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PURPOSE: To develop an innovative machine learning (ML) model that predicts personalized risk of primary ovarian insufficiency (POI) after chemotherapy for reproductive-aged women. Currently, individualized prediction of a patient’s risk of POI is challenging. METHODS: Authors of published studies examining POI after gonadotoxic therapy were contacted, and six authors shared their de-identified data (N = 435). A composite outcome for POI was determined for each patient and validated by 3 authors. The primary dataset was partitioned into training and test sets; random forest binary classifiers were trained, and mean prediction scores were computed. Institutional data collected from a cross-sectional survey of cancer survivors (N = 117) was used as another independent validation set. RESULTS: Our model predicted individualized risk of POI with an accuracy of 88% (area under the ROC 0.87, 95% CI: 0.77–0.96; p

F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917–1924, 2019). This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [11C]-(+)-PHNO. PET scans were performed at baseline and following a single 30 mg or 15 mg dose of F17464 (3 subjects/dose), and blood samples were collected for pharmacokinetic analysis. Receptor occupancy was calculated based upon reduction in binding potential of the tracer following F17464 administration. The relationship between plasma F17464 concentration and D3/D2 receptor occupancy was modeled and the plasma concentration corresponding to 50% receptor occupancy (EC50) calculated. Both doses of F17464 robustly blocked [11C]-(+)-PHNO D3 receptor binding, with substantial occupancy from 1 h post-administration, which increased at 6–9 h (89–98% and 79-87% for the 30 mg and 15 mg groups, respectively) and remained detectable at 22 h. In contrast, D2 binding was only modestly blocked at all time points (< 18%). F17464 exhibited a combination of rapid peripheral kinetics and hysteresis (persistence of binding 22 h post-dose despite low plasma concentration). The best estimate of the EC50 was 19 ng ml−1 (~ 40 nM). Overall, F17464 was strongly D3-selective in healthy volunteers, a unique profile for an antipsychotic candidate drug.

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

Radioactive iodine has been, in various forms, the mainstay of Nuclear Medicine. Iodine-123 is the most widely used iodine isotope for single photon imaging. Iodine-125 continues to be used in diverse applications from in vitro radioassay to in vivo estimation of various pathophysiologic correlates. Iodine-131 (131I), useful for imaging as well as therapy, has contributed more than any other radionuclide to the growth and sustenance of Nuclear Medicine. Positron emission tomography (PET) is an indispensable tool in current clinical practice, spurred by the rapid and increasing availability of radiopharmaceuticals for in vivo imaging. Most clinical PET imaging utilizes fluorine-18; there is a need for positron emitters with longer half-lives, suitable for imaging larger molecules of interest. Iodine-124 (124I) has approximately 23 % positron emission; its 4-day half-life lends itself to sequential imaging, and its dosimetry is comparable to iodine-131. Iodine can be easily attached to a variety of molecules without alteration of physico-chemical or biologic properties. PET with 124I-labeled molecules enables longitudinal in vivo assessment of their distribution; such pharmacokinetic and biodistribution information has considerable utility in oncologic and non-oncologic applications. We will provide a clinical perspective on the physical and chemical characteristics of 124I, as the iodide, as well as radiolabeled to a wide variety of molecules of interest. Radioiodination is accomplished based on the chemical and biologic nature of the ligand to be studied, and issues of relevance will be highlighted. We will conclude by describing the current and potential future clinical applications of 124I-based tracers used for molecular imaging in diagnosis and therapy.

As many as 40 % of breast cancer patients undergoing axillary lymph node dissection (ALND) and radiotherapy develop lymphedema. We report our experience performing lymphatic–venous anastomosis using the lymphatic microsurgical preventive healing approach (LYMPHA) at the time of ALND. This technique was described by Boccardo, Campisi in 2009. LYMPHA was offered to node-positive women with breast cancer requiring ALND. Afferent lymphatic vessels, identified by injection of blue dye in the ipsilateral arm, were sutured into a branch of the axillary vein distal to a competent valve. Follow-up was with pre- and postoperative lymphoscintigraphy, arm measurements, and (L-Dex®) bioimpedance spectroscopy. Over 26 months, 37 women underwent attempted LYMPHA, with successful completion in 27. Unsuccessful attempts were due to lack of a suitable vein (n = 3) and lymphatic (n = 5) or extensive axillary disease (n = 1). There were no LYMPHA-related complications. Mean follow-up time was 6 months (range 3–24 months). Among completed patients, 10 (37 %) had a body mass index of ≥30 kg/m2 (mean 27.9 ± 6.8 kg/m2, range 17.4–47.6 kg/m2), and 17 (63 %) received axillary radiotherapy. Excluding two patients with preoperative lymphedema and those with less than 3-month follow-up, the lymphedema rate was 3 (12.5 %) of 24 in successfully completed and 4 (50 %) of 8 in unsuccessfully treated patients. Our transient lymphedema rate in this high-risk cohort of patients was 12.5 %. Early data show that LYMPHA is feasible, safe, and effective for the primary prevention of breast cancer-related lymphedema.

Spices are extensively used to enhance the taste and flavor of foods and are known to possess several medicinal properties. Myristica fragrans, Parmelia perlata, Illicium verum, Trachyspermum copticum and Myristica malabarica, the commonly used spices in India were assessed for antidiabetic activity in streptozotocin induced diabetic rats. In the in vitro insulin secretion studies on isolated islets of Langerhans, M. fragrans, T. copticum and M. malabarica showed dose dependent insulin secretion. At 1 mg/ml, P. perlata showed significant in vitro alpha-glucosidase inhibitory activity with IC(50) value of 0.14 mg/ml followed by M. malabarica (0.64 mg/ml), I. verum (0.67 mg/ml), M. fragrans (0.85 mg/ml) and T. copticum (0.92 mg/ml). The DPPH free radical scavenging activity of the extracts at a concentration of 1 mg/ml was as M. malabarica (90.45%), M. fragrans (89.89%), I. verum (87.22%), P. perlata (76.70%) and T. copticum (38.14%). P. perlata showed the highest phenolic content (i.e., 118.5 mg gallic acid equivalents/g) followed by M. malabarica (84.13 mg gallic acid equivalents/g). M. malabarica showed the highest flavonoid content (i.e., 38.35 mg quercetin equivalents/g). Regular use of these spices may prevent postprandial rise in glucose levels through inhibition of intestinal alpha-glucosidase and may maintain blood glucose level through insulin secretagogue action.

The primary purpose of this study was to assess the biodistribution and radiation dose resulting from administration of (18)F-EF5, a lipophilic 2-nitroimidazole hypoxia marker in ten cancer patients. For three of these patients (with glioblastoma) unlabeled EF5 was additionally administered to allow the comparative assessment of (18)F-EF5 tumor uptake with EF5 binding, the latter measured in tumor biopsies by fluorescent anti-EF5 monoclonal antibodies.(18)F-EF5 was synthesized by electrophilic addition of (18)F(2) gas, made by deuteron bombardment of a neon/fluorine mixture in a high-pressure gas target, to an allyl precursor in trifluoroacetic acid at 0° then purified and administered by intravenous bolus. Three whole-body images were collected for each of ten patients using an Allegro (Philips) scanner. Gamma counts were determined in blood, drawn during each image, and urine, pooled as a single sample. PET images were analyzed to determine radiotracer uptake in several tissues and the resulting radiation dose calculated using OLINDA software and standard phantom. For three patients, 21 mg/kg unlabeled EF5 was administered after the PET scans, and tissue samples obtained the next day at surgery to determine EF5 binding using immunohistochemistry techniques (IHC).EF5 distributes evenly throughout soft tissue within minutes of injection. Its concentration in blood over the typical time frame of the study (∼3.5 h) was nearly constant, consistent with a previously determined EF5 plasma half-life of ∼13 h. Elimination was primarily via urine and bile. Radiation exposure from labeled EF5 is similar to other (18)F-labeled imaging agents (e.g., FDG and FMISO). In a de novo glioblastoma multiforme patient, focal uptake of (18)F-EF5 was confirmed by IHC.These results confirm predictions of biodistribution and safety based on EF5's characteristics (high biological stability, high lipophilicity). EF5 is a novel hypoxia marker with unique pharmacological characteristics allowing both noninvasive and invasive measurements.

The ability to induce and sustain angiogenesis is regarded as one of the hallmarks of cancer growth and metastasis. Marked advances in understanding vascular physiology and mechanisms of angiogenesis have led to the development of vascularly-targeted anti-cancer therapies. Two broad subclasses of agents are in clinical use currently: those with anti-angiogenic activity (i.e. those that target angiogenic pathways) and those that have direct cytotoxic activity against proliferating endothelial cells (i.e. vascular disruptive agents (VDAs)). This article reviews the various imaging modalities, including magnetic resonance imaging, computed tomography, photon emission imaging (positron emission tomography and single photon emission computed tomography), ultrasound and optical (near-infrared absorption and scattering) techniques that have been used in an attempt to assess the status of tumor neovasculature in vivo. In each case, we describe the basic imaging methodology, methods for image quantification, technical standardization and reproducibility, and current and potential clinical applications for monitoring the status of tumor neovasculature before and during treatment with vascular targeted agents.

The monoclonal antibodies M195 and HuM195 target CD33, a glycoprotein found on myeloid leukemia cells. When labeled with iodine-131 ((131)I), these antibodies can eliminate large disease burdens and produce prolonged myelosuppression. We studied whether (131)I-labeled M195 and HuM195 could be combined safely with busulfan and cyclophosphamide (BuCy) as conditioning for allogeneic BMT. A total of 31 patients with relapsed/refractory acute myeloloid leukemia (AML) (n=16), accelerated/myeloblastic chronic myeloid leukemia (CML) (n=14), or advanced myelodysplastic syndrome (n=1) received (131)I-M195 or (131)I-HuM195 (122-437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90-120 mg/kg) followed by infusion of related-donor bone marrow (27 first BMT; four second BMT). Hyperbilirubinemia was the most common extramedullary toxicity, occurring in 69% of patients during the first 28 days after BMT. Gamma camera imaging showed targeting of the radioisotope to the bone marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272-1470 cGy. The median survival was 4.9 months (range 0.3-90+ months). Three patients with relapsed AML remain in complete remission 59+, 87+, and 90+ months following bone marrow transplantation (BMT). These studies show the feasibility of adding CD33-targeted radioimmunotherapy to a standard BMT preparative regimen; however, randomized trials will be needed to prove a benefit to intensified conditioning with radioimmunotherapy.

Anticancer antibodies offer promise of high sensitivity and specificity for the detection of disease, as they bind to tumour-associated antigens usually found only on a given type of tumour. Most studies have shown that radioimmunodetection is superior to other imaging modalides in the detection of disease outside the liver. Indium-111 (111In)-labelled satumomab pendetide is the first radiolabelled monoclonal antibody to be marketed for detection of disease. It is approved for single-time use for the detection of extrahepatic abdominal disease in colon and ovarian cancer. Optimal radionuclide-antibody conjugation is still not a reality. Antibody labelling with technetium-99m (99mTc), although still under development, appears promising. 111In has suitable half-life and imaging characteristics, but is expensive and has a complex radiation decay scheme, increasing radiation burden; 111In-labelled antibodies result in high hepatic and sometimes bone marrow uptake, precluding their use in the evaluation of hepatic disease. Radioiodine labelling, although easy, is limited to well-equipped nuclear medicine centres. Furthermore, mouse antibodies invariably evoke an immune response in humans, precluding repeated administration. The nontoxicity, specificity and affinity of antibody binding makes it inevitable that antibodies will be used increasingly in the detection of cancer. Several advances still need to be realised: (a) development of nonimmunogenic molecules such as all-human or humanised antibodies or antibody fragments; (b) development of better linkers, allowing stable conjugation of nuclide to antibody; and (c) characterisation of more restricted and better expressed tumour antigens that will permit rapid targeting of antibody to tumour.

Positron emission tomography (PET) is unique in being able to detect nanomolar changes in concentration. This has resulted in an array of radiotracers that target important parameters of neoplastic cell behavior, notably hormone receptors [1] and hypoxia states [2]. Also being studied in clinical trials are “reporter” tracers that track inoculation or activation of a gene of interest [3]. An increasing array of metabolic tracers have been labeled to positron emitters, initially with carbon-11 and increasingly with fluorine-18. These appear largely unlikely to displace F-fluorodeoxyglucose ([F]FDG) as the standard PET imaging tracer, especially for staging [4] and, perhaps more importantly, evaluation of response to therapy [5]. The other determinants of metabolic state— such as radiolabeled acetate, which may be more useful in certain situations because of the route of excretion (e.g., the lack of urinary radioactivity, which permits better delineation of the pelvis) and/or metabolic characteristics (e.g., amino acid rather than carbohydrate metabolism)— will always be complementary to [F]FDG, and therefore one must always consider the incremental value of these radiotracers. The incremental value may contribute to patient management, but it is more likely that the lasting contribution will be to our understanding of cancer biology. The incremental value of tracers other than [F]FDG in the management of a cancer patient will be difficult to assess; [F]FDG PET is part of standard of care in an increasing number of cancer types. Similarly, the incremental value of dual-phase [F]FDG PET studies, as demonstrated so elegantly in the accompanying report by Lyshchik et al. to which this Editorial Commentary relates, is worthy of further investigation. The cost of the incremental value would include, in busy centers, the lost opportunity costs of not carrying out routine standard of care studies in that time period, and one would need to weigh whether, as in this case, the cost of determining a better prognostic subtype of a terrible disease is worth the extra effort. Lyshchik et al. have contributed by demonstrating that not only is deoxyglucose uptake into a cancer cell important, but the retention of the agent is an even better indicator of aggressiveness, perhaps reflective of the anaerobic oxidative need for glucose (as opposed to fatty acid). Studies of this nature can be carried out in the community as well, and will gain in clinical value once better therapeutics are available. Moreover, the unique insights that these studies offer maywell lead to development of more targeted therapies. PET will add immensely to our knowledge and understanding of the cancer phenotype (and, someday, of genotype); these studies therefore need to be done, certainly in academic centers. The ever-expanding body of clinical knowledge available from PET—perhaps the most sensitive whole-body imaging modality for in vivo quantitation —must be employed, nay exploited, to understand the myriad aberrations that constitute this fascinating and deadly condition. The authors have demonstrated convincingly that this can be done even with the most “common” of PET tracers.