In vivo tracking and monitoring of adoptive cell transfer has a distinct importance in cell‐based therapy. There are many imaging modalities for in vivo monitoring of biodistribution, viability and effectiveness of transferred cells. Some of these procedures are not applicable in the human body because of low sensitivity and high possibility of tissue damages. Shortwave infrared region (SWIR) imaging is a relatively new technique by which deep biological tissues can be potentially visualized with high resolution at cellular level. Indeed, scanning of the electromagnetic spectrum (beyond 1000 nm) of SWIR has a great potential to increase sensitivity and resolution of in vivo imaging for various human tissues. In this review, molecular imaging modalities used for monitoring of biodistribution and fate of administered cells with focusing on the application of non‐invasive optical imaging at shortwave infrared region are discussed in detail. Plasticity and migration capacity of stem cells has opened up new prospects towards treating a wide range of human diseases in recent years and sheds light on expanding fields of regenerative medicine.2Biodistribution pattern, viability and fate of therapeutic cells in the target tissue after infusion are main causes of contradictory results among published studies.2.1It is suggested that increasing number of cell passages during in vitro expansion leads to the enlargement and widening of the cell size. This issue is considered as one of the important reasons for cell entrapment in lung and obstruction of subsequent small capillaries after intravenous cell infusion.2.2Cell delivery route has also a major effect on the localization and fate of transplanted cells in the living body.2.2.1Cell transplantation through the systemic circulation is achieved via intravenous, intra‐arterial and intraperitoneal routes. Various animal studies have demonstrated that the vascular bed of the lung is the first place where intravenously administered cells convene, which can cause small venule obstruction.Surprisingly, low‐dose cell delivery for treatment of ischaemic stroke through intra‐arterial pathway leads to the improvement of inflammation and decreases rate of embolus formation in vessels.Another undesirable side effect of intra‐arterial cell administration is the fragmentation of infused cells due to the shear forces of arterial blood flow. These damaged cells may be rapidly removed from the circulation through the liver and spleen, causing shorter blood half‐life of infused cells.2.2.2Theoretically local infusion of therapeutic cells to the parenchyma may increase the number and retention of the transplanted cells in the target tissueConversely, other studies have reported that infusion of high dosage of therapeutic cells directly to the myocardial tissue results in increased localization of transferred cells,2.3In addition, time‐point of cell transplantation into damaged tissues can have a significant effect on cellular localization, engraftment and regeneration of damaged tissues.2.4Also, characterization of optimal cell density that can regenerate the damaged tissue without adverse effects such as tumorigenicity2.5In addition, cell infusion rate must be adjusted in such a timing that maximal cell viability is maintained during injection.2.6It is also believed that majority of administered cells may encounter rapid clearance from the body due to the harsh and unfavourable environmental conditions such as anoikis, ischaemia, inflammationIn summary, route of migration, biodistribution, dosages, mechanical entrapment of transplanted cells due to enlarged size during successive in vitro expansion, infusion rate and host immunological factors might have detrimental effects on cell engraftment and fate in accordance with Figure Accurate tracking and in vivo real‐time monitoring of the injected cells will solve the discrepancies between various studies regarding localization, engraftment and interaction of cells with surrounding microenvironment.3Information about therapeutic cell function and fate is mostly obtained from fluorescence microscopy and immunohistochemical methods after obtaining biopsy samples from the patients. However, these methods are relatively invasive techniques and may lead to tissue damages and disruption of cellular structures.Molecular imaging technology is a growing and powerful platform that can provide valuable information about localization site and fate of cells after transplantation.3.1To track and monitor translocation and fate of administered cells, target cells have to be labelled by contrast agent or molecular probes that can act as tracers. Two main methods could be used for cell labelling in molecular imaging: direct and indirect labelling. By direct labelling, nanoparticles or chemical agents are delivered into the cell structure prior cell administration into the body. Although the ex vivo labelling of administered cells for various imaging modalities is simple and allows accumulation or internalization of dye in cell surface or internal structure (unless nucleus), there are several challenges. One major obstacle is that intensity of signals produced by labelled cells reduces with cell division over time; thus, direct cell labelling is not appropriate for long‐term tracing of transferred cells in target organs. Other challenges of direct cell labelling are toxicity, bleaching and limited sensitivity of chemical agents used for cell labelling. Indirect labelling is carried out through genetic engineering of cells by reporter genes such as green fluorescent protein (GFP) or bioluminescent luciferase. Genetic modification of cells using exogenous reporter gene that target the cell nucleus results in stable expression of detectable proteins  in target cells and future progeny. However, this labelling is hampered to find clinical importance due to stable integration of transgene into cellular genome and risk of mutagenesis.3.1.1111Indium (111In)‐oxine or 99m technetium (99mTc) chelates for single‐photon emission computed tomography (SPECT) imagingDirect cell labelling in molecular in vivo imaging can be done by various compounds including radioactive, paramagnetic or fluorescent agents.3.1.2Renilla luciferase, Gaussia luciferase, Metridia luciferase, Vargula luciferase or Bacterial luciferase has been employed as reporter genes.The indirect cell labelling allows visualization of the administered cells by the use of various reporter genes such as iron‐storage protein, ferritin, in MRI detection, the herpes simplex virus thymidine kinase type 1 (HSV1‐tk) and human membrane protein sodium‐iodide symporter (NIS) have also been used for positron emission tomography (PET) and hybrid SPECT/CT, respectively.3.23.2.1Imaging in computed tomography relies on differential absorption of ionizing X‐rays by various tissue components in the body.Nonetheless, different studies have shown that gold nanoparticles (AuNP) can be used safely to label, monitor and detect mesenchymal stem cells by conventional CT imaging in vivo.3.2.218F‐FDG) and [64Cu]‐pyruvaldehyde‐bis (N4‐methylthiosemicarbazone) (64Cu‐PTSM). Single‐photon emission computed tomography (SPECT) imaging relies on detection of two low‐energy γ (gamma) photons being emitted from radioisotopes including 111In‐oxine and technetium (99mTc) exametazime (99mTc‐hexamethyl propylene amine oxime [HMPAO]).Positron emission tomography (PET) imaging is based on radiotracers that emit positron. After production, radiotracers are unstable, immediately lose their energy and generate some particles named as positrons. These particles interact with neighbouring electrons via annihilation process, and two produced photons (each having 511 keV energy) can be detected by PET scanners.Because penetration in tissue depth in PET and SPECT has no limitation, their cell tracking sensitivity is high, and PET is more sensitive than SPECT.Although labelling procedure of therapeutic cells with PET and SPECT radiotracers is easy in vitro, cell tracking and monitoring should be performed immediately as a result of short half‐life of the agents in vivo. Radiotracers that are currently used in preclinical and clinical studies are removed through liver metabolism and renal clearance.3.2.319F). By placing the sample in the magnetic field, the spins polarize towards the main magnetic field. After polarization and alignment of the nucleus, radiofrequency (RF) pulse is applied to the sample that leads to excitation of nuclei and thus causes excitation from lower energy to higher and an unstable state. After removing RF pulse, the nuclei polarize towards the original magnetic field and transit to lower energy state. So, the excess energy of nuclei is released while emitting RF signals being detected by RF coils.Magnetic resonance imaging is a kind of non‐invasive imaging technique that uses a powerful magnetic field to induce polarization of hydrogen nuclei (protons) in water molecules or fluorinated molecules (19F) agents.3+, ensuring the presence of adequate contrast between the various regions in the body requires large amounts of these contrast agents. Thus, application of PARACEST media in higher concentration for long period of time may result in toxic effects. The major limitation related to the cell labelling with the iron oxide nanoparticles is that macrophage engulfs labelled cells after cell death in the body. Thus, approximately 10% of these nanoparticles can be seen in the macrophages and finally lead to misinterpretation of results related to the location and survival of therapeutic administered cells.Longitudinal relaxation time agents  offer positive contrast (bright) by reducing adjacent hydrogen proton T1 relaxation time. T2 agents (iron‐based agents and reporters) reduce the T2 relaxation time of hydrogen protons and offer hypointense (dark) contrast. Other MRI contrast agents include diamagnetic or diamagnetic chemical exchange saturation transfer (DIACEST), paramagnetic CEST (PARACEST) and perfluorocarbon  that are used extensively in the clinic for diagnostic purposes are classified as tomographic imaging modalities. They are dependent on deep penetrating radiations such as the X‐ray (CT), high‐energy subatomic particles (PET and SPECT) and strong magnetic fields (MRI).Indeed, therapeutic cells can be labelled indirectly through genetic engineering, using bioluminescent reporter gene such as firefly luciferase or fluorescent reporter gene such as GFP.Photinus pyralis, North American firefly), Renilla luciferase  and Gaussia luciferase (isolated from Gaussia princeps) are photoprotein‐enzymes that catalyse D‐luciferin substrate in the presence of ATP and O2 causing light mission.Optical bioluminescence imaging is based on genetic modification of cells with reporter genes and is considered as a promising method to track cell localization and destiny in live animals. Indeed, bioluminescence imaging relies on the detection of emitted lights from genetically modified cells that express enzyme proteins during chemical reactions in body. Firefly luciferase  that is excreted from Aequorea Victoria jelly fish as a by‐product uncovered in 1961. Other fluorescent proteins include fluorochromes, which emit red and far‐red light and also mutant forms of the GFP gene that emit yellow or cyanin light.Direct labelling of therapeutic cells for OFI generally consists of in vitro cell labelling prior to in vivo administration by fluorophores (fluorescent probe) or nanoparticles. Then, labelled cells are excited using photons in defined wavelengths of spectral region and emitted light from cells is detected with high sensitive detector or camera.Major endogenous chromophores (light absorbers) that significantly absorb the light in the visible light include water, lipids, oxyhaemoglobin and deoxyhaemoglobin that particularly has a high absorption peak in the visible region of the spectrum.4The use of visible region of electromagnetic spectrum in the range of 400‐650 nm is suitable to get image from accessible or superficial tissues such as colon and skin, but not for structures locating in the deeper parts of the body such as nucleus or stem of the brain due to the scattering and absorption by tissue components.During the last two decades, many efforts have been made to increase image contrast by diminishing between the tissue scattering and absorption of light photons along with reducing disruptive autofluorescence signals due to increasing the tissue depth to avoid potential deleterious effects of tissue parameter on in vivo fluorescence imaging.The results of the various studies demonstrated that longer wavelength lights have more penetration depths than the visible light. This phenomenon is due to the decrease in photon scattering and absorption by biological tissues. Extending optical fluorescence imaging from the visible region (400‐650 nm) to near‐infrared region of the spectrum  offers considerable improvement in the image contrast compared to fluorescent imaging in the visible region. Indeed, by using longer wavelengths in the NIR I window, the transparency of opaque tissue will increase as a result of the better penetration of photons to the tissue media. Also, at the longer wavelengths, autofluorescence of the biological tissue does not visualize or is negligible.,Optical spectroscopy using exogenous fluorophores that emit light in the range of NIR I window is extensively used in the clinic as an important diagnostic method to evaluate blood flow inside the brain and determine tumour margin for precise resection and removal of cancerous tissue during surgery.Figure .125, 126Figure . Same asIn spite of various SWIR emitting fluorophore production during recent years, quantum yields of these fluorescent probes are very low.An interesting published study has revealed the beneficial effects of narrow‐range quantum dots (QDs) for fluorescence in vivo imaging purposes.4.12S quantum dots that emit light in the biological SWIR window. They demonstrated the dynamic process of Ag2S QD‐labelled MSC biodistribution and homing in response to SDF‐1α on the cutaneous wound healing.Optical fluorescence imaging is expected to contribute to the development of cell‐based therapy because it can detect labelled cells with high resolution.Despite several promising studies in the SWIR region of spectrum related to therapeutic cell visualization and detection, higher efficient and biocompatible SWIR emitting fluorophores are needed for further advancement in this field of molecular imaging. Consequently, SWIR‐based imaging can open up new ways towards non‐invasive in vivo fluorescent imaging with high spatial and temporal resolution at cellular levels.5Because there are critical challenges related to the translation of cell‐based therapy to the clinic, in vivo tracking of infused cells for the purpose of cell engraftment and fate is essential for obtaining insights about therapeutic cell efficacy. With this respect, optical fluorescence imaging in SWIR windows (extended NIR) is thought to be a great imaging modality due to its inherent increased lengths of light penetration in non‐homogeneous and opaque tissues. Thus, researchers can achieve better image contrast and high spatiotemporal resolution necessary for in vivo cell tracking using this modality. There has been focused on applications of SWIR‐based in vivo imaging during the last years due to lack of destructive ionizing radiation compared to other imaging modalities  along with other mentioned advantages Table . TherefoThe authors declare that they have no conflicts of interest.LF contributed to the literature research, drafting, interpretation and writing of manuscript. MV and ES contributed to the supervision, drafting, interpretation and writing of manuscript. ES gave the final approval of the article to be published. Also, all authors critically revised the manuscript draft.


Illicit drugs are an uncommon etiology of acute myocarditis but should be evocated in young population. This association may result in further complications, mainly ventricular arrhythmia and therefore increases sudden cardiac deaths among young abusers. Withholding drug intoxication to prevent recurrent events is a major key of management. Toxicomania is a worldwide health and social problem. In 2015, World Health Organization estimates that 255 millions of people are drug users and more than 10% of them have health disorders A 38‐year‐old man was admitted in our cardiology department for palpitations and dizziness. He was a 27 pack‐years smoker and a multidrug abuser since 10 years. In fact, he was consuming twice a week cocaine and four joints a day of cannabis. An electrocardiogram (ECG) was rapidly performed. It showed a regular wide QRS tachycardia at 220 beats/min with a negative concordance pattern in all precordial leads and an extreme axis deviation  and a daily three joints of cannabis abuser for 3 years. He is also a monthly cocaine consumer for <1 year. He presented to emergency department for new‐onset palpitations. An immediate ECG demonstrated a regular wide QRS tachycardia at 170 beats/min with left bundle branch block pattern and left QRS axis Fig. , Panel AAccording to Lake Louise consensus criteria, CMR findings suggestive of myocarditis are as follows: (1) Regional or global myocardial signaling intensity increase in T2‐weighted images suggestive of edema; (2) Increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium‐enhanced T1‐weighted images suggestive of hyperemia and capillary leakage; 3) At least one focal lesion with nonischemic regional distribution in inversion recovery prepared gadolinium‐enhanced T1‐weighted images (late gadolinium enhancement) suggestive of necrosis and fibrosis. In the setting of clinically suspected myocarditis, CMR findings are consistent with myocardial inflammation, if at least two of the above‐cited criteria are present  At leastIn a series of 40 autopsies performed in the context of cocaine‐associated deaths, it was demonstrated that myocarditis with mononuclear infiltrate was responsible of 20% of deaths and was nearly 10 times more common than acute thrombotic coronary occlusion.This finding showed that drug abuse induced myocarditis could be responsible of sudden cardiac death likely via ventricular arrhythmia, which was the relevant complication in our two patients.The evocated mechanism of VT, in this case, is scar‐related macroreentry due to the development of necrosis and fibrosis as shown by CMR In our both cases, the VT morphology on ECG have suggested an apical VT exit; however, myocardial scars on CMR were specially located in the subepicardial layers of lateral wall of the left ventricle.In the first case, cocaine seems to be the etiology of the myocardial damage owing to the more established association between cocaine and myocarditis and also the existence of ECG signs of cocaine intoxication revealed after the reduction of VT. In fact, complete right bundle branch block, shown in our case, was described to be the consequence of sodium channel blockade, the main mechanism of action of cocaine In both cases, the diagnosis of drug‐induced myocarditis was a diagnosis of exclusion. Autoimmune and viral myocarditis should be mentioned. Nonetheless, given the history of the two patients and the electrocardiographic pattern in the first case, in relation with cocaine and or Marijuana should raise suspicion for a causal association. Performing an endomyocardial biopsy could help the etiological diagnosis, since in drug abuse myocarditis, contraction band necrosis could be demonstrated and could confirm the causal association In our patients, we preferred not to prescribe beta blockers as it is contraindicated in case of cocaine intoxication because of the risk of coronary vasospasm and myocardial infarction Ventricular tachycardia is a challenging finding, in which CMR plays a key role for the diagnosis of potential reversible causes mainly acute myocarditis. This complicated situation can be induced by illicit drug abuse. Such an uncommon association should notably be evocated in young population and must lead to definitively stop abusing the culprit drug.SO, OG: conceived of this case report. All authors read and approved the final manuscript.None declared.


Pleural metastasis of thyroid carcinoma is very rarely encountered in the evaluation of pleural effusion and diagnosis may be challenging. However, an anaplastic transformation of papillary thyroid carcinoma (PTC), although a rare condition, should be considered even after a prolonged period of patient follow‐up. Here we report a case of anaplastic thyroid carcinoma mimicking malignant pleural mesothelioma diagnosed nine years after the initial diagnosis of PTC and detail the clues used to orient and confirm the diagnosis. Metastasis of thyroid carcinoma to the pleura is a rare condition, although anaplastic transformation of previous papillary thyroid carcinoma (PTC) is one of the most aggressive cancers. In this situation, the diagnostic exploration of a prevailing pleural effusion can be a challenge for pulmonary physicians. Indeed, in usual cases of anaplastic thyroid carcinoma (ATC), metastases occur in the thyroid and regional lymph nodes rather than at a distant site. Characterization of the pleural fluid may sometimes contain subtle clues which may assist clinicians in making the correct diagnosis.Here, we briefly report and discuss a difficult diagnostic case of anaplastic thyroid carcinoma which developed at the pleural site mimicking a malignant pleural mesothelioma.A 77‐year‐old patient presented with a history of progressive dyspnea of one week due to a pleural effusion on the left side. He had never smoked and retired after working as a warehouseman including a few years in shipyards where he had been exposed to asbestos. He was mainly treated for an obesity‐hypoventilation syndrome with noninvasive ventilation. He had a past medical history of PTC treated by total thyroidectomy nine years previously and additional radioiodine therapy for mediastinal relapse one year later with a prolonged survey showing he maintained a stable condition.On examination, the patient required 8 L/min oxygen support and chest radiograph showed a massive pleural effusion on the left side. Thoracic computed tomography (CT) detected atelectasis of the left and right lower lobes and pleural effusion on the left side. The 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography/computed tomography (PET/CT) fused imaging found important 18‐FDG uptake in the left pleura  and moderate hypermetabolism of two mediastinal (SUVmax 7.6 g/mL) and one subdiaphragmatic pillar (SUVmax 8 g/mL) nodes .In conclusion, we report the first case of single‐component anaplastic thyroid carcinoma at the unique pleural metastatic site mimicking a malignant pleural mesothelioma. Owing to its scarcity and poor prognosis, this disease may be underdiagnosed. It could be evoked typically in patients with a past history of PTC, even after long‐term patient follow‐up. Pleural thyroglobulin, PAX‐8 immunostaining and molecular analysis may also be useful to orient and confirm the diagnosis.No authors report any conflict of interest.


All species, including humans, are cohabited by a myriad of microbial species, which massively influences body function in a diet‐, exercise‐ and age‐dependent manner. The microbiome composition differs between individuals, partly due to the polymorphic immune system, as well as the environment, making the microbe–host interplay unique in each one of us. Ageing is a gradual loss of function in part due to reduced repair mechanisms and accumulation of tissue damage through mechanisms largely unknown. Accumulating evidence suggests that our indigenous microbes, a known major regulator of human physiology, are also connected to regulate the ageing process through signalling pathways and metabolites though the biological mechanisms are unknown. At an ageing meeting in Singapore in 2018, investigators discussed the current understanding of microbe regulation and its impact on healthy ageing. This review summarizes the highlights from the meeting and conveys some of the new ideas that emerged around gut microbes and the biology of ageing. While highly speculative, an idea emerged in which gut microbes constantly respond and evolve to environmental cues, as part of an ageing process, thus serving as a second messenger to support and attenuate organ decline in a diet‐, gender‐ and age‐dependent manner. Bio‐active – having a biological effect.Calorific value – energy contained in food, determined by measuring the heat produced by the complete breakdown of it.Circadian rhythmicity – is a roughly 24‐h cycle in the physiological processes of living beings. It is usually endogenously generated and can be modulated by external cues such as sunlight and temperature.Cognitive ability – general mental capability involving reasoning, problem‐solving, planning, abstract thinking, complex idea comprehension and learning from experience.Cognitive function – refers to multiple mental abilities such as learning, thinking, reasoning, attention, remembering, problem solving and decision making.Degenerative pathways – pathways resulting in changes that affect tissues and organs to deteriorate increasingly over time.Disease susceptibility – an increased likelihood of developing a disease based on the genetic make‐up, often due to the inheritance of a genetic variation from the parent.Diurnal rhythmicity – patterns of activity or behaviour that follow the day and night cycle, repeating every 24 h.Dysbiosis – a term used for a microbial imbalance on or inside the body, such as an impaired microbiota where microbiome become deranged, with predominant species being underrepresented and normally contained species increasing to fill the void.Ecological niche – the role and position a species has in its environment; how it meets its needs for food and shelter, how it survives, and how it reproduces.Glycaemic index – is the value assigned to foods based on how slowly or how quickly they cause increases in blood glucose levels. It is a number from 0 to 100 assigned to a food, with pure glucose arbitrarily given the value of 100.Holistic interventions – economical, non‐invasive, non‐pharmacologic alternatives to traditional medical care that expand the repertoire of therapies to manage and control diseases.Induced pluripotent stem cell – adult cells that have been genetically reprogrammed to an embryonic stem cell‐like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells.Mass spectrometry – an analytical technique that measures the mass‐to‐charge ratio of ions in order to quantify known materials, identify unknown compounds within a sample and to elucidate the structure and chemical properties of different molecules.Metabolite – intermediate end product of metabolism, usually a small molecules.Metabolome map – a map of the global collection of low molecular weight metabolites produced by cells during metabolism providing a functional readout of cellular activity and physiological status.Metabolome – complex set of small molecule chemicals found within a cell, organelle, tissue, biofluid or the entire organism.Microbiome – the microorganisms in a particular environment of the body or a part of the body.Neural niche – a zone in which stem cells are retained after embryonic development for the production of new cells for the nervous system.Neurodegenerative diseases – conditions that primarily affect the neurons in the brain and spinal cord causing them to die or be damaged. Examples of diseases would be Parkinson's, Alzheimer's and Huntington's.Neurotoxic effects – damage to the peripheral or central nervous systems due to the exposure to natural or man‐made toxic substances, which can alter the activity of the nervous system to disrupt or kill nerves.Niche – a specialized and specific zone or area.Non‐senescent – organisms that do not exhibit any measurable decline in survival characteristics such as strength or mobility with age, do not have a gradually increasing death rate with age and also do not exhibit any measurable reduction in reproductive ability with age.Operant paradigm – behaviour that is modifiable and controlled by its consequences.Personalized nutrition – an approach that uses information on individual characteristics to develop targeted nutritional advice, products, or services to assist individuals achieve lasting beneficial dietary behaviour changes.Phenotype – a composite of the individual's observable characteristics as a result of the interaction between its genotype with the environment.Physiology – the way in the body or specific body parts and organs function and interact with one another.Plasticity – the ability of living organisms to change their “state” in response to any stimuli and showing an adaptive response for optimal survival.Polymorphic – a discontinuous genetic variation resulting in the occurrence of different types of individuals among the members of a single species.Post‐prandial – during or relating to the period after meal: dinner or lunch.Precision medicine – also known otherwise as personalized medicine, is an approach to patient care that empowers healthcare providers to select and administer treatments most likely to be effective to patients based on the genetic understanding of their disease.Symbiotic – interaction between two different organisms living in close physical and long‐term biological association enabling a mutually benefiting relationship.et al, et al, et al, Throughout evolution, complex organisms have acquired prokaryotic organelles such as mitochondria and chloroplasts to optimize biological functions  . Activation of Atg1 induces the machinery to secrete indoles by nearby microbe secretion  intervention study revealed the possible beneficial effects of attenuating cognitive decline through multi‐domain lifestyle interventions   they require to maintain diversity and thus homeostasis, it will undoubtedly have positive repercussions on body function. This echoes the sentiments of Plutarch, who advocated that we have the power to build up physical and mental qualifications, which we are then able to exploit in our old age Trench, . If we lThe average lifespan in Classical Greece was reported to be 25 years but increased to 42 years after they crossed adulthood due to high infant mortality Angel, , and it (i)The mechanisms underlying microbiome changes by age and the reasons are currently unknown. Current theories suggest impairment in barrier integrity, thus allowing microbes to breach barriers and indirectly elicit low‐grade inflammation. Another theory implies that gradual loss of organ function forces gut microbes to respond to the reduced physiological efficacy and as a consequence, increase in the generation of energy from the alimentary tract to the host through changes in microbiome composition. Both models are not mutually exclusive. More research is highly warranted.(ii)Increasing the knowledge by which microbes and microbial metabolites influence signalling pathways and organ function within an ageing organism across gender. Of outmost importance is to identify microbial metabolites that directly or indirectly support healthy ageing or attenuate accelerated ageing. This includes also molecules that stabilize barrier integrity.(iii)Undertake research to identify major “orchestral” microbe leaders that directly or indirectly influence microbiome diversity and richness relevant to its functions. An example is Akkermansia.(iv)et al, We have yet to explore the first tailor‐made microbiome intervention study in line with the biology of a given individual. The lessons from non‐responder/responder experiments using probiotic intervention approach from the Elinav laboratory (Zmora (v)There is an unmet need to develop a better understanding of how gut microbes and their metabolites contribute to organ‐to‐organ communication either in early life or when organ function declines by age. This includes also the topological distribution of microbes in different compartments. For example, which are the temporal–spatial cues that guide homing to a specific part of the body?(vi)Virtually nothing is known when microbes and the host end up having opposing needs. When does this occur, what are the signalling cues and underlying molecular mechanisms that trigger these situations? Is there room for man‐made interventions that can attenuate the conflict of interest between microbes and the host without massive violation of microbe–microbe interactions, like we do with pathogens and antibiotics? Future experiments involving antimicrobial peptides or phage therapy are therefore of interest.(vii)Utilizing existing knowledge by providing SCFA to increase barrier integrity; does it come with unwanted side effects yet to be discovered especially since SCFA also has the ability to remodel chromatin structure? Systems biology analysis in human cohort studies is therefore highly warranted and this is an area where the food industry should together with academia, clarify the effects of microbial intervention and maintaining barrier function and overall metabolic homeostasis.(viii)The rapidly growing number of old people worldwide is intimately associated with increased number of human beings with chronic lifestyle diseases because of increased lifespan. There is unmet need to undertake longitudinal studies among old people that is not subject to disease. Within these groups of people, there are those at risk to develop disease. A systems biology approach including non‐invasive fMRI analysis combined with multiple omic analysis, metagenomics and metabonomics of stool and fluid samples will open for discovery of novel biomarkers that can be used for future intervention studies prior to disease at an individual level.(i)Dr. Paul Blatchford, Commonwealth Scientific & Industrial Research Organization (CSIRO) Health and Biosecurity, Adelaide, Australia(ii)Professor Atsushi Iriki, Riken Brain Science Institute, Japan(iii)Professor Dusko Ehrlich, King's College, London, UK(iv)Professor Elaine Holmes, Imperial College, London, UK(v)Professor Eran Elinav, Weizmann Institute of Science, Israel(vi)Professor Miia Kivipelto, Karolinska Institute(vii)Professor Thomas Bosch, Zoologisches Institut, University of Kiel, GermanyThe authors declare that they have no conflict of interest.


Recurrent pregnancy loss (RPL) is one of the most common reproductive disorders which is defined as the occurrence of recurrent miscarriage before 24 weeks of gestation and is observed among 1%–5% of women.Various factors are associated with RPL such as immunological disorders, maternal age, obesity, alcohol, chromosomal abnormality, endocrine disorders, and uterine abnormalities. About half of the RPL cases are related with chromosomal abnormalities. Therefore, RPL genetic tests are mainly limited to karyotyping. However, there is a significant proportion of RPL cases without any chromosomal abnormalities that can be related to the single‐gene aberrations. Therefore, it is required to prepare a diagnostic panel of genetic markers besides karyotyping.In the present review, we have summarized all the significant reported genes until now which are associated with RPL among Iranian women. We categorized all the reported genes based on their cellular and molecular functions in order to determine the molecular bases of RPL in this population.This review paves the way of introducing a population‐based diagnostic panel of genetic markers for the first time among Iranian RPL cases. Moreover, this review clarifies the genetic and molecular bases of RPL in this population. Higher and lower expressions of IL‐6 and TGF‐β respectively have been observed among cases with pregnancy loss  is secreted by Th17 cells which are related to the Treg cells and regulate the immunological rejection of foreign tissues  in URSA compared with controls  and RPL among a sample of Iranian cases. The −308G allele was also a protective factor against spontaneous abortion  is produced by a wide range of immune and nonimmune cells which are involved in regulation of Th1 and Th2 differentiations  is also produced by endothelial cells and is associated with Th2 activation  polymorphism and RPL in which the CC genotype can be a RPL risk factor among a subpopulation of Iranian cases. Moreover, they also observed the GA genotype of IL‐33 (rs1929992) polymorphism as a RPL risk factor among Iranian subjects  is produced by Th‐17 cells following IL‐23 induction. It has been observed that there was a significant different frequency of IL‐17F (rs763780) gene polymorphism between a group of Iranian RPL and control subjects which showed that this polymorphism can be correlated with a high RPL risk in this population  is a glycoprotein observed in endothelial cells and macrophages and is associated with upregulation of IL‐4 and IL‐10 anti‐inflammatory cytokines. Moreover, it is involved in shifting the Th1/2 balance toward the Th2 responses  as a ligand of the TGFβ family activates the SMAD transcription factors and can be associated with regulation of early ovarian follicle development  polymorphism among a sample of Iranian RSA patients in comparison with controls who showed this polymorphism as a RSA risk factor in Iran  is a pivotal antioxidant enzyme that functions as a protector against the ROS‐related cell damage through conversion of hydrogen peroxide to oxygen and water  is one of the members of deubiquitinating enzymes (DUB) involved in the regulation of cell growth, differentiation, and tumorigenesis  or CD4+cells are a class of T cells mainly involved in adaptive responses. Th cells differentiate into the Th1 and Th2 subtypes which are associated with cell‐mediated and humoral immune responses, respectively. Although, successful pregnancy is associated with Th2‐related cytokines, there is reduced Th1 cytokine production during pregnancy  is an angiogenic cytokine which increases the vascular permeability and is involved in the regulation of proliferation and differentiation of endothelial cells  targets PTEN during the regulation of angiogenesis. Moreover, miR‐21 overexpression activates the ERK and AKT signaling pathways which results in VEGF upregulation and increased angiogenesis  is a heparin sulfatase that releases 6‐O‐sulfate groups from heparin sulfates which change the growth factor binding sites in proteoglycans  polymorphism and increased risk of recurrent miscarriage among a subpopulation of Iranian patients in which there were higher frequencies of GG and AA homozygous genotypes among patients. Moreover, higher frequency of AG genotype among healthy cases showed a correlation between this genotype and higher chance of successful pregnancy  is one of the components of NADH dehydrogenase complex, which is the largest complex in the electron transport chain. The T4216C variation of ND1 has been observed in 30% of a subpopulation of Iranian RPL cases which can be introduced as a polymorphism with secondary effects on RPL  inhibitor that has an important role in thrombotic disorders and increased PAI‐1 concentration can be associated with placental damage through aberration in coagulation and fibrinolysis  polymorphism among Iranian RSA cases compared with healthy subjects  is a fibrinogen receptor that is associated with platelet activation and thrombosis stimulation  as a key thrombophilic factor converts angiotensin I to angiotensin II and is associated with platelet aggregation and fibrinolysis. It has been reported that there was a correlation between ACE I/D polymorphism and RPL among a sample of Iranian population in which the DD genotype was more frequent in RPL compared with control cases. It was concluded that the ACE D allele can increase RPL risk and can be considered as a diagnostic factor among Iranian RPL cases  is involved in methionine formation from homocysteine. The Iranian RPL cases had significantly higher frequencies of MTHFR 677C ⁄T and 1298A ⁄C polymorphisms compared with the control group  is a transmembrane glycoprotein which functions as a complement factor I cofactor to suppress C3 convertase complex and maintains complement activation  is normally expressed in several locations such as fetal trophoblasts, pancreatic islets, and endothelial precursors  is another member of the HLA proteins involved in feto‐maternal tolerance through interaction with CD94/NK G2A complex which has a critical role in NK cell suppression. It has been observed that there was higher frequency of HLA‐E 0101 polymorphism among a sample of Iranian RSA cases compared with controls, whereas HLA‐E 0103 was more frequent among controls. Moreover, the HLA‐E0101/0103 heterozygous genotype was correlated with fetus maintenance among Iranians  encode the major histocompatibility complex proteins as the regulators of immune system. The HLA system helps immune system to discriminate between self and nonself cells. The HLA expression at feto‐maternal interface can be associated with a successful pregnancy  that regulates the interaction between NK cells and their target cells  and CD161 (OMIM: 602890) are cell surface markers involved in cytokine production and cytotoxicity  cells are cytotoxic lymphocytes associated with maternal immune system suppression. They are the most abundant immune cells in uterine implantation site and act as the first cellular immune defense mechanism. NK cells are classified into CD16+CD56dim and CD16−CD56bright NK cells   is a nuclear receptor highly expressed in the female reproductive system  is a hormone mainly produced by adipocytes and is involved in the energy balance and body weight homeostasis (Zhang et al., Vitamin D is a lipid‐soluble hormone involved in bone and mineral metabolism by binding with nuclear vitamin D receptor (9Recurrent pregnancy loss is a serious growing problem among the young couples. Despite various clinical and experimental tests, still there is not an accurate and efficient diagnostic method during the early stages of pregnancy in cases without any known cause. Therefore, it is required to determine targeted genomic methods besides karyotyping, clinical, and pathological examination. In the present review, we summarized all the reported single gene abnormalities among Iranian RPL cases to pave the way of introducing a population‐based panel of genetic markers in this population. We categorized all the reported markers to clarify the molecular bases of RPL. We observed that the majority of reported markers belonged to the regulatory T cells which highlights the role of these immune cells in RPL among Iranian women.None declared.


Health Science Reports by Asselah and colleagues investigated the additional benefit of extending treatment duration of the ombitasvir/paritaprevir/ritonavir plus ribavirin regimen to up to 24 weeks for patients with HCV genotype 4 and compensated cirrhosis.The optimal antiviral regimen for hepatitis C virus (HCV) genotype 4 is still a subject of investigation. The report in this issue of  Ombitasvir/paritaprevir/ritonavir plus ribavirin for 24 weeks in patients with HCV GT4 and compensated cirrhosis (AGATE‐I Part II)This article discusses:  This genotype is predominantly found in patients from Egypt. Its prevalence varies widely by regions, with the highest prevalence reported in the Middle East and sub‐Saharan Africa.Health Science Reports by Asselah et alFour all‐oral direct‐acting antiviral (DAA) combination therapy regimens are recommended as anti‐HCV therapy for treatment‐naïve patients with HCV genotype 4 infection in the guidelines from the European Association for the Study of the Liver (EASL)There is substantial genetic heterogeneity in HCV genotype 4, and many subgenotypes have been reported, although, with the exception of subtypes 4a and 4b, the prevalence of these subtypes is low. The efficacy of DAA regimens by subgenotype is unclear and will be the subject of further research. Although some trials that focused on patients with HCV genotype 4 have included more than 100 patients,The ideal DAA regimen for HCV genotype 4 has not been fully established, although there are multiple DAA treatment options for patients with HCV genotype 4, particularly those with the predominant subtypes, and overall efficacy in clinical trials has been reported to be as high as with other genotypes. We expect the accumulation of more findings on the efficacy of various regimens, and on different subtypes, perhaps based on real‐world results, to confirm the high rates observed of sustained virologic response in patients with HCV genotype 4.None declared.


It is easy to argue that vaccine development represents humankind’s most important and successful endeavour, such is the impact that vaccination has had on human morbidity and mortality over the last 200 years. During this time the original method of Jenner and Pasteur, i.e. that of injecting live‐attenuated or inactivated pathogens, has been developed and supplemented with a wide range of alternative approaches which are now in clinical use or under development. These next‐generation technologies have been designed to produce a vaccine that has the effectiveness of the original live‐attenuated and inactivated vaccines, but without the associated risks and limitations. Indeed, the method of development has undoubtedly moved away from Pasteur’s three Is paradigm  towards an approach of rational design, made possible by improved knowledge of the pathogen–host interaction and the mechanisms of the immune system. These novel vaccines have explored methods for targeted delivery of antigenic material, as well as for the control of release profiles, so that dosing regimens can be matched to the time‐lines of immune system stimulation and the realities of health‐care delivery in dispersed populations. The methods by which vaccines are administered are also the subject of intense research in the hope that needle and syringe dosing, with all its associated issues regarding risk of injury, cross‐infection and patient compliance, can be replaced. This review provides a detailed overview of new vaccine vectors as well as information pertaining to the novel delivery platforms under development. Vaccines are arguably the most important medical technology developed to date, and have provided dramatic reductions in disease morbidity and mortality since Edward Jenner first tested his smallpox vaccine in 1798 Although vaccines have been undeniably successful, improvements in vector production, delivery and ease of use would be of great benefit. Historically, vaccine development has been based on the ‘three Is’ paradigm of Louis Pasteur  Delivery is an important issue, because the majority of vaccines used currently are still administered with a hypodermic needle, either intramuscularly (e.g. hepatitis B or inactivated poliomyelitis), subcutaneously (e.g. measles or yellow fever) or intradermally [e.g. bacillus Calmette–Guérin (BCG)]. The hypodermic needle is the mainstay of vaccine delivery technology because it provides a direct, low‐cost method of administration with instant validation that the dose has been delivered and an impressive efficacy profile defined over decades of use. However, the many drawbacks and limitations of needle and syringe delivery are beginning to make it look like a rather out‐dated approach. Prime among these limitations is the effect pain and fear of needles has on patient compliance and ultimately vaccination rates This review begins by giving a broad overview of novel approaches in vaccine design and composition and describes how formulation approaches are improving delivery platforms (see below: ‘Novel vaccine designs’ and ‘Novel vaccine delivery platforms’). A further notable means of improving vaccine efficacy, the development and use of technologies for the improved administration of vaccines, is then covered in the later section (see below: ‘Vaccine administration routes and technologies’).Virus‐like particles (VLPs) are highly ordered, repetitive structures that contain a high density of viral capsid proteins. This high density of capsid proteins provides copious amounts of conformational viral epitopes, capable of eliciting strong immune responses Being simpler in composition, VLPs also allow faster production of vaccine than traditional methods, which is especially useful for treatment of highly mutating pathogens such as influenza. Traditional production of an influenza vaccine takes 9 months after a new annual strain has been sequenced, but VLP production takes only 3–12 weeks Vaccines that use either live‐attenuated or inactivated pathogens contain a wide array of different antigens, both polysaccharide‐ and protein‐based. However, only a small number of these may be required to induce protective immunity Plasmodium sporozoites conjugated to the hepatitis B surface antigen. This conjugate vaccine subsequently assembles into a VLP.Peptide‐ or polysaccharide‐based vaccines tend to be less immunogenic than when they are present on the surface of a pathogen, thus they require the inclusion of an adjuvant when being administered Long‐term gene expression from plasmid DNA has been demonstrated to be achieved by intramuscular injection in mice in‐vivo delivery The limitations of DNA vectors have resulted in RNA‐based vaccines gaining momentum in recent years The main focus of RNA‐based vaccine development has been cancer, with numerous Phases I–III clinical trials in progress Due to the history of success of vaccination using live‐attenuated viruses, inactivated viruses or bacteria, attempts have been made to apply a similar approach to vaccinate against cancer. Attenuated tumour cells have been administered to induce an immune response against specific types of cancers. Two types of whole cell vaccines have been used: autologous and allogenic. Autologous cell vaccines have been tested on a variety of cancers, including lung, colorectal, melanoma, renal and prostate cancer ex vivo. The newly matured, antigen‐loaded dendritic cells are then readministered to the patient to induce anti‐tumour immunity. Dendritic cell vaccines have been tested against prostate, melanoma, renal and glioma tumours in clinical trials Another kind of cellular‐based vaccination exploits a patient’s own immune cells, specifically their dendritic cells. Dendritic cell vaccines can be formulated by loading a patient’s autologous dendritic cells, that are simultaneously treated with immunoadjuvants with either tumour‐associated antigens or nucleic material encoding for tumour‐associated antigens From this section, it is clear that there is a range of novel vaccines with impressive immunological activity. It is notable that the majority of these have been designed and are being used under the presumption that conventional needle‐and‐syringe delivery offers the best route to their optimal efficacy. The following sections provide information on vaccine formulation delivery platforms and administration routes/technologies which may be worthy of consideration as a means to challenge this dogma and perhaps enhance vaccine utility further.in vivo; a lipid‐linked polyethylene glycol (PEG), to increase in‐vivo stability; cholesterol, to increase structural stability; and a phospholipid, which supports the formation of a lipid bilayer. Cationic liposomes, unlike their anionic counterparts, are able to bypass the endosomal–lysomal route of degradation in cells Liposomes are spherical vesicles with a lipid bilayer formed of biocompatible phospholipids. Their main use in vaccinology is either as a delivery vehicle or as an adjuvant Antigens can be encapsulated within, conjugated to the surface of, or embedded within the lipid bilayer Polymeric particles have been increasingly researched in the field of vaccine delivery due to their potentially advantageous biocompatibility and biodegradability Many inorganic particle‐based vaccines have been studied, despite their low biodegradability. Their main advantage lies in how much control can be achieved over their synthesis Gold particles are highly stable and can be easily synthesized in a variety of different shapes and sizes Aluminium is a commonly used adjuvant in vaccines Calcium phosphate particles are a promising candidate for vaccine applications as they are bioresorbable, non‐toxic, have adjuvanting properties and can easily be loaded with antigen in vivo Silica‐based particles are a popular form of inorganic particle in vaccine research, as they are biocompatible and their interactions with cells can be modified by altering their size and shape Carbon nanoparticles have also been studied extensively for drug and vaccine delivery Plant cells are an attractive vaccine delivery platform for oral administration because of the ease and low cost with which large populations could be vaccinated. Furthermore, their tough cell wall is able to protect intracellular material from harsh environments encountered within the stomach Similar to plant cells, single‐cellular algae also have a tough cell wall, making them another attractive delivery platform. Algae‐based vaccines have many advantages over plant cell‐based vaccines: they are easier to genetically modify, they can be grown in bioreactors and do not require large areas of land, seasonal conditions or extended durations to grow Lycopodium clavatum (clubmoss) and Ambrosia elatior (ragweed) spores can be chemically cleaned to remove any native proteins present that risk being allergenic, before being refilled with proteins of interest for vaccination Pollen grains are naturally occurring plant‐based materials that have also recently been investigated as a vaccine delivery platform Bacteria and viruses can be genetically modified to produce antigenic material from another pathogen Outer membrane vesicles are naturally occurring, non‐replicating vesicles produced by Gram‐negative bacteria Immunostimulating complexes (ISCOMs) are spherical cage‐like particles that are spontaneously formed by mixing phospholipids, cholesterol, saponin and protein antigens Emulsions are heterogeneous liquid systems commonly used in vaccines as adjuvants. Their simplest iteration is in the form of water‐in‐oil or oil‐in‐water, but they can be formulated in more complex multiple emulsion systems such as water‐in‐oil‐in‐water Using a needle and syringe is a very effective method of introducing a substance to the body, as the barrier properties of the skin are very easily breached by a needle. However, use of needles and syringes has many disadvantages, such as pain, needle phobia, risk of needle‐stick injuries and transmission of infections, all of which lead to increased cost and poor patient compliance Some studies have investigated the use of passive delivery methods to administer vaccines transdermally Arguably, the most explored method of transdermal delivery is in the use of microneedles, which consist of 10s to 1000s of pointed microsized projections fabricated onto a surface Electricity has also been used to facilitate the delivery of drugs and vaccines transdermally in two differing methods, iontophoresis and electroporation. Iontophoresis relies on the application of an electrical current to drive charged particles into the skin through electrostatic effects Sonophoresis is the use of ultrasound to improve transdermal drug and vaccine delivery Biolistics involves the use of high pressures to accelerate vaccines to velocities high enough to allow penetration of the stratum corneum and epidermal cell membranes versus $15 Transdermal delivery is an attractive goal because of the potentially easy and pain‐free access it provides to a rich immunological milieu. However, in addition to the unique limitations faced by each of the technologies described above, there is also a general challenge to overcome the huge inter‐ and intraperson hetrogeneity in stratum corneum thickness, hydration levels and hair‐follicle density. Furthermore, in order to depose needle and syringe as the preferred administration technology, all the approaches described above will also face the challenge of matching the impressive needle‐and‐syringe price point. It might be argued that patients in more economically developed countries may be prepared to pay a premium for more bespoke ‘pain‐free’ alternatives to needle and syringe. A suggestion supported by the increased cost of Flumist  of vaccine development is increasingly being phased out for a more rational design paradigm. Occurring alongside the progress of these new rationally designed vaccines is the development of improved and more patient acceptable delivery techniques to target and sustain the pain‐free administration of antigen more effectively. Enhancing methods for administering these vaccines is crucial in reducing the number of needle‐stick injuries and lowering the burden on medical staff by making vaccines more amenable to self‐administration. Unfortunately, new administration technologies  will never be able to match the dose level that can be delivered using a needle and syringe. However, it is hoped that by combining the new delivery methods with the raft of new more effective vaccines this limitation may be negated. Understanding the particular mechanism‐of‐action of new vaccines and vaccine delivery platforms and how their benefits can be enhanced and their limitations mitigated by matching to particular administration routes and technologies will be essential to this process. Vaccines are the world’s most effective, life‐saving, medical technology to date. The literature review presented here indicates that the range of complementary approaches and technologies emerging from research and clinical testing will allow the beneficial impact of vaccines to continue to grow. Potential barriers to the widespread uptake of these approaches will be the cost involved and the complexities of some of technology required, and so these aspects deserve careful consideration during the development phase alongside the scientific and technical challenges.J. W. acknowledges funding from the University of Oxford, the EPSRC and BBSRC Centre for Doctoral Training in Synthetic Biology (grant EP/L016494/1) and the Defence Science and Technology Laboratory (DSTL) (grant DSTLX‐1000102376). R. C. is supported by the EPSRC under the Oxford Centre for Drug Delivery Devices OXCD3 (Grant EP/L024012/1).The authors declare no competing interests.


Of all the gynecologic tumors, ovarian cancer (OC) is known to be the deadliest. Advanced‐stages of OC are linked with high morbidity and low survival rates despite the immense amount of research in the field. Shortage of promising screening tools for early‐stage detection is one of the major challenges linked with the poor survival rate for patients with OC. In OC, therapeutic management is used with multidisciplinary approaches that includes debulking surgery, chemotherapy, and (rarely) radiotherapy. Recently, there is an increasing interest in using immunomodulation for treating OC. Relapse rates are high in this malignancy and averages around every 2‐years. Further treatments after the relapse are more intense, increasing the toxicity, resistance to chemotherapy drugs, and financial burden to patients with poor quality‐of‐life. A procedure that has been studied to help reduce the morbidity rate involves pre‐sensitizing cancer cells with standard therapy in order to produce optimal results with minimum dosage. Utilizing such an approach, platinum‐based agents are effective due to their increased response to platinum‐based chemotherapy in relapsed cases. These chemo‐drugs also help address the issue of drug resistance. After conducting an extensive search with available literature and the resources for clinical trials, information is precisely documented on current research, biomarkers, options for treatment and clinical trials. Several schemes for enhancing the therapeutic responses for OC are discussed systematically in this review with an attempt in summarizing the recent developments in this exciting field of translational/clinical research. This review article provides an in‐depth information on current treatment strategies and available clinical trials for ovarian cancer. Systematic review of strategies for enhancing the therapeutic response in ovarian carcinoma summarizing the recent developments in translational and clinical research. Cancer statistics from 2019 show that the estimated number of new cases is 22 240 with deaths around 14 170 cases.Several aspects influence the progression of the disease. Genetic and epigenetic factors are the most important ones among them. Nearly 10%‐15% of familial OCs result from breast cancer gene mutations BRCA1 and BRCA2.2Ovarian carcinoma is heterogeneous in nature. The disease progresses through several molecular level changes. Mainly there are three areas in the ovary where the tumor is developed. Surface epithelium is where majority of the malignancy is developed from. It is presented in different type of histology. Serous ovarian carcinoma (SOC) is the most common one and is presented at old age. Endometrioid carcinoma is presented at young age and associated with endometriosis. Mucinous carcinoma and clear cell carcinoma are also presented at young age. The other areas where the OC is developed are the germ cells and stroma.The complexity in these malignancies arises from the microenvironment affected by changes in genetic factors. The degree of complexity varies according to the changes in epigenetic factors too. Understanding the tumor microenvironment is key for its diagnosis, treatment options, and survival. The microenvironment varies for different type of ovarian carcinomas with changes in gene expression leads to different tumor markers. The tumor markers play crucial role for the development of targeted therapies.3Low endurance rate for OC patients is because of the late‐stage detection and diagnosis of the disease. Early stage detection and diagnostic tools for screening OC are not efficient. Research is in progress for developing efficient diagnostic processes for OC. Transvaginal ultrasound (TVUS) is one of the current screening process for OC. Blood test for CA125, a tumor marker for OC is another common screening test for OC.4As the disease progresses, it gets even harder to treat and manage the patients. Only 20% of those affected cases have an early detection of the ailment. Many healthcare professionals confused OC with other urologic, abdominal, and gynecologic diseases because of the overlap in signs and symptoms, resulting in late detections. Ovaries do not have a peritoneal covering; therefore, the cancer spreads locally to the peritoneal cavity, resulting in symptoms. Absence of effective testing tools and equipments further delay the detection process for OC.4.1Currently, the disease progression and treatment efficacy in OC patients is monitored using TVUS and elevated CA125 expression.4.2This is another maker for OC. Elevated HE4 expression is present in OC patients compared with normal and other nonmalignant diseases for women.4.3A 40‐kD protein associated with cell survival, tumor progression, and adherence. It is present in normal mesothelial cells. Increased levels of mesothelin is presented in blood samples of 40%‐67% of patients with OC.4.4A multiple biomarker‐based test OVA1  is currently used for the evaluation of risk level of OC patients.4.5It is an ongoing clinical trial (NCT02288676) study sponsored by McGill University, Canada. In advanced OC, treatment efficiency was studied using computed tomography (CT) perfusion.http://Clinicaltrial.gov).Numerous studies, and trials involving OC biomarkers that are being conducted across the globe. A summary of the ongoing biomarker studies in OC detection is given in Table 5The treatment strategies for different type of cancer depends on its pathological stages. Early detection will help to have the treatment options that are promising and effective. Current treatment options are combining debulking surgery and drug treatment and radiation therapy. Some of the advanced level treatment options include targeted therapy, immunotherapy, and hormone therapy. Chemotherapy is the most vital part of OC treatment. Chemotherapeutic agents can be administered via intravenously (IV), intraperitonially (IP), or by IV/IP combination. In neo adjuvant treatment plan chemotherapy was done before the surgery. IP/IV combination delivery of chemotherapeutic agents is the preferred mode drug administration for OC patients with cytoreduced disease.Chemotherapeutic agents will be selected for treatment based on the stage of OC. Platinum containing drugs (cisplatin and carboplatin) and taxane family (paclitaxel and docetaxel) are frequently used chemotherapeutic agents for treatment of OC.6The biological phenomena by which the body gets rid of unnecessary cells in order to maintain homeostasis is known as apoptosis. OC, among others, has several genes working against apoptosis, which allows cancerous cells to flourish instead of being killed off. Candidates involved in both intrinsic and extrinsic pathways were studied. Bcl‐2 family proteins and Tyrosine‐protein kinases, respectively, facilitates intrinsic and extrinsic apoptosis, while inhibitor of apoptosis (IAP) proteins are associated with both intrinsic and extrinsic pathways. Bcl2 is anti‐apoptotic Another anti‐apoptotic gene family is the IAP proteins. Survivin is a well characterized inhibitor for apoptotic proteins present in ovarian and other type of cancer cells.Tyrosine‐protein kinase Met (c‐Met) linked to poor treatment outcomes for cancer chemotherapy is upregulated in OC.A class of transcription factors known as specific proteins (Sp) regulates VEGF  expression with functional variation. Thus, Sp transcription factors have crucial impact on tumor expansion and metastasis.7S‐transferases causing de‐toxification of platinum agents and taxol.Research is in progress for understanding the mechanism of drug resistance in OC. Some of these mechanisms include increased DNA repair, overexpression of surface p 170‐glycoprotein, increased cellular levels of glutathione (GSH) and glutathione The “Classical” MDR is resulted from higher level of MDR‐1 gene that code for 170‐kD ATP‐dependent glycoprotein Pgp. Pgp causes reduction of cellular levels of cytotoxic drugs within the cells by transporting the drug outside the cells against the concentration gradient. Chemotherapy often upregulates the expression of P‐gp on cancer cells resulting in MDR. Resistance to multiple drugs is associated with P‐gp overexpression and includes paclitaxel, vincristine, and doxorubicin.In yeast and mammalian system, copper transporter CTR1 is one of the transporters mediating uptake of platinum compounds.Several epigenetic changes have been observed in cisplatin‐resistant human cells that open new avenues to study drug resistance among the OC cells. It has been observed that certain individual cells among the cancer cell population attain the reversible state of drug tolerance to prevent the eradication of the population by potential lethal exposure.Another well‐known carrier, breast cancer resistant protein coded by ABCG2 is found to be overexpressed in ovarian Since the EMT is mediated by several signaling pathways,8Immunotherapy involves various methods enhancing immune system. Exploiting the immune system for tumor recession is an ancient procedure as in 2600 BC The Pharaoh Imhotep self‐infected to enable tumor recession.Anti‐tumor lymphocytes from healthy adults and patients are used in treatment using adoptive cell transfer to stimulate cancer decline.Use of cancer vaccines is another approach to bring about immune activation. T‐cell responses were stimulated by activating the antigen‐presenting cells.Manipulation of immune checkpoints has become the modern revolution in cancer immunotherapy. Cytotoxic T‐Lymphocyte‐Associated Protein 4 (CTLA‐4) and Programmed Cell Death Protein 1 (PD‐1) are Immune checkpoint linked to T cells. These proteins control the equilibrium of immune response and tolerance upon influencing the T lymphocyte activity. Activated T lymphocyte functions as an inhibitor via “negative feedback loop” mechanism and protect normal tissues from tumor‐derived immune response.9http://www.ClinicalTrial.gov that are recruiting patients. Schematic representation for the emerging immunotherapies for OC is given in Figure The success rate for immunotherapy for OC treatment is very low and there is not yet any FDA approval for immune therapies for OC. Motivated by some of the recent encouraging results in other closely‐related tumor types, the scientific community has also started adapting immunotherapy to treat gynecologic cancers. Antibodies and T cells responsive for cancer are detected from ascites, blood, and tumor of advanced‐stage OC patients.10Important factors that help predict the tumor responses to inhibitors for immune checkpoint are the effector immune cell availability, approachability, and the tumor dependence on immune checkpoint pathways. TILs and PD‐L1 are identified as the markers to predict immune response to inhibitors. Using these markers, higher than 50% of advanced SOC estimated to act in response to immune checkpoint inhibitors via adaptive immune resistance. It is nearly absent low‐grade SOC, about 25% in other pathological types cancers.Preliminary data from clinical studies with all the current inhibitors reveals limited efficacy in OC with 15% rates of objective response, ORR. Hence it is very important future studies are required to identify more biomarkers for immune checkpoint inhibitors. 17% of ORR with a rate of 83% disease control is reported for a phase I study of olaparib (Poly ADP ribose polymerase [PARP] inhibitor) and durvalumab (anti‐PD‐L1).11Vaccines used in cancer therapy will activate the immune cells for the elimination of cancerous cells. Specific tumor‐associate antigens (TAAs) are administered using various methods. Some of the common vaccines tested as cancer vaccines are developed using various methods, epigenetic, and genetic. Vaccines are administered as it or along with cytokines or other accelerating factors.http://www.ClinicalTrial.gov) is given in Table CA125, p53 protein, folate receptor‐alpha (FRα), human epidermal growth factor receptor‐2 (HER2), and cancer‐testis antigens, like melanoma‐associated antigen A4 (MAGE‐A4) and New York‐esophageal squamous cell carcinoma11 (NY‐ESO‐1) are potential TAA molecules found in OC..NY‐ESO‐1, a potential molecule for targeted vaccine due to its over expression in OC exhibited stimulated immune response specific to T cells.As noted earlier, oncolytic virus (OV) has shown synergy when combined with checkpoint inhibitor antibodies.Her2/Neu, tumor antigen presents in almost 90% of the recurrent OC cases. Clinical study of 11 patients were given Her2/Neu packed antigen autologous dendritic cells combined with antigens of telomerase reverse transcriptase (human) and pan‐DR peptides.Whole tumor cell vaccines will induce immunologic reaction for a larger range of antigens compared to specific TAA.Another novel therapeutic method is to explore the use cancer cells from the patient to deliver viruses to the tumor.12Peripheral blood lymphocytes (PBLs) are separated from patients’ blood and will be used for the isolation of tumor‐specific lymphocytes. Tumor‐specific PBLs will be grown to supply back to the patient. Anti‐cancer action of PBLs can also be enhanced by genetic modification.13The major limitation to the ACT trials in the beginning stages were the need for isolation and culturing of functional cancer responsive T cells. The emergence of engineered T cells has become a promising tool to enhance the cancer immune therapy.14Regardless of the extensive developments in OC therapy, it is still the deadliest malignancy in women. The biggest hurdle is the shortage of efficient screening procedure that helps to detect the tumor at an early stage. Even though the curing rate for beginning stage OC patient is 90%, about 20% of OC is detected as early as stage1. This reveals the need for future research for finding biomarkers that are more responsive and specific for detection of OC at an early stage.Surgery and chemotherapy are conventional therapy for ovarian carcinoma. Poor prognosis with a recurring progressive cancer is the major challenge to the treatment. The prognosis varies for each patient and it depends on the level of response to preliminary therapy. Drug administration by IP is the efficient way to target OC cells situated the peritoneal area. Removal of all the residual tissues by surgery followed by chemotherapy, is the most ideal cure for OC.® Assays). Newly identified microRNA biomarkers linked to platinum drug resistance are let‐7Sensitivity to chemotherapeutic agents is a crucial parameter in therapeutic efficacy. Research to identify biomarkers for apoptosis and chemo resistance in OC therapy should be one of the prime goals in cancer research (eg, CarisAnother promising technique for OC therapy is silencing gene expression. By this technique, specific sets of genes can be targeted and altered, and it requires less dosage. This technique is still the subject of ongoing research to overcome its challenges like stability and compound delivery to a target site.Diab et al have done a review of targeted therapy for OC for 2010‐2017.Dose‐dense chemotherapy is the promising option currently available for the patients with poor responses to chemotherapy. PARP inhibitors are the most emerging class of new drugs in combination therapy with the traditional chemotherapy drugs listed in Figure 15Ovarian cancer affects the lives of many women around us. Despite continued efforts and steady improvements in treatment over the past few decades, OC still remains the deadliest malignancy in women. The poor clinical outcome is due to the deficiency of effective tools for detecting the disease at an early stage, chemotherapy resistance and increased heterogeneity of the disease. The vast majority of cases have high‐grade papillary serous histology marked by p53 mutations and 25% of cases have either inherited or acquired mutations in BRCA. Primary therapy is initiated with cytoreductive surgery and chemotherapy. Even with optimization of treatment protocols that have improved PFS, only limited gains in OS. Ultimately, approximately 80% of patients develop PROC. Once this occurs, further chemotherapy response rates are about 10%‐15% and survival averages 9‐12 months. Therefore, we are critically in need of developing novel therapies to improve cure rates and provide effective long‐term disease stability for PROC.Targeted therapy is the fast growing modalities for cancer treatment. For targeted therapy drugs or small molecules will be used to block tumor growth. More studies should be done on combination therapies involving one or more of these small molecules as modulators for OC treatment. Such research should be augmented to fight chemo resistance better treatment outcomes. Inhibitors for various genes involved in the signal pathway in tumor growth should be another area of focus for future studies for OC treatment. Study of the various molecules involved in tumor micro environment at various stages of tumor metastasis is crucial for the development of better immunotherapies for OC.None declared. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.Intermittent administration of parathyroid hormone (PTH) stimulates skeletal remodeling and is a potent anabolic agent in bone. PTH‐related protein (PTHrP) is anabolic acting on the same PTH1 receptor and is in therapeutic use for osteoporosis. The body of literature for PTH actions in fracture healing is emerging with promising yet not entirely consistent results. The objective of this review was to perform a literature analysis to extract up‐to‐date knowledge on the effects of intermittent PTH and PTHrP therapy in bone fracture healing. A literature search of the PubMed database was performed. Clinical case studies and articles related to “regeneration,” “implant,” and “distraction osteogenesis” were excluded. A narrative review was performed to deliberate the therapeutic potential of intermittent PTH administration on fracture healing. A smaller number of studies centered on the use of PTHrP or a PTHrP analog were also reviewed. Animal studies clearly show that intermittent PTH therapy promotes fracture healing and revealed the strong therapeutic potential of PTH. Human subject studies were fewer and not as consistent as the animal studies yet provide insight into the potential of intermittent PTH administration on fracture healing. Differences in outcomes for animal and human studies appear to be attributed partly to variable doses, fracture sites, age, remodeling patterns, and bone architectures, although other factors are involved. Future studies to examine the dose, timing, and duration of PTH administration will be necessary to further delineate the therapeutic potential of PTH for fracture healing in humans. © 2019 The Authors.  The fracture healing process begins with hematoma formation followed by an inflammatory phase, a proliferative phase with soft callus formation, callus ossification, and finally the bone remodeling phase. The periosteal and endosteal osteoprogenitors along with neovascularization play a crucial role in the early phase of repair. Hence, pathological conditions that have negative influences on progenitor cell recruitment, angiogenesis, or extracellular matrix formation could result in impaired or delayed healing. Such conditions include but are not limited to radiation therapy, osteoporosis, diabetes mellitus (DM), antiangiogenic therapy, advanced age, steroid therapy, and infection.PTH plays a crucial role in calcium and phosphorus homeostasis and has anabolic effects in bone when administered intermittently.A PubMed search was performed using terms including “parathyroid hormone,” “fracture healing,” “bone,” and “intermittent administration.” Articles related to “regeneration,” “fusion,” “implant,” and “distraction osteogenesis” and clinical case studies were excluded. Although the consideration of PTH or PTHrP in such other instances has merit, they are not discussed in this review in order to focus on fracture healing. In addition, they are covered elsewhere.The effects of intermittent PTH administration on physiological fracture healing have been well studied in animals particularly focusing on the appendicular skeleton Table .Work by Andreassen and colleagues is one of the earliest studies that investigated the effect of PTH (1‐34) daily administration on callus formation and mechanical strength advancement of closed tibial shaft fractures in 3‐month‐old female rats after 20 and 40 days of healing.Sox9 in the callus at day 4 and stimulated proliferation of mesenchymal progenitors significantly at days 4 and 7 in the callus. These results suggest that PTH stimulates chondrogenesis to facilitate endochondral bone repair. Work by Kakar and colleagues confirmed these findings using a mouse fracture healing model.Sox9, Sox5, Col2a1, and Col10) during early healing (days 5 and 7) and the expression of osteogenesis‐related genes (Runx2 and Sp7) at days 10 and 14. It was further revealed that the levels of nuclear‐localized nonphosphorylated β‐catenin increased in osteogenic and chondrogenic cells in the callus of the PTH group, suggesting that the activation of the Wnt signaling pathway is at least one mechanism of the promoted fracture healing by PTH.Since the doses used in the above studies were relatively high, the question remained whether a lower PTH dose, more relevant to a human dose, could have a similar effect on fracture healing. In 2002, Nakajima and colleagues performed a study to address this question.PTH accelerates endochondral ossification by stimulating callus formation and remodeling.Alkhiary and colleagues investigated the effect of PTH withdrawal on subsequent fracture healing.Nearly all animal studies that show the beneficial effects of PTH were performed using rodent fracture healing models. Since bone remodeling in young rodents utilizes different mechanisms than in humans,High‐energy trauma causes open fractures and often results in fracture nonunion,Impaired fracture healing occurs in patients with metabolically compromised conditions, such as osteoporosis, diabetes, and advanced age. Intermittent PTH therapy has positive effects on fracture healing in animals with those conditions Table .Kim and Jahng induced estrogen deficiency in 4‐month‐old female rats by performing ovariectomy.Fracture healing is often compromised in patients with advanced age. It has been reported that proliferation and osteoblastogenesis of mesenchymal stem cells decline age‐dependently,Compromised fracture healing is found in patients with diabetes mellitus (DM).Almost all studies using animals with PTH effects on fracture healing have been performed in long bones, which typically heal via the process of endochondral ossification. Most of the maxillofacial bones develop by intramembranous ossification in which mesenchymal tissue directly converts into bone without intermediate cartilage formation. Because the ossification process is distinct between maxillofacial and long bones, it raises the question of whether PTH administration could exert a beneficial effect in maxillofacial bone fracture healing. Rowshan and colleagues investigated the effect of intermittent PTH administration on mandibular fracture healing in rats.The results of animal studies collectively support that intermittent PTH administration promotes fracture healing. Human case studies report PTH as successful in the treatment of nonunion or delayed union of fracture healing.Aspenberg and colleagues conducted a multicenter randomized controlled clinical trial to test the hypothesis that daily teriparatide [rhPTH (1‐34)] at the 20 or 40 μg dose would accelerate fracture healing in humans.n = 27). In the subgroup analysis, the authors evaluated the callus formation 5 weeks after fracture. Callus formation was arbitrarily classified as rich, intermediate, or poor using radiographs in a blinded manner. There were 9 patients classified as rich, and they all received teriparatide (6 patients with 40 μg and 3 patients with 20 μg). Another 9 patients were classified as poor of which 7 patients received placebo. The subgroup analysis revealed a strong trend that 40 μg of teriparatide had a more prominent positive effect on radiographic callus formation than 20 μg.Aspenberg and Johansson, who were co‐authors of this study, extracted a subgroup of patients from the cohort for further assessment.p < 0.001). The study further evaluated the functional outcome with the use of a timed up‐and‐go (TUG) test and found significantly improved function in the PTH group versus controls. The results of the study strongly indicated that PTH (1‐84) treatment promoted healing of pelvic fractures in elderly patients with severe osteoporosis.In 2011 Peichl and colleagues investigated the effect of PTH (1‐84) on pelvic‐fracture healing in 65 postmenopausal severe osteoporotic patients.n = 78) or placebo (n = 81) was administered daily for 6 months. The primary endpoint was the occurrence of revision surgery rate at 1‐year post‐fracture. The study found that the rate of revision surgery was not different between groups (17% in the PTH group and 14% in controls). Moreover, no differences were noted in radiographic healing between groups at 10 weeks, 6 months, or 12 months. This particular clinical study indicated that teriparatide failed to reduce the risk of revision surgery and to improve radiographic signs of fracture healing compared with placebo.Falls often cause a hip fracture in the elderly population, which then results in a dramatic decline in BMD and a slow recovery.n = 86), whereas 35 mg oral risedronate was administered once weekly (n = 85) for 78 weeks. At study end, teriparatide treatment resulted in a significant increase in the BMD values of the lumbar spine and femoral neck compared with risedronate treatment. Although the study was not intended to analyze fracture healing, it should be noted that teriparatide treatment resulted in significantly less pain at week 18 and better function (faster TUG test) at weeks 6, 12, and 18.Malouf‐Sierra and colleagues reported the results of a multicenter randomized clinical trial that evaluated the effect of teriparatide and risedronate on femoral neck BMD in patients with pertrochanteric hip fracture.The short‐term effects of teriparatide administration on fracture healing were studied in premenopausal women with lower‐extremity stress fractures .Johansson performed a study to determine the effect of teriparatide on healing of proximal humerus fractures in 40 postmenopausal women who never received bisphosphonates.Patients who develop osteoporotic bone fractures are often already receiving bisphosphonate therapy before a fracture occurs. Because bisphosphonates are retained in bone for years after the cessation of drugs and continue suppressing bone remodeling, there is a concern that bisphosphonates may hinder fracture healing.Although PTH and bisphosphonates are used for the treatment of osteoporosis, their actions are distinct. PTH promotes bone turnover, whereas bisphosphonates suppress it. Aspenberg and colleagues compared the therapeutic effects of teriparatide (20 μg/d) with risedronate (35 mg/week) on recovery after pertrochanteric hip fractures.A retrospective study was performed to compare the effects of teriparatide (20 μg/d) with alendronate (35 mg/week) on healing of osteoporotic vertebral compression fractures.Many patients with osteoporosis receive bisphosphonate therapy. Since bisphosphonates suppress bone remodeling for years even after their cessation, those patients are expected to respond to PTH therapy differently from those without a history of bisphosphonate treatment. The bone anabolic effect of PTH therapy was shown to be blunted when teriparatide was used after or concomitant with alendronate treatment.An AFF is a rare complication associated with long‐term bisphosphonate treatment.PTH and PTHrP both bind to the same receptor (PTH1R) with similar bioactivity in their N‐terminal region. This forms a rational foundation that PTHrP would be osteoanabolic as well as benefit fracture healing and several studies have supported this Table .In 2000, Bostrom and colleagues utilized a rabbit ulnar model with a 1 mm defect and superimposed steroid associated compromised wound healing.Renewed interest in PTHrP has surfaced since abaloparatide was approved by the FDA for the treatment of postmenopausal osteoporosis in 2017. Abaloparatide, a PTHrP 1‐34 analog, is identical to PTHrP in the first 20 amino acids and then has 50% similarity in amino acids 21 to 34. Abaloparatide has selective activation of the PTH1R and has been described as having an advantage over teriparatide in that it does not activate osteoclasts to the same extent.As with PTH, preclinical studies using PTHrP or an analog are promising; however, there is a need in general for more mechanistic studies to better strategize therapeutic options. To date, there are no apparent human studies using abaloparatide for the purpose of fracture healing.Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia with elevated or inappropriately normal serum PTH levels. PHPT mainly affects the skeleton and kidney, but their involvement is relatively mild in developed countries. Patients with PHPT have a low BMD in cortical bone‐rich sites, such as the distal one‐third radius and femoral neck, while the BMD is spared at trabecular sites such as the lumber spine.Stein and colleagues studied the cortical and trabecular microstructures at the radius and tibia using high‐resolution peripheral quantitative tomography (HR‐pQCT).Because bone is a target organ of PTH, continuously elevated serum PTH levels in PHPT patients likely affect bone fracture healing. A study showed that continuous teriparatide infusion to mice resulted in delayed healing of tibial fractures.The results of animal studies clearly indicate that intermittent PTH administration promotes fracture healing by accelerating callus formation and ossification. The results of human subject studies are also supportive of PTH promoting fracture healing yet are fewer and not as overwhelming. The doses used in animal studies range from 1 to 200 μg/kg/d with the majority being 10, 30, and 40 μg/kg/d. When these doses are converted to human equivalent doses using the body surface area (BSA) normalization method, 10, 30, and 40 μg/kg for rats are comparable to 97, 292, and 389 μg for a human weighing 60 kg.PTH therapy affects the entire body even though it is intended to use for the promotion of fracture healing. Therefore, bone mass in nonfracture sites in the same skeleton is increased. However, as shown in a study by Nakajima and colleagues,Osteoporosis is a major health care concern for the elderly population. Roughly 1 in 2 white women and 1 in 5 men are predicted to have an osteoporosis‐related fracture in their lifetime in the US.As for craniofacial bones, the majority of fractures in young and elderly populations occur due to traffic accidents, sports, interpersonal violence, or falling.In summary, intermittent administration of PTH increases bone mass and has been approved as a therapeutic agent for the treatment of osteoporosis. Although promising, its optimal therapeutic potential in bone fracture healing is yet unclear. Accumulating evidence indicates that the intermittent administration of PTH promotes fracture healing in animals. However, the off‐label use of PTH in human clinical trials suggests benefits for fracture healing fall short of the overwhelmingly positive results in animals. In particular, research on the effects of PTH in maxillofacial fracture healing is far from satisfactory. Since findings from animal studies and case reports are encouraging, future studies to examine the dose, timing, and duration of PTH administration are necessary to delineate the optimal therapeutic potential of PTH for fracture healing.Both authors state that they have no conflicts of interest.


An 82‐year‐old male, who had undergone sigmoid colon cancer surgery (at the age of 78 years) and primary lung cancer surgery (at the age of 81 years), was found to have a cavitating lesion in the left lower lobe on chest computed tomography (CT). A chest CT that had been performed just before the primary lung cancer surgery revealed a small thin‐walled cyst at the same site at which the cavity was detected in the current CT. Bronchoscopic examination revealed no evidence of malignancy. A follow‐up chest CT performed 5 months later revealed that the lesion had grown and that the cyst contained a well‐defined lobular nodule. Video‐assisted thoracoscopic left basal segmentectomy was performed. The histopathological diagnosis was metastasis from colon cancer. We report this unusual case in which a pulmonary metastasis changed over time from a cystic lesion to a nodular lesion. Pulmonary cystic metastasis (PCM) from colon cancer is rare; furthermore, in most cases, the lesions are multiple and unresectable. We report a surgical case of a solitary pulmonary metastasis in which the lesion evolved and enlarged from a cyst to a solid lesion with time.An 82‐year‐old male who had undergone sigmoidectomy for colon cancer three years ago was diagnosed as having primary lung adenocarcinoma Fig. A, and unThe unique and complex characteristics of the clinical course of this patient were as follows: the patient developed a solitary PCM, which was surgically resectable; the pulmonary lesion increased in size, and its appearance was changed from a thin‐walled cyst to a thick‐walled cavity and then to a nodule; histopathology confirmed the tumour as a PCM from colon cancer in the patient who had been diagnosed as a case of metachronous colon and lung cancer.It is clinically important to distinguish whether pulmonary cysts are malignant or non‐malignant (e.g. infectious). Primary lung cancer and pulmonary metastases are also known to rarely occur as thin‐wall cystic pulmonary lesions Multifocal/diffuse cysts can occur in cases of lymphoid interstitial pneumonia, Birt‐Hogg‐Dubé syndrome, tracheobronchial papillomatosis, or primary and metastatic cancers Because of the tendency of the tumour to increase in size with time, we presumed it to be a malignant tumour at first. Left lower lobectomy would have had to be selected if it were a second primary lung cancer. However, we avoided it so as to preserve the pulmonary function, because the patient was old and had already undergone right lower lobectomy. Wedge resection would have been suitable in the case of metastatic tumour; however, it was difficult anatomically. Therefore, we thought that segmentectomy was the most suitable for this patient, irrespective of whether the tumour was a second primary lung cancer or a metastatic lung tumour. To obtain more correct pre‐operative information about the tumour in this case, we should have performed CT‐guided biopsy.The possibility that the tumour was primary enteric adenocarcinoma of the lung still remains. However, since the patient had the history of sigmoid colon cancer, we made the diagnosis of metastatic colon cancer. It is important that pulmonary metastasis is considered in the differential diagnosis in patients with a past history of malignant tumour presenting with solitary or multiple pulmonary cysts.The patient has lived without any recurrence of the tumour for 32 months after the last pulmonary resection. However, careful post‐operative follow‐up is necessary to detect any new metastatic lesion.Appropriate written informed consent was obtained for publication of this case report and accompanying images.


Dear Editor, The development of targeted topical treatments for inherited skin tumour syndromes, such as naevoid basal cell carcinoma syndrome, is desirable because this approach avoids surgery and is unlikely to cause systemic side‐effects.We studied 28 skin tumour biopsies from 14 patients (who provided consent) in a clinical trial assessing the utility of targeting tropomyosin receptor kinase in CCS. Ethical approval was obtained for this study .NTRK2 and NTRK3 genes, which are known to encode the protein targets of pegcantratinib. Histology sections (level 1) were also obtained to assess expression of proteins regulated by TRK signalling, such as mitogen‐activated protein kinase (ERK) and B‐cell lymphoma (BCL)2. Phosphorylated and total ERK status , giving an indication of drug penetration Fig. a. A reprns level  were alsns level  were alsSerial sectioning has previously been used to determine drug penetration in the skin,Caveats to our method apply. The thickness of the diseased skin that was studied may limit the application of this method; the total depth of the biopsy required in this study was approximately 1·5 mm. Modifications to the number of levels obtained will allow for the study of superficial skin diseases, and optimization can be guided by the histological sections obtained. The extent of gene expression changes will vary with the drug type and penetration in different skin diseases. In addition, we demonstrate data from diverse assays from adjacent sections, not the same cells, owing to technical limitations relating to current assay technology. Nevertheless, our proof‐of‐principle work in skin tumours in CCS provides a novel method that could be adapted to study other topically treated skin tumours or diseases.