLA4 or PD-1, while co-stimulation is provided by CD28, 4-1BB, OX40, or GITR. These signals are being studied in the laboratory and at the clinical level in order to therapeutically modulate T cell responses to tumor cells. T cells can recognize tumor antigens in the same way that these immune cells recognize bacteria, viral antigens, and other foreign peptides. If appropriately activated by the tumor antigen, the immune system can mediate an antitumor gene response. Unfortunately, immune cells with antitumor specificity are not present in abundance and are often inhibited by tumor expression of CTLA4 or PD-1 ligands. Thus manipulation of co-regulatory signals can be used as a strategy by which to strengthen the immune response, via augmentation of T cell co-stimulation and/or blockade of inhibitory signals, in order to effectively treat cancer. In this chapter we review the basic principles and science as well as the ongoing clinical efforts in this area that have had recent success and offer additional promise.

Purpose: The perioperative management of primary extremity soft tissue sarcomas (ESTS) is multidisciplinary including radiation therapy and chemotherapy (CT). The interplay between these modalities and the relative importance of each remain unclear. Our study aims to determine the relative impact of CT and radiotherapy on the outcome of ESTS patients treated with limb-sparing surgery.Materials and Methods: A retrospective review of ESTS registry yielded 97 patients who received neoadjuvant chemotherapy (NCT) and/or adjuvant CT with or without external-beam radiation therapy (EBRT) from January 1, 1999 through December 31, 2009. The cohort comprised 56 males and 41 females whose age at surgery ranged from 17 to 83 years (median, 56 y). Tumor characteristics included the following: 73 lower ESTS; 70 grade 3 lesions; 63 American Joint Committee on Cancer stage III tumors; and 27 lesions with positive microscopic margins. The following outcome parameters were evaluated for the patients' subgroups: overall survival (OS), locoregional control (LRC), and disease-free survival (DFS).Results: EBRT was delivered postoperatively to 81 patients and 49 received CT. Median EBRT dose was 63 Gy (range, 50 to 72 Gy). At median follow-up of 54.6 months, the 5-year OS, LRC, DFS was 68.9%, 87.1%, 66.5%, respectively. On multivariate analysis, positive surgical margins negatively impacted LRC, DFS, and OS (hazard ratio [HR] = 10.43, P=0.004), (HR=2.37, P=0.03), (HR=2.26, P=0.038), respectively. EBRT use improved LRC (HR=0.24, P=0.018) and DFS (HR=0.36, P=0.021). The impact of EBRT on DFS was retained (HR=0.28, P=0.006) in the high-grade ESTS subgroup who received CT. The 5-year local failure rate was 6.5%, 28.6%, and 22.2% (P=0.019) for patient receiving NCT, adjuvant chemotherapy, and no CT, respectively.Conclusion: Our data support the use of NCT followed by limb sparing surgery and adjuvant EBRT in ESTS for local failure reduction with a trend toward improved DFS.

3081 Background: Ix is a cytotoxic microtubule-stabilizing agent with anti-proliferative and anti-angiogenic properties. S is a multi-targeted receptor tyrosine kinase inhibitor. IX and S combination may be synergistic, since S may increase delivery of Ix to the tumor by inducing vascular normalization. Methods: Patients (pts) with advanced STs were enrolled in a phase I, dose-escalation study to assess safety, pharmacokinetics (PK), angiogenesis biomarkers and to determine the recommended phase II dose. Eligibility: age > 18, ≤ 4 prior systemic therapies (tx), ECOG PS 0-2, measurable/evaluable disease and good organ function. Treatment schedules: A (weekly Ix, 3 out of 4-weeks): starting dose 7.5 mg/m2 IV (1A), 15 mg/m2 IV (2A) and 20 mg/m2 IV (3A). Schedule B (every 3 weeks): starting dose 20 mg/m2 IV (1B), 30 mg/m2 IV (2B) and 40 mg/m2 IV (3B). In both schedules, S was given continuously starting on day 8 of cycle 1 at 37.5 mg PO daily. A standard 3 + 3 design was used and dose-limiting toxicities (DLTs) assessed in the first cycle. Results: 30 patients were enrolled. Two pts withdrew before starting tx. Baseline characteristics: median age: 61.5 (25-78); males/females: 19/9; most frequent STs: colorectal -CRC- (16), pancreas (2), prostate (2); median PS: 1; median of prior tx: 3. Number of pts evaluable for toxicity/dose escalation/efficacy: 28/23/21. One DLT was observed in schedule 3A (grade (gr) 3 DVT) and 2 in schedule 3B (gr 4 mucositis/gr 3 dehydration; gr4 neutropenia). Other gr 3 /4 AEs (non DLTs): leukopenia (18%), neutropenia (25%), lymphopenia (21%), anemia (14%), thrombocytopenia (7%), leukocytosis (4%), fatigue (25%), neuropathy (7%), mucositis (7%), nausea (7%), vomiting (4%), hyperglycemia (4%), syncope (4%), abdominal pain (4%) and GI bleed (4%). Median # of cycles (evaluable pts): 3 (range1-10). Three pts achieved PR (2 with CRC). Eight patients had SD (5 with CRC). 10 patients had PD. Conclusions: The combination of Ix and S appears to have acceptable toxicity and encouraging activity in heavily pretreated pts. The recommended phase II dose for S is 37.5 mg po daily with Ix 20 mg/m2 in Schedule A and Ix 30 mg/m2 in schedule B. Angiogenesis biomarkers and PK analyses are underway.

Abstract Background: Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class. VFL inhibits tubulin polymerization. Ixabepilone (IXA), a microtubule inhibitor, binds directly to -tubulin subunits, leading to suppression of microtubule dynamics. These agents have complementary mechanisms of action and relatively non-overlapping toxicities. This study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of an alternating regimen of VFL and IXA in patients (pts) with advanced cancer and to recommend a Phase 2 dose. Materials and Methods: This was an open-label Phase 1 doseescalation study of IXA and VFL in pts with advanced cancer. IXA was administered as a 3-hour infusion alternating every 3 weeks (wks) with VFL administered as a 20-minute infusion. A cycle was defined as 6 wks (42 days), with DLT assessment during Cycle 1. Doses started at 30 mg/m2 IXA and 250 mg/m2 VFL (IXA30+VFL250). VFL doses were first escalated to a maximum of 320 mg/m2. Once an intolerable dose or the maximum dose of VFL was reached, IXA was to be escalated with a maximum dose level of IXA 40 mg/m2. A standard 3+3 escalation design was used. The MTD was defined as the dose level below which ≥2/6 pts experienced a DLT. Results: This was the first clinical study to evaluate vinflunine and ixabepilone as an alternating regimen. Nine pts were enrolled and treated; 3 each at IXA30+VFL250, IXA30+VFL280, and IXA30+VFL320. Further enrollment and dose escalation was stopped when the study was closed due to termination of VFL development at BMS. The treated pts consisted of 8 males / 1 female, 3 with SCLC, 4 with NSCLC, and 2 with sarcomas. The majority of pts were white (8 of 9). Median Age was 63 years (range 38–85). ECOG performance status was 0 (n=1) or 1 (n=8). Adverse events were summarized by treatment. Of interest, 3 pts experienced grade 1 peripheral neuropathy (1 IXA, 2 VFL); 5 pts with grade 3/4 neutropenia (2 IXA, 2 VFL, 1 IXA/VFL); 2 pts with grade 2 constipation (2 VFL). Serious adverse events (SAEs) were reported in 3 of 9 treated pts. The SAEs of pyrexia grade 2, neutropenia grade 2, and leucopenia grade 3 were considered related to study drug in 1 patient. None of the SAEs or non-serious AEs led to discontinuation of study treatment. Two pts experienced progression of disease which resulted in death. Antitumor activity (as defined by RECIST and assessed by the investigator) was observed: confirmed partial response in 1 pt with NSCLC (IXA30+VFL320 dose level) and stable disease lasting from 2.5 to 9 months in 3 pts (2 with SCLC in IXA30+VFL250 and 1 with NSCLC in IXA30+VFL280). Conclusions: There were no DLTs observed in the dose levels examined and the MTD was not reached due to termination of study. The toxicity of the alternating regimen was manageable. Antitumor activity was observed in all dose cohorts. The alternating regimen of vinflunine and ixabepilone may warrant further investigation. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C237.

Primary angiosarcoma of the spleen is a very rare neoplasm with a poor prognosis. The definitive diagnosis is usually based on the histologic evaluation of the splenectomy specimen. We describe a case of angiosarcoma diagnosed by fine-needle aspiration cytology prior to splenectomy. A 69-year-old white woman presented with heterogeneous lesions in the spleen during a follow-up computed tomographic scan for a history of liposarcoma of the right buttock. A malignant endothelial neoplasm was diagnosed by fine-needle aspiration cytology using immunocytochemistry, and a splenectomy confirmed the presence of angiosarcoma. To our knowledge, this is the first well-documented and confirmed case of primary angiosarcoma of the spleen diagnosed by fine-needle aspiration cytology. This report emphasizes the value of fine-needle aspiration cytology as an important diagnostic tool in splenic neoplasms.

Increasingly, patients of advanced age are coming for evaluation of periampullary tumors. Although several studies have demonstrated the safety of resecting periampullary tumors in older patients, few long-term survival data have been reported. Between 1983 and 1992 various periampullary masses were resected in 70 patients over age 65 (range 65–87 years). Total pancreatectomy was performed in 11 patients, and 59 patients underwent pancreaticoduodenectomy. The mean duration of hospitalization was 17 ± 15 days. Major complications occurred in 27 patients (39%), and operative mortality rate was 8.5%. Overall median survival was 24 months; and 5-year survival was 25%. Perioperative outcome was compared in patients aged 65 to 74 years and in patients ≥75 years old. The older age group required longer periods in the surgical intensive care unit postoperatively, but the long-term survival was similar in the two age groups. Radical resection with the intent to cure periampullary tumors is safe in selected patients of advanced age, and long-term survival is in the range of expected survival for younger patients with the same tumors.

S mall cell carcinoma (SCC), also referred to in the lungs as oat cell carcinoma or a neuroendocrine tumor, is a distinct histologic and biologic disease entity characterized by an aggressive clinical course and a high disease-related mortality. In 1926, Barnard’ described the first case of SCC, originating in the lungs. This histology now accounts for approximately 90,000 of the 150,000 cases of lung cancer that are diagnosed yearly in the United States.2 Nonpulmonary SCC was first described by Duguid and Kennedy in 1930.3 Since that time, extrapulmonary SCCs have been described in numerous organs including pharynx,4 larynx,5 trachea,(j esophagus7 stomach,8 small intestine,9 colon,1° nasal sinuses,ll salivary glands,12 thymus, l3 skin,14 breast,l* cervix,16 as well as prostate, l7 urinary bladder,18 kidney,19 and ureter.20 These neoplasms appear to have the same aggressive biologic behavior and share similar microscopic, immunohistochemical, and often ultrastructural characteristics as SCC of the lung. SCC originating in the urinary tract is rare; it is most often reported arising in the urinary bladder or prostate. In view of its rarity, there is a relative scarcity of information on the clinicopathologic behavior and optimum treatment strategies for this tumor. In recent years, however, genitourinary SCCs have been diagnosed with increasing frequency This appears to be due to an increased use of immunohistochemical studies in the evaluation of anaplastic tumors. The present review was undertaken to discuss the current concepts of histogenesis and to analyze the existing data on the pathologic characteristics, clinical behavior, and treatment response of SCC of the bladder and prostate.

Small-cell carcinoma of the esophagus is a rare tumor and has received little attention until recent years. It should be differentiated from the far more common poorly differentiated squamous-cell carcinoma of the esophagus, because treatment by surgical resection alone or by radiation therapy results in limited survival of a few months. It is now recognized that esophageal small-cell carcinoma presents with early widespread dissemination and is chemosensitive, similar to primary small-cell carcinoma of the lung. We report on a patient with small-cell carcinoma of the esophagus treated with combination chemotherapy consisting of cyclophosphamide, vincristine, and VP-16 followed by local radiation therapy. Pathologic complete remission was achieved. The patient is currently in remission 22 months after diagnosis, the longest survival reported thus far.

Small-cell carcinoma of the esophagus is a rare tumor and has received little attention until recent years. It should be differentiated from the far more common poorly differentiated squamous-cell carcinoma of the esophagus, because treatment by surgical resection alone or by radiation therapy results in limited survival of a few months. It is now recognized that esophageal small-cell carcinoma presents with early widespread dissemination and is chemosensitive, similar to primary small-cell carcinoma of the lung. We report on a patient with small-cell carcinoma of the esophagus treated with combination chemotherapy consisting of cyclophosphamide, vincristine, and VP-16 followed by local radiation therapy. Pathologic complete remission was achieved. The patient is currently in remission 22 months after diagnosis, the longest survival reported thus far.

Extrapulmonary small cell carcinoma is rare. Small cell carcinoma of the colorectum has been reported in 73 patients. Patients with colorectal small cell carcinoma present with signs and symptoms related to the primary site. Usually patients present with advanced stage. Rarely do patients with colorectal small cell carcinoma present with signs and symptoms related to the central nervous system (CNS). We report two patients who presented with CNS signs. The two patients underwent craniotomy for definitive diagnosis and resection in one patient. In both cases, pathology was consistent with pure small cell carcinoma. Post-operatively, a search for a primary revealed the rectum and the hepatic flexure of the colon to be the sites. Patients were started on combination chemotherapy. One patient achieved a complete remission and the second is currently receiving chemotherapy with a partial response. This is the first report of colorectal small cell carcinoma presenting as CNS lesion(s).