Gene Edited T Cell Therapies for Inborn Errors of Immunity.

Inborn errors of immunity (IEIs) are a heterogeneous group of inherited disorders of the immune system. Many IEIs have a severe clinical phenotype that results in progressive morbidity and premature mortality. Over 450 IEIs have been described and the incidence of all IEIs is 1/1,000-10,000 people. Current treatment options are unsatisfactory for many IEIs. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative but requires the availability of a suitable donor and carries a risk of graft failure, graft rejection and graft-versus-host disease (GvHD). Autologous gene therapy (GT) offers a cure whilst abrogating the immunological complications of alloHSCT. Gene editing (GE) technologies allow the precise modification of an organisms' DNA at a base-pair level. In the context of genetic disease, this enables correction of genetic defects whilst preserving the endogenous gene control machinery. Gene editing technologies have the potential to transform the treatment landscape of IEIs. In contrast to gene addition techniques, gene editing using the CRISPR system repairs or replaces the mutation in the DNA. Many IEIs are limited to the lymphoid compartment and may be amenable to T cell correction alone (rather than haematopoietic stem cells). T cell Gene editing has the advantages of higher editing efficiencies, reduced risk of deleterious off-target edits in terminally differentiated cells and less toxic conditioning required for engraftment of lymphocytes. Although most T cells lack the self-renewing property of HSCs, a population of T cells, the T stem cell memory compartment has long-term multipotent and self-renewal capacity. Gene edited T cell therapies for IEIs are currently in development and may offer a less-toxic curative therapy to patients affected by certain IEIs. In this review, we discuss the history of T cell gene therapy, developments in T cell gene editing cellular therapies before detailing exciting pre-clinical studies that demonstrate gene editing T cell therapies as a proof-of-concept for several IEIs.

Results of abdominoperineal resections for failures after combination chemotherapy and radiation therapy for anal canal cancers.

Thirty patients treated with combination chemotherapy (CT) and radiation therapy (RT) for anal canal carcinoma were reviewed retrospectively to analyze the results of abdominoperineal resection (APR) for treatment failures. Mean follow-up was 34.9 months. Twenty-four patients had squamous carcinomas, and six had cloacogenic carcinomas. Twenty-five had negative inguinal lymph nodes, and five had positive inguinal lymph nodes. The group received 5-fluorouracil, mitomycin C, and 30 to 50 Gy of RT. Biopsy was obtained at six weeks posttherapy. Seventeen of 22 patients (77 percent) with primary tumors of less than 5 cm and negative nodes were disease free at 37 months post-CT-RT. None of the seven patients with primary tumors of greater than 5 cm or positive nodes were free of disease. APR was done for positive biopsy in eight patients and for local recurrence (disease detected after six months of treatment) in one patient. Eight of nine patients who had APR died of disease (mean, 20 months), and one of nine died of other causes. A review of published series, including our data, reveals 24 cases of APR post-CT-RT for positive biopsy, with 17 of 24 (71 percent) dead of disease within three years. APR for CT-RT failures has a poor prognosis. Future protocols may determine whether further CT-RT will improve survival. APR for palliation should always remain an option.

Telephone surveys as a method for obtaining dietary information: a review.

The use of telephone surveys has increased significantly in the past decade. One advantage of telephone surveys is the ability to reach a large number of individuals: 97% of the US population owns telephones. Another advantage is cost savings: telephone surveys cost as little as one quarter to one half the amount of face-to-face surveys. Computer-assisted telephone interviewing has improved data collection, coding, and analysis. Random-digit dialing and a number of statistical advances such as weighting and stratification have significantly enhanced sample selection and research design of telephone surveys. The increasing need to collect dietary information from populations in an affordable fashion has expanded the use of telephone dietary surveys. To date, telephone dietary surveys have been used for follow-up after initial face-to-face contact has been made. The most common dietary instruments used are the 24-hour recall and the food frequency questionnaire. This review indicates that well-designed and well-administered telephone surveys are as good as, and may be better than, other methods for obtaining dietary information.

Measuring the effectiveness of the Star Parenting Program with parents of young children.

This study evaluated the effectiveness of the STAR Parenting Program, designed specifically for parents with children between the ages of 1 and 5 yr. The 8-hr. program was completed by 35 parents. There was a significant increase in parents' favorability and a significant decrease in anxiety afterwards. Parents also significantly lowered their expectations, reduced the emotionality of their reactions to their child's problem behaviors, and increased their use of time-out and tangible rewards following training. These changes were maintained at a 6-wk. follow-up.

Endoscopic examination of the colon and rectum distal to a colostomy.

We report results of the endoscopic examination of the colon distal to a colostomy in 85 patients. Almost half had symptoms related to the excluded bowel. Whereas severe colitis or tumor may be asymptomatic, many patients had discomfort, pain, bleeding, and discharge. Endoscopic examination revealed abnormal findings in 80% of the patients. These were as uncomplicated as mucous plugs or as serious as polyps or carcinoma. We found a high incidence of diversion colitis in the excluded colon. Because of these abnormal findings, endoscopy of the bowel distal to a colostomy at regular intervals is recommended. Mucous plugs and scybala should be treated by irrigation, while polyps and carcinoma should be treated as they would in the nondiverted colon. Diversion colitis can be treated medically with local steroids, or surgically. In most cases, even in severe colitis, we recommend closure of the colostomy. Removal of the excluded colon is seldom necessary.

The fate of the forgotten rectal pouch after Hartmann's procedure without reconstruction.

The rectal pouches of 45 patients who underwent Hartmann's procedure and were not scheduled to have a colostomy closure were examined with an endoscope at least 1 year after operation. Twenty-five patients had no symptoms related to the rectal pouch. The rest had pain, mucous discharge, moderate-to-severe bleeding, or discharge of small bowel contents. Endoscopic findings included moderate-to-severe proctitis in 20 patients, 10 of whom had no symptoms. Polyps were found in four patients (two asymptomatic) and carcinoma in seven (one asymptomatic). Of 24 patients operated upon for diverticulitis, 12 had proctitis and 2 had polyps. Of 14 patients with carcinoma, 4 had proctitis, 1 polyps, and 5 carcinoma. Of two patients with benign polyps, one had polyps and one, carcinoma and of five patients with inflammatory bowel disease, four had proctitis and one, carcinoma. The treatment of polyps and carcinoma is the same as for other patients with these conditions. Proctitis should be treated with reanastomosis. The frequent presence of abnormality in the rectal pouch indicates the need for regular follow-up examinations of these patients.

Malignant transformation of anorectal giant condyloma acuminatum (Buschke-Loewenstein tumor).

Giant condyloma acuminatum, originally described by Buschke and Loewenstein in 1925 as a lesion of the penis, is more rarely seen in the anorectum and is characterized by clinical malignancy in the face of histologic benignity; however, malignant transformation to frankly invasive squamous-cell carcinoma has been described. Malignant transformation has been reported in 15 patients with "ordinary" condylomata acuminata as well. Twenty giant condylomata acuminata have been previously reported, six of which (30 percent) went on to develop squamous-cell carcinoma. The authors report eight cases of giant condylomata acuminata with invasive squamous-cell carcinoma developing in four patients. Light and electron microscopic methods were used to verify the diagnosis of squamous-cell carcinoma and/or giant condyloma acuminatum in our cases. Human papillomavirus (HPV), known to cause condylomata acuminata, is also known to induce these tumors. The authors support the hypothesis that giant condyloma acuminatum represents an intermediate lesion in a pathologic continuum from condyloma acuminatum to squamous-cell carcinoma. These lesions have a propensity for recurrence, likelihood of malignant transformation, and significant mortality. Therefore, early and radical local excision, and in cases of recurrence, invasion, or malignant transformation, abdominoperineal resection, along with vigilant follow-up, provides the only current hope for cure.

The pathogenesis of hemorrhoids.

The structure of the anal canal was examined in histology slides. Hemorrhoids are normal features of the human anatomy. They are pads that bulge into the lumen. Hemorrhoids have three parts: 1) the lining, which can be mucosa or anoderm; 2) the stroma with blood vessels, smooth muscle, and supporting connective tissue; and 3) the anchoring connective tissue system, which secures the hemorrhoids to the internal sphincter and the conjoined longitudinal coat. The anchoring and supporting connective tissue system deteriorates with aging. The hemorrhoids not only bulge, but descend into the lumen. This becomes observable in the third decade of life, with individual differences. The veins become distended as they lose their support. The descended loose lining becomes more sensitive to pressure from straining and to trauma from the stool. There can be a stasis in the veins, with clot formations and swelling, or erosions of the lining, with bleeding. The hemorrhoids become symptomatic.

The prevalence of hemorrhoids.

The clinical records of 835 patients were reviewed. Five hundred ninety four had symptoms of hemorrhoids (symptomatic group) and 241 had no symptoms (asymptomatic group). Eight-six per cent of the entire group had hemorrhoids, 88 per cent among the symptomatic group and 82 per cent among the asymptomatic group. It was felt that if the prevalence rate of hemorrhoids in the symptomatic and asymptomatic groups is similar or close to similar in every age, it is likely that a certain number of people will have hemorrhoids in every age group irrespective of the presence or absence of symptoms. If the prevalence rate is high, it would seem to support the theory that hemorrhoids are normal parts of the human body, not a disease but a sign of aging. Although the difference in the prevalence rate overall in the symptomatic and asymptomatic groups, 88 versus 82 per cent was mathematically significant, this was due to the large sample size and it was small enough to be without clinical importance. No significant differences in the prevalence rate between symptomatic and asymptomatic patients within age groups were found.

Evaluation of sexual dysfunction in the female following rectal resection and intestinal stoma.

Problems of sexual dysfunction were surveyed by questionnaire mailed to women who had undergone rectal resection and ostomy surgery over a ten-year period. Completed questionnaires were returned by 30 respondents, 19 to 54 years of age, who indicated both physical and psychological problems. Many of the problems were solved by the patients themselves, but the way can be made easier with the help of an understanding surgeon and knowledgeable stoma therapist who can create a climate in which the patient may feel at ease asking for guidance concerning sexual matters.

Age-related changes and scar formations of perianal connective tissue.

Changes in perianal connective tissue were studied using specimens from juvenile cadavers and resected tissue from adults. The fibers of the anal sphincter muscles lie in a connective tissue mesh which anchors the muscle fibers, the anal mucosa and skin, and the entire anal canal. The connective tissue mesh is present in the newborn and has similar patterns in every age group, but the ratio of the amount of connective tissue/muscle tissue (C/M ratio) increases with age. The increase of the C/M ratio may have a role in the development of weakness of the sphincters and mucosal or rectal prolapse in the elderly. After injuries or operation no pure collagen scar formation was observed in the sphincter muscles, but there was an increase in the C/M ratio. In inflammatory bowel diseases, when severe anal stenosis is present, the connective tissue web and sphincter are intact and the scar formation is confined to the submucosal and subcutaneous layers.

Subcutaneous emphysema of the lower extremity of gastrointestinal origin.

Two cases of subcutaneous emphysema of the left lower extremity secondary to perforations of the rectum ,nd sigmoid colon are presented. Although this is an extremely rare syndrome, the true incidence is probably higher, as some cases will be misdiagnosed as gas gangrene unless careful clinical and postmortem examinations are performed. Only rapid recognition of the probable origin of the gas, coupled with aggressive, definitive therapy, can prevent the usually fatal course of this condition. In the absence of trauma to the chest or infection in a previously normal leg, subcutaneous emphysema of a limb should alert the physician to the possibility of a gastrointestinal perforation as a source of the gas. Perforations of the gastrointestinal tract into the subcutaneous tissue can occur anywhere from the neck to the lower extremities.

The importance of the perianal connective tissue in the surgical anatomy and function of the anus.

The anatomy of the perianal connective tissue has been reviewed. The most important element is the conjoined longitudinal coat, the axis of the connective-tissue system. Fibers of the longitudinal coat penetrate the internal and external sphincter, interlacing with each other as well as the perimysium and endomysium and forming a fibroelastic network. The fibers and bundles of the internal and external sphincters lie in the meshes of this network with innumerable attachments to it. The fibroelastic network continues through the perianal fat to the pelvic wall and is connected to the lower levator fascia and the perianal skin, insuring the firm anchoring of the anus. During sphincter contraction the fibroelastic network moves together with the sphincters. Thus, the sphincter function is the integration of the contraction of the muscle fibers attached to the web. The elastic elements of the network pull the anal canal slightly apart, but the muscle tone overcomes this and keeps the anus closed. Surmounting the elasticity of the web causes the muscle function to be elastic as well. Surgical procedures such as stretching, transecting the sphincters, whether sharply or gradually, can lead to scar formation with loss of elasticity or mobility in that part of the sphincter and secondary impairment of function.

Dysplasia of the quadriceps mechanism: hypoplasia of the vastus medialis muscle as related to the hypermobile patella syndrome.

Disturbance of the patellofemoral mechanism is the most common cause of dysfunction in the knee, especially in athletes of all age groups. This is primarily a congenital familial abnormality due to poor development in the vastus medialis. The patella develops in the line of maximum pull of this muscle group; in this congenital condition it develops in line with the stronger antagonist to the vastus medialis, the vastus lateralis muscle. Therefore, the position in the extremity that the patella assumes is the result of abnormal muscle development. This brings about other changes in the lower extremity that increase the tendency of the patella to migrate laterally. This condition, hypoplasia of the vastus medialis muscle, exists in a large number of people (about 40% of my patient population) in an asymptomatic form that predisposes them to degenerative changes of the patellofemoral articulation later in life, even without symptoms related to dysfunction of the patellofemoral mechanism. These individuals are also predisposed to disturbances of the patellofemoral mechanism which may cause symptoms, that is, the painful knee for which they seek medical attention. The symptomatic types of dysplasia of the quadriceps mechanism are usually brought on by injury to the medical quadriceps retinaculum that stretches or tears it, allowing the lateral migration to increase and producing pain in the inner aspect of the knee. Disuse atrophy of the vastus medialis accentuates the clinical picture as the condition worsens. As the asymptomatic type may progress into the midly symptomatic variant and eacy may worsen into a more serious disabling variety as reinjury occurs, it is important to recognize each type and to treat them properly.