Introducing N-Sulfinylamines into Visible-Light-Induced Carbene Chemistry for the Synthesis of Diverse Amides and α-Iminoesters.

A rare example of visible-light-mediated diverse reactivity of N-sulfinylamines with different types of carbene precursors has been disclosed. Acylsilanes and aryldiazoacetates have been utilized as nucleophilic and electrophilic carbene precursors into the N═S═O linchpin, to achieve valuable amides and α-iminoesters, respectively. Interestingly, diazocarbonyls can also participate in the amidation reaction with N-sulfinylamines via in situ generated ketenes. This operationally simple modular method offers a mild, transition-metal-free, and coupling-reagent-free protocol to fabricate structurally diverse amides and a promptly accessible technique to achieve α-iminoesters, where visible light remains as a key promoter.

An audit to analyse the two-week wait pathway at an oral cancer specialist district general hospital.

Background The incidence of head and neck cancers is increasing, alongside a decrease in associated mortality. Currently, medical and dental practitioners can refer patients to be seen urgently within two weeks. The appropriateness of these referrals has been disputed. In 2020, the Department of Health aims for patients to be given cancer diagnoses within 28 days from referral.Methods A retrospective audit was conducted for all patients referred under the two-week wait pathway in a six-month period. In the first cycle of this audit, one month's worth of urgent referrals were analysed; given the small sample size, very few recommendations could be made. The audit cycle was repeated and it analysed six months' worth of data, which gave a much more representative study. All patients were analysed to see if the 14-day period had been breached. Positive cancer patients were further assessed to see if their diagnosis had been given within 28 days and treatments within 62 days.Results Of the 569 patients seen, there was a positive malignancy diagnostic yield of 7.38%. Nineteen patients breached the 14-day wait. Of the positive patients, 45.2% received their diagnosis more than 28 days from referral, and 22.2% of these patients received treatment after 62 days.Conclusion The department performed well despite the high number of referrals. This audit has touched on some key issues which have been discussed in detail in this article. Furthermore, this audit recommends a concerted effort to improve oral cancer detections skills among GDPs and GMPs. While all referrals may be appropriate from a primary care point of view, this audit makes it apparent that better differentiation is needed between malignant and routinely manageable lesions. All secondary care units alongside general practitioners can learn from the findings of this audit.

The reconstructive oral cancer patient: what the general dental practitioner needs to know.

The rate of oral cancer is on the rise; lesions are often being picked up late meaning it is necessary for patients to undergo multidisciplinary head and neck reconstruction. Working in a specialist head and neck oncology unit this year has opened my eyes as to how this patient subgroup is managed, with regards to both a surgical and restorative basis. This article has been written to help inform GDPs about the upcoming NHS guidelines, 'The NHS Oral Cancer Toolkit', in the management of oral cancer patients. Furthermore, I hope that the reader gains an appreciation for what the oral cancer patient endures on their toilsome journey. This article is designed as a refresher on the restorative management of the oral cancer patient. After having read this article you will have an improved awareness of the '8-step' oral cancer screen and an insight as to what happens when the patient is sent on the urgent cancer pathway. Most importantly, this paper will refresh your learning on what the GDP needs to do in the preoperative and postoperative phases with regards to the oral health and wellbeing of the reconstructive oral cancer patient.

Desmoplastic melanoma: a 12-year experience with sentinel lymph node biopsy.

AIMS: Given the paucity of data regarding nodal involvement in desmoplastic melanoma (DM), we decided to review the incidence of nodal metastasis in our patients with DM to better define guidelines regarding the performance of sentinel lymph node biopsy (SLNB) in this specific melanoma subtype. METHODS: Using a prospectively maintained database, we reviewed all patients who underwent treatment for melanoma at the Yale Melanoma Unit in a twelve-year period (1998-2010), during which 3531 cases were treated. We identified 24 patients (0.7%) diagnosed with DM. These patients' records were studied for clinical and histologic parameters and clinical outcomes. RESULTS: Twenty-two patients from the DM group had SLNB, of which four (18%) were diagnosed with micro-metastasis. These four patients were all treated with completion lymphadenectomy and none had additional positive nodes in the remainder of the nodes. Patients were followed after surgery for a median of 25 months (range 2-60 months). Two patients (9%) developed local recurrence, two (9%) in-transit recurrence, and six (27%) showed distant metastases (three patients were pure DM and three patients showed mixed morphology). Patients with mixed DM had a higher rate of nodal metastasis (25%) vs those with pure DM (14%). CONCLUSIONS: Other authors have reported that patients diagnosed with pure DM were less likely to have a positive SLN (0-2%) than those patients with the mixed DM subtype (12-16%). Our findings of higher incidence rates of regional lymph node metastases in both the pure and mixed DM subtypes (14% and 25%) compel us to continue to still recommend that SLNB be considered in patients with both subcategories, pure and mixed DM. LEVEL OF EVIDENCE: Level IV.

A Variant in a MicroRNA complementary site in the 3' UTR of the KIT oncogene increases risk of acral melanoma.

MicroRNAs (miRNAs) are small ∼22nt single stranded RNAs that negatively regulate protein expression by binding to partially complementary sequences in the 3' untranslated region (3' UTRs) of target gene messenger RNAs (mRNA). Recently, mutations have been identified in both miRNAs and target genes that disrupt regulatory relationships, contribute to oncogenesis and serve as biomarkers for cancer risk. KIT, an established oncogene with a multifaceted role in melanogenesis and melanoma pathogenesis, has recently been shown to be upregulated in some melanomas, and is also a target of the miRNA miR-221. Here, we describe a genetic variant in the 3' UTR of the KIT oncogene that correlates with a greater than fourfold increased risk of acral melanoma. This KIT variant results in a mismatch in the seed region of a miR-221 complementary site and reporter data suggests that this mismatch can result in increased expression of the KIT oncogene. Consistent with the hypothesis that this is a functional variant, KIT mRNA and protein levels are both increased in the majority of samples harboring the KIT variant. This work identifies a novel genetic marker for increased heritable risk of melanoma.

Surgical considerations in the management of malignant melanoma of the ear.

Malignant melanomas of the external ear are rare and are difficult lesions to treat because of the cosmetic importance and the reconstructive difficulty of their location. The literature suggests that these lesions have a worse prognosis than melanomas occurring elsewhere and that radical resection is the "correct" treatment. To clarify this issue, we examined 21 consecutive patients (19 male, 2 female) with malignant melanoma of the ear seen at the Yale-New Haven Hospital over the last 10 years. Nineteen patients had a diagnosis of primary malignant melanoma of the ear, one had a local recurrence, and one had an in-transit melanoma from an unknown primary site. The mean thickness of the lesions was 2.7 mm. Two patients had palpable nodes, which in both cases turned out to be histologically positive for tumor. All patients underwent local excision and reconstruction using chondrocutaneous or fasciocutaneous flaps or skin grafts. There was one local recurrence (0.5 mm original thickness); there were two patients with regional recurrences, both of whom died within a year with disseminated disease. Forty-three percent have been followed for 5 or more years and all are alive and free of disease. This suggests that malignant melanoma of the ear may be safely treated by conservative excision and reconstruction.

Surgical management of the primary melanoma.

Conservative margins of resection have proven safe for malignant melanomas arising in a wide variety of anatomic sites. Reconstruction, however, can be a challenge in cosmetically sensitive areas. This article summarizes the authors' management philosophy, including reconstruction.

Lymphatic mapping and sentinel lymph node biopsies.

Once melanoma cells leave the skin and travel to the lymph nodes, they have metastasized, thereby reducing chances for the patient's long-term, disease-free survival. Methods for tracing and removing lymph nodes include elective lymph node dissection, lymphoscintigraphy, and sentinel lymph node biopsy. This article reviews the concepts, procedures, and effectiveness of these techniques.

Regional lymph node dissections in malignant melanoma.

Considerable controversy surrounds the application of regional lymphadenectomy in the treatment of cutaneous melanoma in patients with clinically negative nodes; however, therapeutic lymph node dissection for clinically positive nodes has shown clear benefits. Opponents of elective lymph node dissection (ELND) for clinically negative nodes believe that because 80% of patients with clinical Stage I disease have histologically negative nodes at the time of resection of the primary tumor, prophylactic excision of the regional nodes is unnecessary. Some clinicians have failed to demonstrate a survival advantage for ELND. With the recent introduction of sentinel lymph node dissection, it may be possible to select patients who are likely to benefit from ELND. The authors recommend ELND based on the identification of metastatic cells within the sentinel lymph node in all patients with primary melanomas with a thickness of at least 1.0 mm.

The use of isolated limb perfusion to manage recurrent malignant melanoma.

Hyperthermic isolated limb perfusion (ILP) effectively treats locally recurrent metastatic disease in malignant melanoma of the extremities. The goal of ILP is to decrease the rate of further recurrent disease and eradicate tumor load to achieve wound hygiene and preservation of limb function. This article reviews the development over the last 45 years of ILP in the treatment of malignant melanoma, describes the surgical technique of ILP, and reviews the results of clinical trials with various chemotherapeutic agents. It discusses the recent addition of tumor necrosis factor alpha to the list of drugs currently being explored in hyperthermic ILP, in the ongoing attempt to improve the treatment for recurrent malignant melanoma of the extremities.

The rising level of medical student debt: potential risk for a national default.

At the turn of the 20th century, mostly as a result of the Flexner report, medical education changed dramatically by establishing a scientific basis for the study of medicine within the institutions of the major universities. There have been major and dramatic changes in medicine during the past 80 years that have improved medical education in the United States, but these changes have also placed major economic strains on students who have educational debts. If medicine is a social responsibility to the public, then the public should share the responsibility of identifying and supporting new approaches to funding and financially managing the teaching of future physicians. There is no universal solution because there are various approaches institutions may take to structure these financial responsibilities. This article describes trends in medical student educational debt, identifies the financial needs of medical students, and proposes ways of addressing those needs to avert a possible national financial crisis among medical students. We must invest in medical students because they will be the leaders we need to help care for our society and our own families in the next century.

Follow-up recommendations for patients with American Joint Committee on Cancer Stages I-III malignant melanoma.

BACKGROUND: Guidelines for follow-up of melanoma patients are not established. In 1987, a follow-up protocol was instituted at the Yale Melanoma Unit to improve upon the detection of disease recurrence in patients with American Joint Committee on Cancer Stage I-III cutaneous melanoma. The follow-up protocol consists of a patient education program and a surveillance schedule based on stage of disease. METHODS: The authors retrospectively reviewed the records of 373 patients who were seen and followed according to the surveillance protocol in the Yale Melanoma Unit between January 1988 and December 1994 to determine 1) the time interval between the initial visit and recurrence; 2) the most common method of detecting recurrences; 3) whether the surveillance schedule or the patient detects more recurrences, i.e., asymptomatic recurrences versus symptomatic recurrences; 4) whether there is any survival difference between asymptomatic and symptomatic recurrences. RESULTS: The 5-year overall survival rates for Stage I, II, and III patients were 95%, 72%, and 52%, respectively. Of the 78 recurrences, 44 (56%) were detected by physician-directed surveillance examinations and 34 (44%) by patients. Most recurrences were found within the first (47%) or second (32%) year of follow-up. The estimated 6-month hazard rates for death or recurrence were 0.0044, 0.0088, and 0.0278 for Stage I, II, and III patients, respectively. The group of asymptomatic patients with recurrence had a survival advantage over the symptomatic recurrence group. In addition, patients with locoregional recurrence had better survival than those with distant recurrence. CONCLUSIONS: Although many recurrences arise rapidly and are recognized early by patients, in this study more than half were found by surveillance examinations before symptoms were manifest. Based on the hazard ratio for recurrences, the authors recommend the following surveillance schedules in addition to the patient education program for detection of recurrences: 1) Stage I, annually; 2) Stage II, every 6 months for Years 1-2 and annually thereafter; 3) Stage III, every 3 months for Year 1, every 4 months for Year 2, and every 6 months for Years 3-5; 4) at Year 6 and beyond, all patients should have surveillance annually, due to the risk of late recurrence and/or metachronous multiple primaries.

The predictive value of lymphoscintigraphy for nodal metastases of cutaneous melanoma.

Lymphoscintigraphy is used to identify ambiguous drainage patterns in cutaneous melanoma of the head, neck and trunk. This study evaluated the efficacy and reliability of lymphoscintigraphy to identify the drainage nodes in 51 patients undergoing both elective and therapeutic lymphadenectomy over a seven-year period. All 13 patients who had lymph node metastases during this follow-up period had the metastatic disease in the very lymph node basins identified by lymphoscintigraphy. Most significantly, none of the 51 patients had metastatic disease in lymphatic basins that were not previously identified by lymphoscintigraphy.

Salvage of open tibial fracture with segmental loss of tibial nerve: case report and review of the literature.

We report a case history, treatment, and follow-up of an open comminuted distal tibial fracture with significant soft tissue loss and segmental loss of the tibial nerve and posterior tibial artery. This constellation of injuries with an insensate plantar foot has often been an indication for amputation. In this instance, a functional distal extremity was salvaged with the use of Ilizarov fixation, delayed primary tibial nerve cable grafting, and staged soft tissue coverage. Clinical follow-up and review of the literature on the techniques used are offered for consideration.

Breast reconstruction in previously irradiated patients using tissue expanders and implants: a potentially unfavorable result.

There exists a paucity of definitive information on the suitability of implant reconstructions in previously irradiated breast cancer patients. This controversial topic prompted a review of our prosthetic reconstructions in this select group of patients. A retrospective study of patients treated between 1976 and 1993 with lumpectomy and radiation therapy for early breast cancer revealed 67 patients with local recurrences. Nine of these patients (10 breasts) underwent a two-stage prosthetic reconstruction following a salvage mastectomy. The average age was 47.9 years. The mean dose of irradiation was 6,070 cGy. The average interval from radiation therapy to placement of a tissue expander was 4.6 years. In one patient (10%) the tissue expander extruded. The average follow-up for 8 patients (9 breasts) who underwent exchange to a permanent prosthesis was 5.1 years. In four reconstructions (40%) there was an uneventful postoperative course. Two cases (20%) were difficult to expand and the final result lacked projection. One patient (10%) developed an infection requiring removal of the permanent prosthesis. Two patients (20%) developed Baker class III or IV capsular contractures. Overall, in our group of 10 implant reconstructions, 60% of the patients resulted in either a complication or an unfavorable result.

Safety and efficacy of isolated perfusion of extremities for recurrent tumor in elderly patients.

BACKGROUND: The treatment of bulky recurrent melanotic lesions of extremities with isolated limb perfusion with high dose chemotherapy offers palliation in a number of patients. However, the question is raised whether these major surgical procedures are too risky to warrant performing them in elderly patients. METHODS: Sixty-seven limbs were perfused in 60 patients with various drugs from 1976 through 1996 (35, imidazole carboxamide; 7, cisplatin; 20, carboplatin; 5, thiotepa). Among the 67 perfusions, 20 were in patients aged 70 years and older. Perfusion was performed for 16 upper extremities and 51 lower extremities by using the pump oxygenator for 1 hour. RESULTS: A total of 19 complications were noted after a total of 14 of the 67 perfusions (21%) (postoperative edema, 5; seroma, 4; wound separation or infection, 9; nonfatal pulmonary embolus, 1). The complications in 4 of 20 perfusions in the older patients (20%) were less than in 15 of 47 perfusions in the younger patients (32%). Among the 17 patients older than 70 years of age who were treated with perfusions for recurrent disease, four patients (24%) are alive with no evidence of disease (NED) for a median of 29 months (range, 16 to 80 months); one patient is now more than 6 years with NED after her third perfusion for repeated in-transit disease. Another 2 of 17 patients (12%) are alive with disease for a median of 89 months (range, 54 to 123 mos). The remaining 11 patients (64%) are dead of their disease. These data are comparable to the control rates in the group of younger patients in the study. Overall, half of all the patients (14 of 28) who died of their disease in both groups had maintained local control of their involved extremities. CONCLUSIONS: Aggressive treatment in selected patients with regional isolated perfusion of limbs for melanoma can lead to significant palliation of symptoms and salvage of limbs with adequate disease-free control and occasional survival benefit. This series of patients was associated with meaningful disease control and with few serious complications. Perfusions are tolerated well by patients in their 70s and 80s; therefore advanced age is not a contraindication to this procedure in carefully selected patients.

Hypopharyngeal cancer patient care evaluation.

A survey was conducted to identify demographics and standards of care for treatment of hypopharyngeal squamous cell carcinoma in the United States. Data were accrued from voluntary submission of cancer registry and medical chart information from 769 hospitals representing 2939 cases diagnosed from 1980 to 1985 and 1990 to 1992. Clinical findings, diagnostic procedures employed, treatment practices, and outcome are presented. Overall, 5-year disease-specific survival was 33.4%, which segregated to 63.1% (stage I), 57.5% (stage II), 41.8% (stage III), and 22% (stage IV). Survival was best for patients treated with surgery only (50.4%), similar with combined surgery and irradiation (48%), and worse with irradiation only (25.8%). This analysis provides a standard to which current treatment practice and future clinical trials may be compared.

Patterns of care for cancer of the larynx in the United States.

OBJECTIVE: To assess case-mix characteristics, treatment patterns, and outcomes for laryngeal cancer using the largest series of patients to date. DESIGN: Analyses performed on retrospectively collected survey data submitted by hospitals for diagnostic periods 1980 through 1985 and 1990 through 1992 (with a 9-year follow-up for the long-term group). SETTING: Broad spectrum of US hospitals (N = 769). PATIENTS: Consecutively accrued series of patients with laryngeal cancer (N = 16,936), with only squamous cell carcinomas (N = 16,213) analyzed. INTERVENTIONS: Surgery, radiation therapy, and chemotherapy. MAIN OUTCOME MEASURES: Descriptive analyses of case-mix, diagnostic, and treatment characteristics plus recurrence and 5-year, disease-specific survival outcomes. RESULTS: There was a slight increase across these years in stage IV disease and in radiation therapy (with or without surgery and/or chemotherapy). Overall diversity of management of this disease (by site and stage) was apparent. Five-year survival rates indicated a large difference between modified groupings of the T and N classifications, separating stages III and IV cases into localized disease (87.5% for T1-T2; 76.0% for T3-T4 cases) and regional metastasis (46.2%). CONCLUSIONS: Regardless of improvements in entering data in hospital records (most commendably, staging), more rigorous standards are needed. Also, the small increase in advanced-stage patients indicates that efforts toward early detection have not been successful. The rise in radiation therapy perhaps reflected an increased use of nonsurgical treatment for early-stage patients and organ-sparing radiochemotherapy protocols for advanced-stage patients. Regrouping stages III and IV cases into localized disease vs regional metastasis appears to predict survival better. Ongoing refinements of the American Joint Committee on Cancer staging scheme will hopefully improve this cancer's classification.

Regional isolated perfusion of extremities for melanoma: a 20-year experience with drugs other than L-phenylalanine mustard.

Recurrent melanoma of the extremities can lead to bulky symptomatic lesions that become difficult management problems. Treatment of these tumors with isolated limb perfusion with high dose chemotherapy may offer palliation in a number of patients. Unfortunately, the most commonly used drug, L-phenylalanine mustard, has been known to have significant associated tissue toxicity. Therefore, during the years 1976-1995, we perfused 67 limbs in 60 patients with various other drugs: 36 with dimethyltriazeno imidazole carboxamide, 6 with cisplatin, 20 with carboplatin, and 5 with thiotepa). Perfusion was performed for 16 upper extremities and 51 lower extremities using the pump oxygenator for 1 hour. Among the 60 patients, 17 were treated prophylactically for high-risk melanoma, whereas 43 were treated for local and in-transit recurrences. The technique of perfusion successfully isolated the limbs from the systemic circulation: the median leaks over time were 0.5-1.6 percent for the upper extremities, and 0.2-7.5 percent for the lower extremities. Among the 43 patients treated with therapeutic isolated limb perfusion, 11 patients (26 percent) are alive with no evidence of disease for a median of 58 months (range: 8 months to 17 years 9 months), and another 5 patients (12 percent) are alive with recurrence for a median of 45 months (range: 27 months to 10 years 7 months). Four patients required two perfusions, and two patients required three perfusions (one patient has no evidence of disease 6 years after her third perfusion for recurring in-transit disease). There were 19 complications noted after 14 of the 67 perfusions (21%): postoperative edema, 5; seroma, 4; wound separation/infection, 9; and nonfatal pulmonary embolus, 1. In our experience, aggressive treatment in selected patients with regional isolated perfusion of limbs for melanoma has provided meaningful palliation and salvage of the limbs with adequate disease-free control, and occasional survival benefit. This regional treatment modality is associated with meaningful control and with few serious complications, especially when compared with studies using L-phenylalanine mustard. This series illustrates the safety of controlling limb recurrence with this technique, even with repeat perfusions in the same patient.

Restructuring academic departments of surgery at university medical centers.

BACKGROUND: The present administrative and financial structures of clinical departments in most medical schools date back to the beginning of the 20th century when changes were brought about as a result of the Flexner report. Since that time, there have been significant changes in the health care industry that compel us to reevaluate our goals in order to meet the needs of the 21st century. METHODS: This paper proposes that we need to consider the administrative restructuring of our departments from the vertical hierarchical system to the horizontal matrix system in order to facilitate cost-effective use of our manpower as well as facilities. It also proposes a financial restructuring of the departments to cut the costs of billings and collections of the clinical practice, to develop a long-term program to raise departmental endowments, and to develop an effective incentive plan. RESULTS: A novel mechanism is proposed to provide "stock options" for the faculty. Such a system would reward academic and clinical productivity, retain productive faculty, and offer options for those who are not productive. CONCLUSIONS: In order to flourish in the health care marketplace, academic programs must be willing to promote a change in the culture of the departments and adapt to a more business-oriented environment.