Since the first approval of gemtuzumab ozogamicin (Mylotarg; Pfizer; CD33 targeted), two additional antibodydrug conjugates (ADC), brentuximab vedotin (Adcetris; Seattle Genetics, Inc.; CD30 targeted) and inotuzumab ozogamicin (Besponsa; Pfizer; CD22 targeted), have been approved for hematologic cancers and 1 ADC, trastuzumab emtansine (Kadcyla; Genentech; HER2 targeted), has been approved to treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, the toxicity profiles are comparable with those of standard-of-care chemotherapeutics, with dose-limiting toxicities associated with the mecha-nism of activity of the cytotoxic warhead. However, the enthusiasm to develop ADCs has not been dampened; approximately 80 ADCs are in clinical development in nearly 600 clinical trials, and 2 to 3 novel ADCs are likely to be approved within the next few years. While the promise of a more targeted chemotherapy with less toxicity has not yet been realized with ADCs, improvements in technology combined with a wealth of clinical data are helping to shape the future development of ADCs. In this review, we discuss the clinical and translational strategies associated with improving the therapeutic index for ADCs.

A 28-year-old man presented with a leiomyosarcoma of the spermatic cord after 3 weeks of increasingly painful swelling of the left upper hemiscrotum. The tumor was high-grade, Stage III pT2b N0 M0 (American Joint Committee on Cancer, 2002). A firm, nonreducible mass was palpable over the left upper hemiscrotum and distal inguinal canal. He denied any local trauma or unexpected weight loss and had no gynecomastia or vomiting. Four years before admission, he had undergone ipsilateral inguinal hernia repair, during which no tumor mass was noted. An ultrasonographic examination of the scrotum was performed using a linear 7.0 MHz transducer. This revealed an extratesticular, hypoechoic mass-like lesion extending cranially into the left inguinal canal. Color Doppler ultrasonography showed minimal vascularity. The left epididymis and testis were normal. The patient underwent en bloc resection, revealing a solid, round tumor measuring 6 6 6 6 4.5 cm 3 , separate from the ipsilateral testis and epididymis. Pathology demonstrated a high-grade paratesticular leiomyosarcoma stemming from the spermatic cord ( Figure 1A and B). Comprehensive studies did not show any metastases in the lungs, liver, or lymphatic system. Definitive therapy with radical inguinal orchiectomy and wide excision of surrounding soft tissue confirmed a negative surgical margin of the initial en bloc resection.Preoperative serum beta human chorionic gonadotropin (b-hCG) concentration was 43.88 ng/mL (immunoradiometric assay, CIS bio), whereas the postoperative bhCG level decreased to normal (less than 0.15 ng/mL). Immunohistochemistry for b-hCG (DAKO, 1:200) revealed focal staining ( Figure 1C) in the resected tumor.

Objectives To evaluate the safety and efficacy of chidamide to reverse HIV‐1 latency in vivo and to compare the effects of four clinically tested histone deacetylase (HDAC) inhibitors on non‐histone proteins in vitro. Methods Participants received chidamide orally at 10 mg twice weekly for 4 weeks while maintaining baseline antiretroviral therapy. The primary outcome was plasma viral rebound during chidamide dosing and the secondary outcomes were safety, pharmacokinetic and pharmacodynamic profiles, changes in cell‐associated HIV‐1 RNA and HIV‐1 DNA, and immune parameters. Western blotting was used to compare the in vitro effects of the four HDAC inhibitors on HSP90, NF‐κB and AP‐1. Results Seven aviraemic participants completed eight oral doses of chidamide, and only grade 1 adverse events were observed. Cyclic increases in histone acetylation were also detected. All participants showed robust and repeated plasma viral rebound (peak viraemia 147–3850 copies/mL), as well as increased cell‐associated HIV‐1 RNA, during chidamide treatment. Furthermore, we identified an enhanced HIV‐1‐specific cellular immune response and a modest 37.7% (95% CI: 12.7–62.8%, P = 0.028) reduction in cell‐associated HIV‐1 DNA. Compared with the other three HDAC inhibitors, chidamide had minimal cytotoxicity in vitro at clinically relevant concentrations and showed mechanistically superior effects on non‐histone proteins, including HSP90, NF‐κB and AP‐1. Conclusions Chidamide safely and vigorously disrupts HIV‐1 latency in vivo, which makes it a promising latency‐reversing agent.

Background: Cetuximab has been proved to be effective alone or in combination with other chemotherapeutic agents in the treatment of various malignancies. The aim of this report was to describe our experience of using cetuximab with chemotherapeutics agents to treat advanced-stage biliary tract cancer. Case Reports: We retrospectively analyzed the outcomes of 5 biliary tract cancer patients receiving cetuximab-containing therapy. Four of them had stage IV disease, and 1 patient had incomplete resection at the time of diagnosis. Epidermal growth factor receptor (EGFR) expression and K-ras status were assessed when a specimen was available. After cetuximab treatment, complete response was achieved in 1 patient, partial response in 3 patients, and stable disease in 1 patient. Three surgical specimens were available, and all revealed positive EGFR expression. Only 1 surgical specimen was adequate for K-ras mutation test, and the wild type was confirmed. Complete response was found in the patient who had wild type K-ras. The progression-free survival of these patients varied from 4 to 16 months. Conclusions: Cetuximab-containing therapy might be an effective treatment for advanced biliary tract cancer.