Small bowel obstruction: a recurrence of melanoma during the second trimester of pregnancy

Background: The incidence of melanoma is on the rise in the United States and is particularly prevalent among women of childbearing age. Obtaining a complete history and understanding the unpredictable behavior of melanoma is essential to make the diagnosis of recurrent disease during pregnancy. Case: A 35-year-old G2P1 at 23 weeks and 1 days’ gestation with a remote history of (treated) cutaneous melanoma underwent an exploratory laparotomy for small bowel obstruction. Pathology was consistent with recurrent metastatic melanoma. Conclusion: Metastatic melanoma diagnosed during pregnancy is rare. There are no guidelines on how or when to proceed with treatment of metastatic disease or delivery of the fetus. Immunotherapy is changing the management of melanoma and is extending life expectancy. The significant survival benefits for mother with immunotherapy may outweigh the risks of preterm delivery for the baby

Mapping the immune environment in clear cell renal carcinoma by single-cell genomics

Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD4

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease

Results from a phase 1b/2 study of ibrutinib combination therapy in advanced urothelial carcinoma

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0–37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC

The Future of Immunotherapy-Based Combination Therapy in Metastatic Renal Cell Carcinoma

In the past two decades, there has been a significant improvement in the understanding of the molecular pathogenesis of Renal Cell Carcinoma (RCC). These insights in the biological pathways have resulted in the development of multiple agents targeting vascular endothelial growth factor (VEGF), as well as inhibitors of the mammalian target of the rapamycin (mTOR) pathway. Most recently, checkpoint inhibitors were shown to have excellent clinical efficacy. Although the patients are living longer, durable complete responses are rarely seen. Historically, high dose interleukin 2 (IL2) therapy has produced durable complete responses in 5% to 8% highly selected patients—albeit with significant toxicity. A durable complete response is a surrogate for a long-term response in the modern era of targeted therapy and checkpoint immunotherapy. Numerous clinical trials are currently exploring the combination of immunotherapy with various targeted therapeutic agents to develop therapies with a higher complete response rate with acceptable toxicity. in this study, we provide a comprehensive review of multiple reported and ongoing clinical trials evaluating the combination of PD-1/PD-L1 inhibitors with either ipilimumab (a cytotoxic T-lymphocyte-associated protein 4, CTLA-4 inhibitor) or with anti-VEGF targeted therapy

Lung cancer in the very elderly: incidence, presentation, and diagnostic decision-making. A retrospective analysis at a teaching community hospital

Background and objectives: Lung cancer presentation and decision-making in the very elderly patient population, 80 years of age and older, was studied given the projected increase in cancer incidence in the very elderly and yet only limited management guidelines. Design and setting: A 10-year experience at the Unity Health System of Rochester, NY, was reviewed using tumor registry data for the entire lung cancer population plus focused medical record review of very elderly patients. A questionnaire survey on the clinical approach to lung cancer in the elderly was distributed to medical staff involved in their care.Participants, measurements, and results: Of 997 patients, approximately 100 cases each year, the very elderly comprised 18% of patients from year 1998 through 2002, and 23% from year 2003 through 2007. One-third of the very elderly were diagnosed with lung cancer on clinical grounds without tissue confirmation. The majority of this group had cardio-pulmonary symptoms and an advanced clinical stage. The very elderly had no tissue sampling as per their own decision in 12 of 44 of cases, per family decision in 28 of 44, and per physician and other input in 4 of 44. Physicians stated that patient wishes and health-related factors, more so than socio-economic factors, were primary concerns for management decision-making. Conclusions: The number of very elderly lung cancer patients in this community setting has been significant and appears to be increasing. These patients were more likely to have an incomplete diagnostic work-up, with patient and family wishes being the major factor in medical decision-making. The physician approach to these patients emphasized patient autonomy and medical factors

Advanced Stage Melanoma Therapies: Detailing the Present and Exploring the Future

Metastatic melanoma therapies have proliferated over the last ten years. Prior to this, decades passed with only very few drugs available to offer our patients, and even then, those few drugs had minimal survival benefits. Many treatment options emerged over the last ten years with diverse mechanisms of action. Further, combination regimens have demonstrated superiority over monotherapy, especially for targeted agents. Each therapeutic combination possesses different advantages and side effect profiles. In this review, we outline the United States Food and Drug Administration-approved melanoma treatment agents and therapies currently in clinical development, focusing on combination approaches

Tumor Lysis Syndrome in a Retroperitoneal Sarcoma

In the present case, a 49-year-old white female presented to the clinic with a 2-month history of nausea, vomiting, and right upper quadrant pain. On examination a 3-cm mass on the right anterior scalene muscle was noted. A computed tomography scan was performed revealing a 8.7 × 7.7 × 6.1 cm retroperitoneal mass with possible invasion of the inferior vena cava and right renal and left common iliac veins. An excisional biopsy was performed with pathology compatible with spindle cell sarcoma. The patient was then sent for follow-up at the sarcoma clinic as an outpatient. However, before chemotherapy was to be started the patient would be admitted to the hospital with progressively worse nausea and vomiting. At that time the patient’s lab work showed lactic acidosis, acute renal failure, hyperuricemia, hyperphosphatemia, and hypocalcemia, which met the Cairo–Bishop criteria for tumor lysis syndrome (TLS). The patient was admitted to the intensive care unit and kidney dialysis initiated. The patient would become progressively obtunded at which time the family opted for hospice care. The patient eventually succumbed peacefully 3 days after her last admission. In this case report, we briefly review the literature on TLS in solid tumors, and we present a rare case of spontaneous TLS in a retroperitoneal sarcoma