A dedicated structured data set for reporting of invasive carcinoma of the breast in the setting of neoadjuvant therapy: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: The International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations, is an initiative aimed at providing a unified international approach to reporting cancer. ICCR recently published new data sets for the reporting of invasive breast carcinoma, surgically removed lymph nodes for breast tumours and ductal carcinoma in situ, variants of lobular carcinoma in situ and low-grade lesions. The data set in this paper addresses the neoadjuvant setting. The aim is to promote high-quality, standardised reporting of tumour response and residual disease after neoadjuvant treatment that can be used for subsequent management decisions for each patient. METHODS: The ICCR convened expert panels of breast pathologists with a representative surgeon and oncologist to critically review and discuss current evidence. Feedback from the international public consultation was critical in the development of this data set. RESULTS: The expert panel concluded that a dedicated data set was required for reporting of breast specimens post-neoadjuvant therapy with inclusion of data elements specific to the neoadjuvant setting as core or non-core elements. This data set proposes a practical approach for handling and reporting breast resection specimens following neoadjuvant therapy. The comments for each data element clarify terminology, discuss available evidence and highlight areas with limited evidence that need further study. This data set overlaps with, and should be used in conjunction with, the data sets for the reporting of invasive breast carcinoma and surgically removed lymph nodes from patients with breast tumours, as appropriate. Key issues specific to the neoadjuvant setting are included in this paper. The entire data set is freely available on the ICCR website. CONCLUSIONS: High-quality, standardised reporting of tumour response and residual disease after neoadjuvant treatment are critical for subsequent management decisions for each patient.

Dataset for reporting of the invasive carcinoma of the breast: recommendations from the International Collaboration on Cancer Reporting (ICCR).

BACKGROUND AND OBJECTIVES: Current national or regional guidelines for the pathology reporting on invasive breast cancer differ in certain aspects, resulting in divergent reporting practice and a lack of comparability of data. Here we report on a new international dataset for the pathology reporting of resection specimens with invasive cancer of the breast. The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organizations. METHODS AND RESULTS: The established ICCR process for dataset development was followed. An international expert panel consisting of breast pathologists, a surgeon, and an oncologist prepared a draft set of core and noncore data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalized and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for invasive cancer of the breast is intended to promote high-quality, standardized pathology reporting. Its widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve the management of invasive breast cancer patients.

Datasets for the reporting of primary tumour in bone: recommendations from the International Collaboration on Cancer Reporting (ICCR).

BACKGROUND AND OBJECTIVES: Bone tumours are relatively rare and, as a consequence, treatment in a centre with expertise is required. Current treatment guidelines also recommend review by a specialised pathologist. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of bone sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's process for dataset development, an international expert panel consisting of pathologists, an oncologic orthopaedic surgeon, a medical oncologist, and a radiologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were bone tumour experts affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, including a synoptic reporting guide, were published on the ICCR website. CONCLUSION: These first international datasets for bone sarcomas are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve management of bone sarcoma patients.

Datasets for reporting of soft-tissue sarcoma: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Soft-tissue tumours are rare and both accurate diagnosis and proper treatment represent a global challenge. Current treatment guidelines also recommend review by specialised pathologists. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of soft-tissue sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of international pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's guidelines for dataset development, an international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialised soft-tissue sarcoma experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, which included a synoptic reporting guide, were published on the ICCR website. CONCLUSION: These first international datasets for soft-tissue sarcomas are aimed to promote high-quality, standardised pathology reporting. Their adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve patient's management.

Dataset for pathology reporting of ductal carcinoma in situ, variants of lobular carcinoma in situ and low-grade lesions: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: To describe a new international dataset for pathology reporting of ductal carcinoma in situ (DCIS), variants of lobular carcinoma in situ (LCIS) and low-grade lesions (encapsulated papillary carcinoma, solid papillary carcinoma in situ, Paget's disease) produced by the International Collaboration on Cancer Reporting (ICCR). METHODS AND RESULTS: The ICCR, a global alliance of pathology bodies, uses a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Their aim is to support quality pathology reporting and engender understanding between the breast surgeon, pathologist, and oncologist for optimal and uniform patient management globally. Here we describe the dataset for DCIS, some variants of LCIS (namely the pleomorphic and the florid variants), and low-grade lesions by a multidisciplinary panel of internationally recognized experts. The agreed dataset comprises 12 core (required) and five noncore (recommended) elements suitable for both developed and low-income jurisdictions, derived from a review of current evidence. Areas of contention were addressed using a pragmatic approach in the absence of evidence. Use of all core elements is the minimum reporting standard for any individual case. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or noncore. CONCLUSION: This first internationally agreed dataset for DCIS, variants of LCIS, and low-grade lesions reporting will enable their standardization of pathology reporting and enhance clinicopathological communication leading to improved patient outcomes. Widespread adoption will also facilitate international comparisons, multinational clinical trials, and help to improve the management of breast disease globally.

[Penile carcinoma: Practical issues, from the biopsy to surgery]. / Cancer du pénis : problèmes pratiques du quotidien, de la biopsie à la chirurgie.

The management of a penile carcinoma is complex, a collaboration between radiologist, pathologist and urologist is necessary to obtain a correct staging. In this review we try to demonstrate step by step how to achieve a complete pathology report, how to manage the patient (imaging, biopsy, fresh frozen section and surgery).

Dataset for the reporting of carcinoma of the exocrine pancreas: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for cancer of the exocrine pancreas is intended to promote high-quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients.

Functional mapping of the N-terminal arginine cluster and C-terminal acidic residues of Kir6.2 channel fused to a G protein-coupled receptor.

Ion channel-coupled receptors (ICCRs) are original man-made ligand-gated ion channels created by fusion of G protein-coupled receptors (GPCRs) to the inward-rectifier potassium channel Kir6.2. GPCR conformational changes induced by ligand binding are transduced into electrical current by the ion channel. This functional coupling is closely related to the length of the linker region formed by the GPCR C-terminus (C-ter) and Kir6.2N-terminus (N-ter). Manipulating the GPCR C-ter length allows to finely tune the channel regulation, both in amplitude and sign (opening or closing Kir6.2). In this work, we demonstrate that the primary sequence of the channel N-terminal domain is an additional parameter for the functional coupling with GPCRs. As for all Kir channels, a cluster of basic residues is present in the N-terminal domain of Kir6.2 and is composed of 5 arginines which are proximal to the GPCR C-ter in the fusion proteins. Using a functional mapping approach, we demonstrate the role of specific arginines (R27 and R32) for the function of ICCRs, indicating that the position and not the cluster of positively-charged arginines is critical for the channel regulation by the GPCR. Following observations provided by molecular dynamics simulation, we explore the hypothesis of interaction of these arginines with acidic residues, and using site-directed mutagenesis, we identified aspartate D307 and glutamate E308 residues as critical for the function of ICCRs. These results demonstrate the critical role of the N-terminal and C-terminal charged residues of Kir6.2 for its allosteric regulation by the fused GPCR.

Blocking CCR10 Expression Activates m6A Methylation and Alleviates Vascular Endothelial Cell Injury.

BACKGROUND: Cardiovascular disease, one of the most common types of disease in clinical practice today, carries a very high risk of disability and death. This research aims to examine genome-wide changes in injured human dermal microvascular endothelial cells (HDMECs) using the Ribonucleic Acid sequencing (RNA-Seq) technique, and to search for key genes influencing N6-methyladenosine (m6A) methylation, thus gaining new insights into future clinical diagnosis and treatment of cardiovascular diseases (CVDs) and laying a foundation for follow-up research. METHODS: Impaired HDMECs (injury group), established by endotoxin intervention, were analyzed by RNA-Seq for differentially expressed genes (DEGs) relative to normal HDMECs (control group). Then, DEGs that might be associated with m6A methylation were selected for expression blocking to observe m6A methylation alterations. The migration, angiogenesis, and inflammatory response of damaged HDMECs were detected by cell scratch assay, western blotting, and Enzyme-linked Immunosorbent Assay (ELISA) experiments, respectively. RESULTS: In this study, 20 DEGs were screened out from the two groups by RNA-Seq, of which 17 were up-regulated and 3 were down-regulated. The C-C motif chemokine receptor 10 (CCR10) was selected for subsequent analysis. Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) identified elevated CCR10 expression and reduced m6A methylation levels in the injury group (p < 0.05). After blocking CCR10 expression in damaged HDMECs by BI6901 (a CCR10 specific blocker) m6A methylation, cell activity, vascular endothelial growth factor A (VEGFA) and CD31 protein expression, as well as relative length and branches of tube formation were found to be increased compared with the injury group, while the levels of inflammatory factors interleukin-1 (IL-1), interleukin-1 (IL-6) and tumor necrosis factor-α (TNF-α) were decreased (p < 0.05). CONCLUSIONS: Blocking CCR10 expression can activate m6A methylation, promote cell activity, inhibit inflammatory reactions and alleviate HDMEC injury, which may become a breakthrough in future diagnosis and treatment of cardiovascular diseases.

Macroscopic Examination of Surgical Specimen of Papillary Thyroid Carcinoma.

Standardized pathology reporting of thyroid cancer is important for quality clinical management, research as well as education purposes. International Collaboration on Cancer Reporting (ICCR) has produced a Dataset for reporting carcinoma of thyroid. Of the 19 core elements to report, six (operative procedure, operative findings, specimen submitted, tumor focality, tumor site, tumor dimensions) depend on the proper macroscopic examination of the surgical specimen with thyroid carcinoma. The other core elements to report depend on proper and adequate sampling on macroscopic examination. Thus, proper handling, examination, dissection, and sampling of different types, the surgical specimen(s) are needed in different situations for patients with thyroid carcinomas.

The Power of Consumer Activism: An Interview With Leah Margulies [Part 1].

Leah Margulies was Director of the Infant Formula Program at the Interfaith Center on Corporate Responsibility in NYC from 1975 to 1985. She is a founder of the International Nestlé Boycott, Corporate Accountability (formerly INFACT), and one of the founders of the International Baby Food Action Network (IBFAN). She was hired at UNICEF in 1982 to set up the legal office for implementation of the International Code of Marketing Breast-Milk Substitutes, as part of the Baby Friendly Hospital Initiative. Previously, she was legal advisor to the Environment Unit of the United Nations Centre on Transnational Corporations. From 2006 to 2016, she was Project Director of LawHelpNY at the NYC Bar Association. Currently, she works for a legal non-profit, representing low-income Brooklynites, defending them against eviction. She is a lawyer, a second Wave Feminist, and a member of Veteran Feminists of America. She is also a musician and founding member of a pioneering women's rock band that played at the first national women's march for abortion rights in Washington, DC, 1972.

The Power of Consumer Activism From the Kennedy Hearings to the International Code: An Interview With Leah Margulies (Part II).

Leah Margulies was Director of the Infant Formula Program at the Interfaith Center on Corporate Responsibility in New York City (NYC) from 1975 to 1985. She is a founder of the International Nestle Boycott, Corporate Accountability (formerly INFACT), and one of the founders of the International Baby Food Action Network (IBFAN). She was hired at UNICEF in 1982 to set up the legal office for implementation of the International Code of Marketing Breastmilk Substitutes, as part of the Baby Friendly Hospital Initiative. Previously, she was legal advisor to the Environment Unit of the United Nations Centre on Transnational Corporations. From 2006 to 2016, she was Project Director of LawHelpNY at the NYC Bar Association. Currently, she works for a legal non-profit, representing low-income Brooklynites, defending them against eviction. She is a lawyer, a Second Wave Feminist, and a member of Veteran Feminists of America. She is also a musician and founding member of a pioneering women's rock band that played at the first national women's march for abortion rights in Washington, DC, 1972.

Data set for reporting carcinoma of the thyroid: recommendations from the International Collaboration on Cancer Reporting.

Thyroid cancer therapy is increasingly tailored to patients' risk of recurrence and death, placing renewed importance on pathologic parameters. The International Collaboration on Cancer Reporting (ICCR), an organization promoting evidence-based, internationally agreed-upon standardized pathology data sets, is the ideal conduit for the development of a pathology reporting protocol aimed at improving the care of patients with thyroid carcinomas. An international expert panel reviewed each element of thyroid pathology reporting. Recommendations were made based on the most recent literature and expert opinion.The data set uses the most recent World Health Organization (WHO) classification for the purpose of a more clinically and prognostically relevant nomenclature. One example is the restriction of the term minimally invasive follicular carcinoma to tumors with capsular invasion only. It reinforces the already established criteria for blood vessel invasion adopted by the most recent WHO classification and Armed Forces Institute of Pathology fascicle. It emphasizes the importance of the extent of blood vessel invasion and extrathyroid extension to better stratify patients for appropriate therapy. It is the first data set that requires pathologists to use the more recently recognized prognostically powerful parameters of mitotic activity and tumor necrosis. It highlights the importance of assessing nodal disease volume in predicting the risk of recurrence.The ICCR thyroid data set provides the tools to generate a report that will guide patient treatment in a more rational manner aiming to prevent the undertreatment of threatening malignancies and spare patients with indolent tumors the morbidity of unnecessary therapy. We recommend its routine use internationally for reporting thyroid carcinoma histology.

Pathology data set for reporting parathyroid carcinoma and atypical parathyroid neoplasm: recommendations from the International Collaboration on Cancer Reporting.

Standardized pathologic reporting for cancers improves patient care and prognostic determination. However, access in many countries is limited. To address this issue, the International Collaboration on Cancer Reporting (ICCR), a not-for-profit organization, has the mission to develop and disseminate standardized data sets for global use. Within endocrine organs, the parathyroid gland has rarely been included in formal pathologic data sets. Utilizing an expert international panel of eleven members, an evidence-based data set was developed for parathyroid carcinoma and atypical parathyroid neoplasms. This data set consists of sixteen core (required) elements viewed as essential for documentation of these conditions. Characterizing parathyroid carcinomas and atypical neoplasms begins with correlative clinical information, the operative procedure, specimens submitted, and site of the disease. The pathologic features essential to document include parathyroid weight, size, classification, and, when a carcinoma, the tumor grade. Histologic grade of parathyroid carcinoma incorporates other core elements including necrosis, mitotic count, perineural invasion, and lymphovascular invasion. Documenting the extent of disease locally into adjacent organs, regionally, and distally is critical for staging. Pathologic staging is now included as part of the American Joint Committee on Cancer 8th edition and is included in this data set. Ancillary studies should be recorded when performed as noncore elements. Standardized pathologic data sets for endocrine organs including the parathyroid gland are now available through the ICCR website. These essential resources enhance international standardization for documenting these rare tumors for both patient care and future guidelines.

Data set for reporting of carcinoma of the adrenal cortex: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting.

Complete resection of adrenal cortical carcinoma (ACC) with or without adjuvant therapy offers the best outcome. Recurrence is common, and in individual cases, the long-term outcome is difficult to predict, making it challenging to personalize treatment options. Current risk stratification approaches are based on clinical and conventional surgical pathology assessment. Rigorous and uniform pathological assessment may improve care for individual patients and facilitate multi-institutional collaborative studies. The International Collaboration on Cancer Reporting (ICCR) convened an expert panel to review ACC pathology reporting. Consensus recommendations were made based on the most recent literature and expert opinion. The data set comprises 23 core (required) items. The core pathological features include the following: diagnosis as per the current World Health Organization classification, specimen integrity, greatest dimension, weight, extent of invasion, architecture, percentage of lipid-rich cells, capsular invasion, lymphatic invasion, vascular invasion, atypical mitotic figures, coagulative necrosis, nuclear grade, mitotic count, Ki-67 proliferative index, margin status, lymph node status, and pathological stage. Tumors were dichotomized into low-grade (<20 mitoses per 10 mm2) and high-grade (>20 mitoses per 10 mm2) ones. Additional noncore elements that may be useful in individual cases included several multifactorial risk assessment systems (Weiss, modified Weiss, Lin-Weiss-Bisceglia, reticulin, Helsinki, and Armed Forces Institute of Pathology scores/algorithms). This data set is now available through the ICCR website with the hope of better standardizing pathological assessment of these relatively rare but important malignancies.

Data set for the reporting of pheochromocytoma and paraganglioma: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting.

BACKGROUND AND OBJECTIVES: The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each anatomic site, to be used throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to improved patient management and enhanced epidemiological research. METHODS: Pheochromocytoma and paraganglioma are uncommon and are frequently overlooked in registry data sets. Malignant criteria have previously been defined only when there was metastatic disease. RESULTS: With recent recognition of a significant inheritance association and the development of risk stratification tools, this data set was created in order to obtain more meaningful outcomes and management data, using similar criteria across the global pathology community. Issues related to key core and non-core elements, especially clinical hormonal status, familial history, tumor focality, proliferative fraction, adverse or risk stratification features, and ancillary techniques, are discussed in the context of daily application to these types of specimens. CONCLUSIONS: The ICCR data set, developed by an international panel of endocrine organ specialists, establishes a pathology-standardized reporting guide for pheochromocytoma and paraganglioma.

Introduction: Esophageal Squamous Cell Carcinoma-Current Status and Future Advances.

Esophageal squamous cell carcinoma is the most common histological subtype of esophageal cancer. The carcinoma is more common in high-incidence areas such as in Central and Southeast Asia, Eastern and Southern Africa, South America, etc. Common risk factors associated with the cancer are tobacco smoking and excessive alcohol consumption. Dietary factors, genetic factors, microorganisms, and some other environmental factors may contribute to the etiopathogenesis of the disease. Despite the global incidence of esophageal squamous cell carcinoma decreases slightly in the recent years, esophageal squamous cell carcinoma is still a major cause of cancer-related morbidity and mortality worldwide. Further improvement of the outcomes of the patients with the disease could be achieved by early diagnosis, collaborative efforts of multidisciplinary clinical and research teams, use of standardized protocol for pathological reporting and staging of the disease, proper use of cancer tissue, as well as improvement in clinical, pathological, therapeutic, and research approaches to the cancer.

Long-term follow-up after ileocaecal continent cutaneous urinary diversion (Mainz I pouch): A retrospective study of a monocentric experience.

OBJECTIVE: To assess the long-term follow-up after ileocaecal continent cutaneous reservoir (ICCR) and to review the late complications. PATIENTS AND METHODS: In all, 756 patients underwent an ICCR in our department, with long-term follow-up data available in 50 patients. The inclusion criterion was ICCR regardless of the indication and the exclusion criteria were orthotopic neobladder or other continent urinary diversions not performed with the ileocaecum. Patients were followed to record primary outcomes and late complications. Complications were stratified according to the Clavien-Dindo classification. RESULTS: The mean patient age was 44 years and pelvic malignancies were the first indication for urinary diversion. The mean (range) follow-up was 19 (9-36) years. A stoma stenosis was the most frequent outlet-related complication requiring re-intervention, followed by ischaemic outlet degeneration, and stoma incontinence. Six renal units (RUs) developed obstruction at the anastomotic site and were managed by open surgery. Three RUs had to be removed due to deterioration. A dederivation was necessary in three patients (6%). CONCLUSION: The ICCR is a safe and established technique when an orthotopic pouch is impossible. The long-term follow-up shows acceptable complication rates and satisfactory continence conditions. However, large population studies are necessary to confirm this observation.

Ion channel reporter for monitoring the activity of engineered GPCRs.

Ion channel-coupled receptor (ICCR) is a recent technology based on the fusion of G protein-coupled receptors (GPCRs) to an ion channel. Binding of ligands on the GPCR triggers conformational changes of the receptor that are mechanically transmitted to the ion channel gates, generating an electrical signal easily detectable with conventional electrophysiological techniques. ICCRs are heterologously expressed in Xenopus oocytes and offers several advantages such as: (i) real-time recordings on single cells, (ii) standard laboratory environment and inexpensive media for Xenopus oocytes maintenance, (iii) absence of protein purification steps, (iv) sensitivity to agonists and antagonists in concentration-dependent manner, (v) compatibility with a Gi/o protein activation assay based on Kir3.x channels, and (vi) ability to detect receptor activation independently of intracellular effectors. This last characteristic of ICCRs led to the development of a functional assay for G protein-"uncoupled" receptors such as GPCRs optimized for crystallization by alteration of their third intracellular (i3) loop. One of the most widely used approaches consists in replacing the i3 loop with the T4 phage lysozyme (T4L) domain that obstructs the access of G proteins to their binding site. We recently demonstrated that the ICCR technology can functionally characterize GPCRs(T4L). Two-electrode voltage-clamp (TEVC) recordings revealed that apparent affinities and sensitivities to ligands are not affected by T4L insertion, while ICCRs(T4L) displayed a partial agonist phenotype upon binding of full agonists, suggesting that ICCRs could detect intermediate-active states. This chapter aims to provide exhaustive details from molecular biology steps to electrophysiological recordings for the design and the characterization of ICCRs and ICCRs(T4L).